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Final Study Report

( )

MeMuRu-OKA-038208136/038

28 April 2004

GlaxoSmithKline BiologicalsRue de l�Institut 89

1330 Rixensart, Belgium

CONFIDENTIAL

CARS Id : CLIN_200310_17390/ Version : 3.3,Admin. QC/ Modify Date : 30/04/2004

Final Study Report for Clinical Trial208136/038 (MeMuRu-OKA-038)

Title: A phase III, randomized, controlled study to evaluate the immunogenicity andsafety of three production lots of GlaxoSmithKline Biologicals� combined measles-mumps-rubella-varicella (MeMuRu-OKA) candidate vaccine given on a two-doseschedule to healthy children in their second year of life, as compared to separateadministration of GlaxoSmithKline Biologicals� measles-mumps-rubella vaccine(Priorix®) and varicella vaccine (Varilrix®).

This report presents the results of the study during the active phase period.Extension of the study are to be presented in Annex reports for:208136/039 (MeMuRu-OKA-039) Year 1 Follow-up208136/040 (MeMuRu-OKA-040) Year 2 Follow-up208136/041 (MeMuRu-OKA-041) Year 3 Follow-up

Study vaccine GlaxoSmithKline Biologicals' live attenuated Measles(Schwarz strain) � Mumps (RIT 4385 strain) � Rubella(RA 27/3 strain) - Varicella (Oka strain) candidate vaccine(MeMuRu-OKA).

CPMS Study No. 208136/038 (MeMuRu-OKA-038) Active phase period

Indication Active immunization of healthy children during theirsecond year of life against measles, mumps, rubella andvaricella diseases.

Principal Investigators: Prof. Dr. (Germany)Dr. (Austria)Dr. (Austria)Dr. (Austria)Dr. (Austria)

Date of first visit: 16 July 2003Date of last visit (Visit 3): 09 January 2004Coordinating Author: Scientific Writer

Other contributingauthors:

MD, Associate Director, Clinical R & D Scientist, Regulatory Affairs

Biostatistician Central Study Coordinator

The trial was performed according to the Good Clinical Practice guidelines inoperation at the time of the initiation of the trial.

Report Date: 28 April 2004

28 April 2004 GlaxoSmithKline BiologicalsFinal Study Report 208136 (MeMuRu-OKA) 038

Confidential and Proprietary Information


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Synopsis of Final Study Report208136/038 (MeMuRu-OKA-038)

Name of Company:GlaxoSmithKline Biologicals,Rixensart, BelgiumName of Finished Product:N/AName of active substance:Live attenuated measles, mumps,rubella and varicella vaccine

TABULAR FORMATREFERRING TO PART OFTHE DOSSIER

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(for national authority only)

Title of the study : A phase III, randomized, controlled study to evaluate the immunogenicity and safety ofthree production lots of GlaxoSmithKline Biologicals� combined measles-mumps-rubella-varicella(MeMuRu-OKA) candidate vaccine given on a two-dose schedule to healthy children in their second yearof life, as compared to separate administration of GlaxoSmithKline Biologicals� measles-mumps-rubellavaccine (Priorix®) and varicella vaccine (Varilrix®).This report presents the results of the study during the active phase period.Principal Investigators: Prof. Dr. Germany; Dr.

Austria; Dr. Austria; Dr. Austria & Dr.

Austria.Study Centres: Multiple centres in Germany and Austria.Publication (reference): Not published as of 28 April 2004.Study period:Date of first visit: 16 July 2003Date of last visit (Visit 3): 09 January 2004

Clinical phase: III

Objectives of active phase of the study:Co-primary (sequential):• To demonstrate the consistency of three production lots of MeMuRu-OKA candidate vaccine in terms

of measles, mumps, rubella and varicella seroconversion, 42-56 days after the second dose• To demonstrate the non-inferiority of MeMuRu-OKA candidate vaccine to separate administration of

Priorix and Varilrix vaccines in terms of measles, mumps, rubella and varicella seroconversion, 42-56days after the second dose (i.e., 42-56 days after the second vaccination time point given that Varilrixvaccine was only administered as a single dose in the control group).

Secondary:• To assess the immunogenicity of the study vaccines, in terms of antibody titres to each vaccine

component, 42-56 days after the second dose (i.e., 42-56 days after the second vaccination time point).• To assess the immunogenicity of the study vaccines, in terms of seroconversion and antibody titres to

each vaccine component, 42-56 days after the first dose.• To assess the safety of the study vaccines after the first and the second doses.Methodology: Phase III, randomized (1:1:1:1), blinded (double-blind between MeMuRu-OKA groups;single-blind between pooled MeMuRu-OKA groups versus Priorix+Varilrix), controlled study conductedin Germany and Austria with four parallel groups as follows:

Group MeMuRu-OKA lot MJRV 159A48 received two doses of GSK Biologicals� MeMuRu-OKAvaccine lot MJRV 159A48 administered at Visit 1/Day 0 and Visit 2/Week 6Group MeMuRu-OKA lot MJRV 160A48 received two doses of GSK Biologicals� MeMuRu-OKAvaccine lot MJRV 160A48 administered at Visit 1/Day 0 and Visit 2/Week 6Group MeMuRu-OKA lot MJRV 163A48 received two doses of GSK Biologicals� MeMuRu-OKAvaccine lot MJRV 163A48 administered at Visit 1/Day 0 and Visit 2/Week 6Group Priorix+Varilrix received one dose of GSK Biologicals� licensed measles-mumps-rubella(Priorix) vaccine administered concomitantly with one dose of varicella (Varilrix) vaccine at Visit1/Day 0 and a second dose of Priorix administered at Visit 2/Week 6.

Synopsis of Final Study Report 208136/038 (MeMuRu-OKA-038) Page 1




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Three blood samples (4 mL) were collected during the active phase period: a pre-vaccination blood sampleat Day 0; a post-vaccination blood sample at Day 42 after the first vaccination time point; and apost-vaccination blood sample at Week 12, 42 days after the second vaccination time point.Number of subjects:Planned: 480Enrolled: 494 (371 subjects in Group MeMuRu-OKA; 123 in Group Priorix+Varilrix)Completed: 484 (362 subjects in Group MeMuRu-OKA; 122 in Group Priorix+Varilrix)Withdrawal: 10Analysed for safety (Total vaccinated cohort): 472

(356 subjects in Group MeMuRu-OKA; 116 in Group Priorix+Varilrix)Analysed for immunogenicity (ATP immunogenicity cohort): 419

(311 subjects in Group MeMuRu-OKA; 108 in Group Priorix+Varilrix)Diagnosis and criteria for inclusion:Healthy male and female children between 12-18 months of age at the time of first vaccination free ofobvious health problems and with no history of measles, mumps, rubella and/or varicella vaccinationand/or disease. Written informed consent to be obtained from parents/guardians of each subject prior tostudy entry. Test product, dose, mode of administration and lot numbers:Two doses of MeMuRu-OKA vaccine were administered at Day 0 and Day 42 as a single, subcutaneousinjection in the upper left arm (deltoid region). The lot numbers and antigen contents of the vaccinesevaluated in the study are the following: Vaccine Lot Measles

(CCID50)Mumps

(CCID50)Rubella

(CCID50) Varicella

(pfu)

MeMuRu-OKAMJRV 159 A48MJRV 160 A48MJRV 163 A48

103.7

103.8

103.9

104.8

104.6

104.9

104.0

104.0

104.0

103.7

103.7

103.8

Reference therapy, dose, mode of administration and batch numbers: Two doses of Priorix were administered at Day 0 and Day 42 as a single, subcutaneous injection in theupper left arm (deltoid region). One dose of Varilrix was administered at Day 0 as a single, subcutaneousinjection in the upper right arm (deltoid region). The lot numbers and antigen contents of the vaccinesevaluated in the study are the following:

Vaccine Lot Measles(CCID50)

Mumps(CCID50)

Rubella(CCID50)

Varicella(pfu)

Priorix MJR622A44/M 104.0 104.7 104.3

Varilrix VA271 A43/M 104.5

CCID50 = Median cell culture infective dose pfu = plaque forming unitsDuration of treatment: Approximately 12 weeks for each subject.

Criteria for evaluation:Immunogenicity: Measurement of antibody levels against measles, mumps and rubella was performedusing commercial ELISA immunoassays (assay cut-offs: measles: 150 mIU/mL, mumps: 231 U/mL, andrubella: 4 IU/mL) while antibody levels against varicella were measured using a commercial indirectimmunofluorescence (IFA[buffer-modified technique]) test (assay cut-off: 4 dilution-1) in serum samplescollected at Day 0, Day 42 and Week 12. Seropositivity was defined as antibody titre ≥ assay cut-off.





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Seroconversion was defined as the appearance of antibody titre ≥assay cut-off in previously seronegativesubject (i.e., titre < assay cut-off.).Primary endpoint: Measles, mumps, rubella and varicella seroconversion, 42-56 days after the second dose(i.e., 42-56 days after the second vaccination time point as a single dose of Varilrix vaccine was onlyadministered at Day 0 in the control group).Safety: Follow-up of solicited local symptoms (pain, redness and swelling during Day 0-3), solicitedgeneral symptoms (fever, rash [local/general], salivary gland swelling, any signs of meningism includingfebrile convulsions during Day 0-42). For fever, direct measurement of temperature was requested during15 days (Day 0-14) after each dose and screening for signs of fever was requested within Day 15 to Day 42after each dose. Follow-up of any unsolicited symptoms and any serious adverse events occurring during43 days after each vaccination.Results/Discussion:Immunogenicity:For subjects included in the Total vaccinated cohort, <2% were initially seropositive for measles, mumpsor rubella antibodies. Around 7% of subjects were observed to be initially seropositive for varicellaantibodies before the first vaccination. Table 1 presents the seroconversion rates and GMTs for allantigens for subjects included in the ATP immunogenicity cohort.

Table 1: Seroconversion rates and GMTs for all antigens - ATP immunogenicity cohortSeroconversion/ seropositivity GMTs

95% CI 95% CIGroups

Timepoint N n % LL UL Value LL UL

Measles (150 mIU/ml)PI(D42) 306 299 97.7 95.3 99.1 4034.0 3644.0 4465.6MeMuRu-OKA

Pooled lots PII(D84) 307 307 100 98.8 100 6103.9 5639.6 6606.4PI(D42) 106 106 100 96.6 100 2567.3 2143.6 3074.7Priorix+VarilrixPII(D84) 108 108 100 96.6 100 3719.2 3183.7 4344.7

Mumps (231 U/ml)PI(D42) 302 272 90.1 86.1 93.2 917.0 820.5 1024.8MeMuRu-OKA

Pooled lots PII(D84) 307 301 98.0 95.8 99.3 1465.4 1343.8 1598.0PI(D42) 106 101 95.3 89.3 98.5 993.2 848.0 1163.2Priorix+VarilrixPII(D84) 108 107 99.1 94.9 100 1667.8 1441.7 1929.3

Rubella (4 IU/ml)PI(D42) 306 303 99.0 97.2 99.8 58.5 52.9 64.6MeMuRu-OKA


Varicella (4 [dilution-1])PI(D42) 304 303 99.7 98.2 100 216.3 189.1 247.2MeMuRu-OKA


N = number of subjects with available results n/% = number/percentage of subjects with titre within the specified rangeGMT = geometric mean titre calculated on all subjects with an arbitrary value of half the cut-off for seronegative titres95% CI = 95% confidence interval; LL = Lower Limit; UL = Upper LimitPI(D42)= Post-vaccination time point at Day 42 PII(D84) = Post-vaccination time point at Day 84Individual subject data can be found in Appendix table IIIADemonstration of lot-to-lot consistency of MeMuRu-OKA vaccine: For all antigens and each pair wisecomparison, the 90% CI for the difference in seroconversion rates between MeMuRu-OKA lots was withinthe pre-defined limits for equivalence of [-10%, +10%].





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Demonstration of non-inferiority of MeMuRu-OKA pooled lots to separate injections of Priorix andVarilrix: For each antigen, the lower limit of the 95% CI of the difference in seroconversion rate (GroupMeMuRu-OKA pooled lots minus Group Priorix+Varilrix) was above the pre-defined limit for non-inferiority of -10%.After Dose 2: All subjects seroconverted to measles, rubella and varicella in both groups, theseroconversion rates for mumps were 98.0% and 99.1% in Group MeMuRu-OKA pooled lots and GroupPriorix+Varilrix, respectively (Table 1).Safety:Table 2 summarizes the incidence of solicited local and general symptoms during the follow-up periodafter each vaccination.Table 2: Incidence of solicited symptoms (Total vaccinated cohort)

Dose 1 Dose 2MeMuRu-OKA

pooled lots Priorix+VarilrixMeMuRu-OKA

pooled lots Priorix+Varilrix(N=371) (N=123) (N=364) (N=122)

95% CI 95% CI 95% CI 95% CIn % LL UL n % LL UL n % LL UL n % LL UL

Local symptoms (Day 0−−−−3)Pain Any 45 12.1 9.0 15.9 8 6.5 2.8 12.4 53 14.6 11.1 18.6 5 4.1 1.3 9.3

Gr. 3 0 0.0 0.0 1.0 0 0.0 0.0 3.0 0 0.0 0.0 1.0 0 0.0 0.0 3.0Redness Any 113 30.5 25.8 35.4 30 24.4 17.1 33.0 123 33.8 28.9 38.9 27 22.1 15.1 30.5

Gr. 3 3 0.8 0.5 2.3 0 0.0 0.0 3.0 20 5.5 3.4 8.4 0 0.0 0.0 3.0Swelling Any 37 10.0 7.1 13.5 14 11.4 6.4 18.4 52 14.3 10.9 18.3 11 9.0 4.6 15.6

Gr. 3 2 0.5 0.1 1.9 0 0.0 0.0 3.0 9 2.5 1.1 4.6 0 0.0 0.0 3.0General symptomsFever Any 251 67.7 62.6 72.4 60 48.8 39.7 58.0 157 43.1 38.0 48.4 58 47.5 38.4 56.8(Day 0−14) Gr. 3 43 11.6 8.5 15.3 13 10.6 5.7 17.4 22 6.0 3.8 9.0 7 5.7 2.3 11.5Any rash (Day 0−42)

61 16.4 12.8 20.6 16 13.0 7.6 20.3 22 6.0 3.8 9.0 7 5.7 2.3 11.5

N = number of subjects having received the considered dose n/% = number/percentage of subjects reporting the specified symptom CI = confidence interval LL/UL = lower/upper limit of 95% CI Any: local symptom of "any" intensity Gr.3 pain: subject cried when limb was moved, spontaneously painful Gr.3 redness/swelling: >20mm in diameter Any fever = ≥ 38.0°C rectal temperature; ≥37.5°C axillary temperatureGrade 3 fever: >39.5°C rectal temperature; >39.0°C axillary temperatureA single dose of Varilrix was co-administered with Priorix at Visit 1.Redness at injection site was the most frequently reported local symptom following each vaccination(Table 2). Both groups had similar incidence of all solicited local symptoms (any and grade 3) after thefirst dose while higher incidence of pain (any) and redness (any and grade 3) was observed in GroupMeMuRu-OKA pooled lots after the second dose. After Dose 1 of this study, the incidence of any feverduring the 15 days and 43 days of follow-up was observed to be higher in pooled MeMuRu-OKA groupswhen compared to Group Priorix+Varilrix (Table 2). Both vaccine groups presented a similar pattern forfever prevalence with a peak between Day 4 and Day 10 after vaccination. However, for any fever, theobserved peak was higher in Group MeMuRu-OKA pooled lots, while the peaks were similar betweengroups for grade 3 fever. Following Dose 2, no differences between groups were found for the incidence ofboth any and grade 3 fever, and no patterns were identified on prevalence curves over the 43 days offollow-up. The observed incidence of any rash was also similar in both groups after each vaccination(Table 2).





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The following rare adverse events were reported during the follow-up period of the study:1 case (Group Priorix+Varilrix) of parotid/salivary gland swelling of grade 1 intensity, assessed tobe related to vaccination2 cases (MeMuRu-OKA groups) of febrile convulsions of grade 3 intensities, assessed to be relatedto vaccination1 case (Group Priorix+Varilrix) of neck stiffness suspected as a sign of meningism of grade 1intensity, assessed as not related to vaccination

All four subjects recovered from these events.All 12 SAEs reported in the study resolved. Only one SAE was assessed with causal relationship tovaccination.

The child was seen by a physician but was not hospitalized. On thefollowing day, there were no signs of an underlying neurological pathology. Laboratory tests were notperformed. This event was considered by the investigator as medically important and assessed to have apossible relationship to the vaccine.Conclusions:This study met the primary objectives related to the demonstration of lot-to lot consistency of MeMuRu-OKA candidate vaccine as well as the non-inferiority of MeMuRu-OKA pooled lots to separate injectionsof Priorix and Varilrix for all vaccine components:

• The seroconversion rates after the second dose did not vary by more than 10% from one MeMuRu-OKA lot to another for all antigens.

• The seroconversion rates after the second dose in Group MeMuRu-OKA pooled lots did not decreaseby more than 10% when compared to Group Priorix+Varilrix for all antigens.

The incidence of grade 3 fever was similar between MeMuRu-OKA and Priorix+Varilrix groups aftereach dose. For this reason, the higher incidence of low-grade fever (reflecting a peak between Day 4 andDay 10, more pronounced in the MeMuRu-OKA group than in the Priorix+Varilrix group) following thefirst dose was considered of limited clinical relevance. Therefore, this study provides evidence that thecandidate MeMuRu-OKA vaccine was shown to be as safe and as well tolerated as the separate injectionsof Priorix and Varilrix.

Date of report: 28 April 2004Synopsis of Final Study Report 208136/038 (MeMuRu-OKA-038) Page 5




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CONTENTS: TEXT

1. INTRODUCTION/RATIONALE............................................................................................16

2. STUDY OBJECTIVES .............................................................................................................17

2.1 CO-PRIMARY OBJECTIVES (SEQUENTIAL).................................................................................172.2 SECONDARY OBJECTIVES.........................................................................................................17

3. METHODOLOGY....................................................................................................................17

3.1 STUDY DESIGN.........................................................................................................................173.2 PRINCIPAL INVESTIGATORSAND INVESTIGATIONAL SITES.........................................................193.3 ETHICS ....................................................................................................................................19

3.3.1 Protocol amendments/modifications.............................................................................203.4 SELECTION OF STUDY POPULATION..........................................................................................21

3.4.1 Inclusion criteria for the active phase of the study .......................................................213.4.2 Exclusion criteria for the active phase of the study ......................................................213.4.3 Elimination criteria for the active phase of the study ...................................................223.4.4 Precautions to vaccination ...........................................................................................23

3.5 STUDY VACCINE(S) AND ADMINISTRATION..............................................................................233.5.1 Composition of study vaccines......................................................................................233.5.2 Dosage and administration...........................................................................................24

3.6 TREATMENT ALLOCATION AND RANDOMIZATION ....................................................................243.6.1 Randomization of supplies ............................................................................................243.6.2 Randomization of subjects ............................................................................................25

3.7 BLINDING ................................................................................................................................253.8 STUDY PROCEDURES OF THE ACTIVE PHASE PERIOD ................................................................253.9 SUBJECT COMPLETION AND WITHDRAWAL...............................................................................27

3.9.1 Subject completion........................................................................................................273.9.2 Subject withdrawal from the study................................................................................273.9.3 Subject withdrawal from investigational product .........................................................27

3.10 ASSESSMENT OF IMMUNOGENICITY VARIABLES (ACTIVE PHASE) ........................................283.10.1 Intervals between study visits........................................................................................283.10.2 Laboratory assays and time points ...............................................................................283.10.3 Endpoints for sub-optimal response .............................................................................30

3.11 ASSESSMENT OF SAFETY VARIABLES ..................................................................................303.11.1 Non-serious adverse events...........................................................................................303.11.2 Serious adverse events ..................................................................................................343.11.3 Post study adverse events and serious adverse events..................................................343.11.4 Prior and concomitant medication ...............................................................................34

3.12 DATA QUALITY ASSURANCE................................................................................................353.13 STATISTICAL ANALYSES .....................................................................................................35

3.13.1 Primary endpoint ..........................................................................................................353.13.2 Secondary endpoints .....................................................................................................35




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3.13.3 Target sample size.........................................................................................................363.13.4 Study cohorts/data sets analysed ..................................................................................363.13.5 Derived and transformed data ......................................................................................373.13.6 Analysis of demographics .............................................................................................383.13.7 Analysis of efficacy .......................................................................................................383.13.8 Analysis of safety ..........................................................................................................39

3.14 CHANGES IN THE CONDUCT OF THE STUDY .........................................................................393.15 CHANGES IN PLANNED ANALYSES.......................................................................................40

4. STUDY POPULATION............................................................................................................40

4.1 STUDY DATES..........................................................................................................................404.2 SUBJECT ELIGIBILITY AND ATTRITION FROM STUDY.................................................................40

4.2.1 Number and distribution of subjects .............................................................................404.2.2 Study completion and drop-out.....................................................................................414.2.3 Eligibility for analysis...................................................................................................424.2.4 Compliance with protocol specified procedures...........................................................44

4.3 DEMOGRAPHIC CHARACTERISTICS...........................................................................................45

5. ANALYSIS OF IMMUNOGENICITY ...................................................................................46

5.1 DATA SETS ANALYSED.............................................................................................................465.2 CONSISTENCY BETWEEN MEMURU-OKA LOTS......................................................................47

5.2.1 Pre-vaccination serological status................................................................................475.2.2 Seroconversion rates and GMTs - MeMuRu-OKA lots.................................................475.2.3 Lot-to-lot consistency evaluation..................................................................................50

5.3 NON-INFERIORITY OF MEMURU-OKA CANDIDATE VACCINE..................................................515.3.1 Pre-vaccination serological status................................................................................515.3.2 Seroconversion rates and GMTs between vaccine groups............................................525.3.3 Non-inferiority evaluation of MeMuRu-OKA vaccine ..................................................54

6. ANALYSIS OF SAFETY .........................................................................................................58

6.1 OVERALL INCIDENCE OF SYMPTOMS........................................................................................596.2 SOLICITED LOCAL SIGNS AND SYMPTOMS ................................................................................596.3 SOLICITED GENERAL SIGNS AND SYMPTOMS ............................................................................61

6.3.1 Fever .............................................................................................................................616.3.2 Rash ..............................................................................................................................636.3.3 Parotid/salivary gland swelling ....................................................................................656.3.4 Signs of meningism including febrile convulsions ........................................................65

6.4 UNSOLICITED SYMPTOMS ........................................................................................................666.5 CONCOMITANT MEDICATIONS/VACCINATIONS .........................................................................706.6 SERIOUS ADVERSE EVENTS......................................................................................................71

7. DISCUSSION ............................................................................................................................73

8. CONCLUSIONS........................................................................................................................74

9. REFERENCES..........................................................................................................................76




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10. SUPPLEMENTS .......................................................................................................................77

CONTENTS: REPORT TABLES AND FIGURES

Table 1: Principal investigators and investigational sites ........................................19Table 2: Independent Ethics Committees/Institutional Review Boards...................20Table 3: Viral titres of vaccines per dose (0.5 mL)..................................................24Table 4: Vaccines, lot numbers and group allocation ..............................................24Table 5: Outline of study procedures during the active phase of the study..............26Table 6: Laboratory assays .......................................................................................29Table 7: Number of subjects withdrawn from the study and reasons for

withdrawal � Total vaccinated cohort ..............................................................41Table 8: Number of subjects enrolled in the study as well as the number of

subjects excluded from the ATP analyses with reasons for exclusion.............43Table 9: Compliance with respect to documenting safety - Total vaccinated

cohort................................................................................................................45Table 10: Summary of demographic characteristics � Total vaccinated cohort.......46Table 11: Initial serological status of subjects in MeMuRu-OKA groups � Total

Vaccinated Cohort .............................................................................................47Table 12: Seroconversion rates and GMTs for all antigens in MeMuRu-OKA

groups for initially seronegative subjects � ATP immunogenicity cohort .......48Table 13: Measles, mumps, rubella and varicella seroconversion rate difference

between MeMuRu-OKA lots at 42 days after the second dose � ATPimmunogenicity cohort.....................................................................................50

Table 14: GMT ratios between MeMuRu-OKA lots after the second dose ininitially seronegative subjects before Dose 1� ATP immunogenicity cohort ..51

Table 15: Initial serological status of subjects in Group MeMuRu-OKA (pooledlots) and Group Priorix+Varilrix � Total Vaccinated Cohort ..........................52

Table 16: Seroconversion rates and GMTs for all antigens in Group MeMuRu-OKA pooled lots and Group Priorix+Varilrix in initially seronegativesubjects � ATP immunogenicity cohort ...........................................................53

Table 17: Seroconversion rate difference between Group MeMuRu-OKA andGroup Priorix+Varilrix after the second dose � ATP immunogenicitycohort................................................................................................................55

Table 18: GMT ratios between MeMuRu-OKA pooled lots and Priorix +Varilrix after the second dose in subjects who were initially seronegativebefore Dose 1 - ATP immunogenicity cohort ..................................................56

Table 19: Seroconversion rate difference between Group MeMuRu-OKA andGroup Priorix+Varilrix after the first dose � ATP immunogenicity cohort.....56

Table 20: GMT ratios between MeMuRu-OKA pooled lots andPriorix+Varilrix after the first dose in subjects who were initiallyseronegative before vaccination - ATP immunogenicity cohort ......................57




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Table 21: GMT ratio of post-dose 2 over post-dose 1 titer in subjects whoseroconverted after dose 1 for each antigens - ATP immunogenicity cohort...58

Table 22: Incidence and nature of (solicited and unsolicited) symptomsreported during the 43 days of follow-up after each dose � Totalvaccinated cohort..............................................................................................59

Table 23: Incidence of solicited local symptoms during the follow-up periodafter each dose� Total vaccinated cohort .........................................................60

Table 24: Incidence of fever within 15 days (Day 0−14) of follow-up after eachvaccination - Total vaccinated cohort ..............................................................62

Table 25: Incidence of fever within 43 days (Day 0−42) of follow-up after eachdose - Total vaccinated cohort..........................................................................63

Table 26: Incidence of general rash within 43 days (Day 0−42) of follow-upafter each dose - Total vaccinated cohort .........................................................64

Table 27: Percentage of subjects who reported unsolicited symptoms during the43-days of follow-up (Day 0-42) after dose 1 - Total Vaccinated Cohort .......67

Table 28: Percentage of subjects who reported unsolicited symptoms during the43 days (Day 0-42) of follow-up after dose 2 - Total Vaccinated Cohort........69

Table 29: Number and percentage of subjects who took at least oneconcomitant medication within 43 days (Day 0-42) after each dose - TotalVaccinated Cohort............................................................................................71

Table 30: Serious adverse events reported during the follow-up period aftereach dose ..........................................................................................................72

Figure 1: Design of the study ...................................................................................18




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CONTENTS: SUPPLEMENTARY TABLES

Supplement 1: Investigators, study centres and investigational sites.......................77Supplement 2: Number of subjects enrolled and vaccinated in the study - Total

vaccinated cohort..............................................................................................78Supplement 3: Summary of demographic characteristics � ATP Safety cohort ......79Supplement 4 Summary of demographic characteristics � ATP

Immunogenicity cohort ....................................................................................80Supplement 5: Duration of follow-up (days) - Total vaccinated cohort ..................81Supplement 6: Distribution of anti-Measles antibody titres - ATP

Immunogenicity Cohort....................................................................................82Supplement 7: Reverse Cumulative Curve of anti-Measles antibody titres -

ATP Immunogenicity Cohort ...........................................................................83Supplement 8: Distribution of anti-Mumps antibody titres - ATP

Immunogenicity Cohort....................................................................................85Supplement 9: Reverse Cumulative Curve of anti-Mumps antibody titres - ATP

Immunogenicity Cohort....................................................................................86Supplement 10: Distribution of anti-Rubella antibody titres - ATP

Immunogenicity Cohort....................................................................................88Supplement 11: Reverse Cumulative Curve of anti-Rubella antibody titres -

ATP Immunogenicity Cohort ...........................................................................89Supplement 12: Distribution of anti-Varicella antibody titres - ATP

Immunogenicity Cohort....................................................................................91Supplement 13: Reverse Cumulative Curve of anti-Varicella antibody titres -

ATP Immunogenicity Cohort ...........................................................................92Supplement 14: Prevalence of any fever from Day 0 to Day 42 after each dose -

Total vaccinated cohort ....................................................................................94Supplement 15: Prevalence of grade 3 fever from Day 0 to Day 42 after each

dose - Total vaccinated cohort l .......................................................................95Supplement 16: Number of days with any fever (Day 0-42) after each dose -

Total vaccinated cohort ....................................................................................96Supplement 17: Number of days with grade 3 fever (Day 0-42) after each dose -

ATP Safety Cohort ...........................................................................................97Supplement 18: Number of days with generalized rash (Day 0-42) after each

dose - Total vaccinated cohort..........................................................................98Supplement 19: Percentage of subjects with grade 3 unsolicited symptoms

within 43 days (Day 0-42) of follow-up after each dose - Total vaccinatedCohort...............................................................................................................99

Supplement 20: Percentage of subjects who reported unsolicited symptomsconsidered to have a causal relationship to vaccination within 43 daysafter each dose - Total Vaccinated Cohort .....................................................100




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Supplement 21: Incidence of local symptoms during the follow-up period aftereach vaccination with MeMuRu-OKA vaccine - Total vaccinated cohort ....101

Supplement 22: Incidence of fever during the 15-day follow-up (Day 014) aftereach vaccination with MeMuRu-OKA - Total vaccinated cohort..................102

Supplement 23: Incidence of general rash in MeMuRu-OKA groups during the43-day (Day 0-42) follow-up after each dose - Total vaccinated cohort........103

Supplement 24: Number and percentage of subjects in MeMuRu-OKA groupswho took at least one concomitant medication during the 43 days offollow-up (Day 0-42) - Total Vaccinated Cohort...........................................104

Supplement 25: Percentage of subjects with unsolicited symptoms classified byWHO Body System and Preferred Term for adverse events within 43 daysafter dose 1 - Total Vaccinated Cohort ..........................................................105

Supplement 26: Percentage of subjects with unsolicited symptoms classified byWHO Body System and Preferred Term for adverse events within 43 daysafter dose 2 - Total Vaccinated Cohort ..........................................................107




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APPENDICES

Elimination: Codes 109Notes to Appendix tables 110

I A Elimination codesB DemographyCi Dates of birth, vaccination and blood sampling visitsCii Reason for visit not doneD General medical history - physical examinationEi Study conclusionEii Subject(s) whose code was brokenF Vaccination procedure for each subject: list of vaccines administered andall related information

II Reason for vaccine not administeredA Solicited local adverse events (pain [PA], redness [RE] and swelling

[SW])Bi FeverBii Solicited Adverse Events for code RA (rash)Biii Solicited Adverse Events for code RL (local rash at injection site)Biv Biological sampleBv Solicited Adverse Events for code FC (febrile convulsions)Bvi Solicited Adverse Events for code PS (parotid/salivary gland swelling)C Unsolicited adverse eventsCi Unsolicited Adverse Events within 30 days post vaccinationCii Unsolicited Adverse Events started more than 30 days post vaccinationDi MedicationDii Concomitant vaccination

III A Immunogenicity

Appendices: Serious Adverse Events− CLINICAL NARRATIVES− SERIOUS ADVERSE EVENTS TABLE

Appendices: Study Information− PROTOCOL− REPRESENTATIVE SUBJECT INFORMATION SHEET− RELEVANT PAGES OF CRF (UNIQUE PAGES ONLY)− RANDOMISATION LIST− ONE PAGE CV FOR PRINCIPAL INVESTIGATOR(S)− PUBLICATIONS REFERENCED IN THE REPORT




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List of Abbreviations and Definitions of Terms

AE(s) Adverse Event(s)ATP According-to-protocolCCID50 Median Cell Culture Infective DosesCI Confidence IntervalCPMS Clinical Programs Monitoring SystemCSF Cerebrospinal fluideCRF Electronic Case Report FormGMT Geometric mean titreGSK GlaxoSmithKlineHIV Human immunodeficiency virusIFA Immunofluorescence assayIU International unitIU/ml International unit per millilitreMedDRA Medical Dictionary for Regulatory ActivitiesMMR Measles-Mumps-Rubellamg MilligrammIU/ml Milli-international units per millilitremm MillimetrePCR Polymerase Chain Reactionpfu Plaque forming unitsPID Patient identification number® Registered trademark of a companyRDE Remote Data EntrySAE(s) Serious Adverse Event(s)SBIR GlaxoSmithKline RandomizationSC SubcutaneousSOP Standard Operating ProcedureU UnitU/ml Unit per millilitreVZV Varicella-Zoster VirusWHO World Health Organisation




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Glossary of Terms

Adverse event: Any untoward medical occurrence in a patient or clinicalinvestigation subject administered a pharmaceuticalproduct and which does not necessarily have a causalrelationship with the pharmaceutical product (as defined byICH Guideline for Good Clinical Practice).

Eligible: Qualified for enrolment into the study based upon strictadherence to inclusion/exclusion criteria.

Evaluable: Meeting all eligibility criteria, complying with theprocedures defined in the protocol, and, therefore, includedin the according-to-protocol (ATP) analysis.

Solicited adverseevent:

Adverse events (AEs) recorded as endpoints in the clinicalstudy. The presence/occurrence/intensity of these eventswere actively solicited from the subject or an observerduring a specified post-vaccination follow-up period.

Subject(s): Term used throughout the report to denote the enrolledindividual(s), who participated in the clinical study, eitheras a recipient of the investigational product(s) or as acontrol.

Unsolicited adverseevent:

Any adverse event (AE) reported in addition to thosesolicited during the clinical study. Also any �solicited�symptom with onset outside the specified period of follow-up for solicited symptoms were reported as an unsolicitedadverse event.

MeMuRu-OKA GSK Biologicals� combined measles-mumps-rubella-varicella candidate vaccine.

Priorix GSK Biologicals� licensed vaccine against measles, mumpsand rubella.

Varilrix GSK Biologicals� licensed vaccine against varicella.




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1. Introduction/Rationale

Combined measles-mumps-rubella (MMR) and varicella vaccines are both indicatedin children during the second year of life, and can be given concomitantly but atseparate injection sites. The possibility to give both vaccines in a single injection as atetravalent measles-mumps-rubella-varicella vaccine would be of convenience forparents and medical practitioners and could facilitate introduction of varicella intothe routine vaccination.

Two doses of MMR are recommended in many countries. The first dose is generallyadministered in the second year of life and the second dose is administered either at4-6 years or 11-12 years of age, depending on local recommendations. Because thevaccination coverage for the second dose is not always optimal, some countries likeGermany now recommend giving both doses of MMR vaccine in the second year oflife1.

It should also be noted that the occurrence of varicella breakthrough cases andoutbreaks after routine vaccination have been recently reported in the United States 2.This prompted discussion about the need for a second dose of varicella vaccine inchildren through 12 years of age 3. Because of the observation that the occurrence ofbreakthrough cases of varicella increases with the time since vaccination, a seconddose of varicella vaccine to children has been proposed as a strategy to enhanceprotection against varicella disease of any intensity.

Based on these considerations, the availability of a combined measles-mumps-rubella-varicella vaccine that could be given according to a two-dose schedule in thesecond year of life may adequately address vaccination needs against measles,mumps, rubella (increased vaccination coverage for the second dose of MMR) andvaricella (increased protection against any varicella disease, and decreased number ofvaricella breakthrough cases after vaccination) as well as offering the convenience ofless injections.

A tetravalent measles-mumps-rubella-varicella vaccine (referred to as�MeMuRu-OKA�) has been developed by GSK Biologicals to combine the benefitsof MMR and varicella vaccination in a single injection.

The present study was performed to evaluate the consistency of three production lotsof MeMuRu-OKA, as well as the non-inferiority of MeMuRu-OKA in terms ofimmunogenicity and safety when administered according to a two-dose schedule tohealthy children in their second year of life, in comparison to GSK Biologicals'licensed MMR vaccine (Priorix) given according to a two-dose schedule and onedose of GSK Biologicals' licensed Varicella vaccine (Varilrix).

The study is also evaluating the persistence of antibodies against measles, mumps,rubella and varicella as well as the occurrence of varicella breakthrough cases after




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vaccination for a period of three years. This long- term follow-up is currentlyongoing and results will be addressed in separate annex reports (208136 MeMuRu-OKA 039, 040 and 041).

2. Study Objectives

2.1 Co-primary objectives (sequential)

• To demonstrate the consistency of three production lots of MeMuRu-OKAcandidate vaccine in terms of measles, mumps, rubella and varicellaseroconversion, 42-56 days after the second dose.

• To demonstrate the non-inferiority of MeMuRu-OKA candidate vaccine toseparate administration of Priorix and Varilrix vaccines in terms of measles,mumps, rubella and varicella seroconversion, 42-56 days after the second dose(i.e., 42-56 days after the second vaccination time point, given that Varilrixvaccine was only administered as a single dose in the control group).

2.2 Secondary objectives

• To assess the immunogenicity of the study vaccines, in terms of antibody titres toeach vaccine component, 42-56 days after the second dose.

• To assess the immunogenicity of the study vaccines, in terms of seroconversionand antibody titres to each vaccine component, 42-56 days after the first dose.

• To assess the safety of the study vaccines after the first and the second doses.

3. Methodology

The study protocol, a representative subject information sheet and unique pages ofthe individual case report form (CRF) utilized in the study are provided in theAppendices: Study Information.

3.1 Study design

This was a Phase III, controlled, 2-dose vaccination study conducted in multiplecentres in Germany and Austria. Healthy subjects between 12-18 months of age wererandomized (1:1:1:1 ratio) into 4 parallel groups as follows:




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Group MeMuRu-OKA Lot MJRV 159A48 received two doses of GSKBiologicals� MeMuRu-OKA vaccine lot MJRV 159A48 administered at Visit1/Day 0 and Visit 2/Week 6



Group Priorix+Varilrix received one dose of GSK Biologicals� licensedmeasles-mumps-rubella (Priorix) vaccine administered concomitantly withone dose of varicella (Varilrix) vaccine at Visit 1/Day 0 and a second dose ofPriorix administered at Visit 2/Week 6.

Subject's parents/guardians were requested to visit the study centre three timesduring the active phase of the study and one visit per year during the 3-year periodof follow-up. Figure 1 presents the study design.

Figure 1: Design of the study

Visit 1, Day 0 Visit 2, Week 6 Visit 3, Week 12 Visit 4/ Visit 5/ Visit 6/Vaccination 1 Vaccination 2 Year 1 Year 2 Year 3

Randomization (1:1:1:1)

Group MeMuRu-OKA LotMJRV 159A48 (N=120)



Group Priorix + Varilrix (N=120)(Priorix: D0/D42; Varilrix: D0)

Follow-up visits

Active phase period Long-term follow-up period

All vaccines were administered subcutaneously to subjects in their second year oflife (6 weeks apart). The study was conducted in a double-blind manner for GroupsMeMuRu-OKA lots MJRV 159A48, MJRV160A48 and MJRV163A48 and open forGroups MeMuRu-OKA lots MJRV 159A48, MJRV160A48 and MJRV163A48versus Group Priorix+Varilrix.




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Four millilitres (4 mL) of blood were collected from all subjects at each timepoint.For the active phase period, a pre-vaccination (Visit1/Day 0), post-dose 1 (Visit 2/Week 6) and post-dose 2 (Visit 3/Week 12) blood samples were collected. One bloodsample (4 mL) is to be collected per year for subjects who agree to participate in thelong-term follow-up of three years after vaccination.

The duration of the study was approximately 12 weeks for each subject during theactive phase period and 3 years for the long-term follow-up period. The Remote DataEntry (RDE) (active phase period) and paper CRF (follow-up period) were used tocollect individual subject's data.

3.2 Principal investigators and investigational sites

Table 1 presents the four principal investigators in the study. The curriculum vitae ofprincipal investigators are presented in Study Information Appendix of this report.

Table 1: Principal investigators and investigational sites

Principal Investigators Investigational siteGermany:Prof. Dr. med. Austria:Dr. Dr. Dr. Dr.

Supplement 1 presents the list of all investigators, study centres and investigationalsites in the study.

3.3 Ethics

The study was conducted according to Good Clinical Practice and in accordance withthe Declaration of Helsinki as amended in South Africa in 1996. The protocol andstatement of informed consent were approved by the respective Institutional ReviewBoard/Independent Ethics Committee of each study centres of the country beforestudy initiation (Table 2). Written informed consent was obtained from eachparent/guardian prior to entry into the study.




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Table 2: Independent Ethics Committees/Institutional Review BoardsCountry Centre no.* Investigational site

& Dr. med.

&

& Prof. Dr. med.

&

& Dr.

& Prof. Dr. med.

Germany:

& Dr. med.

Austria

* See Supplement 1

Electronic CRFs were assigned for each subject to record individual data. Reportappendix on study information contains the subject information sheet and uniquepages of the CRF utilized in the study.

3.3.1 Protocol amendments/modifications

No protocol amendment or modification was issued during the conduct of this study.




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3.4 Selection of study population

3.4.1 Inclusion criteria for the active phase of the study

All subjects must have satisfied the following criteria at study entry:

• Subjects for whom the investigator believes that their parents/guardians cancomply with the requirements of the protocol (e.g., completion of the diary cards,return for follow-up visits) should be enrolled in the study.

• A male or female child between 12 to 18 months of age at the time of the firstvaccination. Subjects older than 18 months may be enrolled in the study as longas the second vaccination was administered before the subject's second year'sbirthday (i.e. 24 months old).

• Written informed consent obtained from the parent or guardian of the subjects.

• Free of obvious health problems as established by medical history and clinicalexamination before entering into the study.

3.4.2 Exclusion criteria for the active phase of the study

The following criteria should have been checked at the time of study entry. If anyapplied, the subject was not to have been included in the study:

• Use of any investigational or non-registered product (drug or vaccine) other thanthe study vaccines within 30 days preceding the first dose of study vaccine, orplanned use during the study period.

• Chronic administration (defined as more than 14 days) of immunosuppressants orother immune-modifying drugs within six months prior to the first vaccine dose.(For corticosteroids, this referred to prednisone, or equivalent, ≥ 0.5 mg/kg/day.Inhaled and topical steroids were allowed.).

• Planned administration/ administration of a vaccine not foreseen by the studyprotocol from 30 days prior to study start until study conclusion at Week 12.

• Previous vaccination against measles, mumps, rubella and/or varicella.

• History of measles, mumps, rubella and/or varicella/ zoster diseases.

• Known exposure to measles, mumps, rubella and/or varicella/ zoster withinwithin 30 days prior to study start.

• Any confirmed or suspected immunosuppressive or immunodeficient condition,including human immunodeficiency virus (HIV) infection.

• A family history of congenital or hereditary immunodeficiency.




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• History of allergic disease or reactions likely to be exacerbated by anycomponent of the vaccines, including obvious allergic reactions to streptomycin,neomycin, egg proteins, and/or gelatin.

• Major congenital defects or serious chronic illness.

• History of any neurologic disorders or seizures.

• Residence in the same household as the following persons:

- New-born infants (0-4 weeks of age)

- Pregnant mother/ women with a negative history of chickenpox disease andwithout recorded vaccination against chickenpox

- Persons with known immunodeficiency.

• Acute disease at the time of enrolment. (Acute disease was defined as thepresence of a moderate or severe illness with or without fever. All vaccines canbe administered to persons with a minor illness such as diarrhoea, mild upperrespiratory infection with or without low-grade febrile illness, i.e., oraltemperature <37.5°C/ axillary temperature <37.5°C / rectal temperature <38.0°C/ tympanic temperature on oral setting <37.5°C / tympanic temperature on rectalsetting <38.0°C).

• Rectal temperature ≥ 38.0°C or axillary temperature ≥ 37.5°C at the time ofvaccination

• Administration of immunoglobulins and/or any blood products since birth orplanned administration during the study period.

3.4.3 Elimination criteria for the active phase of the study

The investigator was to have checked the following criteria at each visit. Theoccurrence of any of these criteria did not serve as a requirement to discontinue thestudy but served as an indication for possible elimination from analysis.

• Chronic administration (defined as more than 14 days) of immunosuppressants orother immune-modifying drugs during the study period up to Week 12 visit. (Forcorticosteroids, this referred to prednisone, or equivalent, ≥ 0.5 mg/kg/day.Inhaled and topical steroids were allowed.)

• Administration of a vaccine not foreseen by the study protocol during the studyperiod up to Week 12 visit.

• Administration of immunoglobulins and/or any blood products during the studyperiod up to Week 12 visit.




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• Use of any investigational or non-registered product (drug or vaccine) other thanthe study vaccines during the study period, up to Week 12 visit.

3.4.4 Precautions to vaccination

It was recommended that members of the investigation team were immune to thevaccine components under investigation.

Residence in a household in which a susceptible high-risk person (e.g., newbornsbetween 0-4 weeks old, pregnant women with negative history of chickenpox andwithout recorded vaccination against chickenpox, immunocompromised personsincluding those with HIV) was considered as an exclusion criterion. It was, however,recommended that this information be given to the parents/guardians such that, in theadvent of a member of the household becoming high-risk within the period of thestudy, vaccine recipients and especially those that developed a vaccine-associatedrash would avoid close association with these susceptible high-risk individuals. Insuch circumstances the potential risk of transmission of the attenuated virus presentin the vaccine was to be weighed against the risk of infection and subsequenttransmission of natural varicella by individuals who had not benefited fromvaccination.

Additionally, parents/guardians were instructed to avoid the use of salicylates tovaccine recipients during the study period (12 weeks) as Reye�s Syndrome has beenreported following the use of salicylates during natural varicella infection.

3.5 Study vaccine(s) and administration

3.5.1 Composition of study vaccines

All candidate vaccines used in this study were developed and manufactured byGlaxoSmithKline Biologicals.

The Quality Control Standards and Requirements for each candidate vaccine aredescribed in separate release protocols and the required approvals were obtained.Commercial vaccines are assumed to comply with the specifications given in themanufacturer's Summary of Product Characteristics. The vaccine release protocol isarchived in the study file and is available upon request.

Each vaccine was supplied as monodose vials containing a freeze-dried pellet to bereconstituted before use with the corresponding provided diluent (water forinjection). One dose of each vaccine was 0.5 mL in volume. Table 3 presents theantigen content of vaccine used in the study.




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Table 3: Viral titres of vaccines per dose (0.5 mL)

Test vaccine Control vaccines

MeMuRu-OKA lotVirus strainMJRV159A48

(CCID50)MJRV160A48

(CCID50)MJRV163A48

(CCID50)

Priorix

(CCID50)

Varilrix

(pfu)

Schwarz measles 103.7

103.8

103.9

104.0

RIT 4385 (JerylLynn-derived)mumps

104.8

104.6

104.9

104.7

RA 27/3 rubella 104.0

104.0

104.0

104.3

Oka varicella 103.7

103.7

103.8

104.5

CCID50 = median cell culture infective dosepfu = plaque forming unit

The lot numbers of vaccines used in the study including the group allocation ispresented in Table 4.

Table 4: Vaccines, lot numbers and group allocationVaccine Lot number GroupMeMuRu-OKA MJRV159 A48 MeMuRu-OKA lot MJRV159 A48MeMuRu-OKA MJRV160 A48 MeMuRu-OKA lot MJRV160 A48MeMuRu-OKA MJRV163 A48 MeMuRu-OKA lot MJRV163 A48Priorix MJR622 A44/MVarilrix VA271 A43/M Priorix+Varilrix*

* Priorix and Varilrix vaccines were administered concomitantly at separate injection sites.

3.5.2 Dosage and administration

All vaccines were administered subcutaneously into the deltoid region of the arm(MeMuRu-OKA and Priorix vaccines in the left arm and Varilrix vaccine in the rightarm).

The vaccinees were observed closely for at least 30 minutes, with appropriatemedical treatment readily available in case of a rare anaphylactic reaction followingvaccine administration.

3.6 Treatment allocation and randomization

3.6.1 Randomization of supplies

A randomization list was generated at GSK Biologicals, Rixensart, using a standardSAS (Statistical Analysis System) program to number the vaccines. Arandomization blocking scheme (1:1:1:1 ratio) was used to ensure that balancebetween treatment was maintained: a randomization number uniquely identified thevaccine dose administered to the subject.

A 20% over-randomization of supplies was prepared to allow GSK Biologicals take




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advantage of greater rates of recruitment than anticipated at individual centres and toreduce the overall recruitment period. However, the enrolment was to be terminatedwhen 480 subjects had been enrolled. The vaccine doses distributed to the studycentres respected the randomization block.

3.6.2 Randomization of subjects

The treatment allocation at the investigator site was performed by using a centralrandomization call-in system on Internet (SBIR). The randomization algorithm useda minimization procedure stratified by centre 4.

When a subject was eligible, the person in charge of the vaccination accessed therandomization system on Internet. Upon providing a screening identification number(screening ID) for the subject, the randomization system used the minimizationalgorithm to determine the vaccine number to be used for the subject. This vaccinenumber was used as patient identification number (PID) for all data collected on thesubject during the study.

3.7 Blinding

The study was carried out in a double-blind manner with respect to Group MeMuRu-OKA receiving lots MJRV 159A48, MJRV 160A48 and MJRV 163A48 (i.e., theinvestigators/ study personnel and the subjects� parents/guardians were not aware ofwhich lot of MeMuRu-OKA vaccine was administered to the subject). However, dueto different number of injections between groups, the study was performed open withrespect to Group MeMuRu-OKA receiving lots MJRV 159A48, MJRV 160A48 andMJRV 163A48 versus Group Priorix+Varilrix (i.e., the investigator(s)/ studypersonnel and subject�s parents/guardians were aware of which vaccine wasadministered to the subject (i.e., either the single injection of MeMuRu-OKA or theseparate injection of Priorix and Varilrix).

The code was to be broken by the Clinical Safety physician only in the case ofmedical events for which the investigator/physician in charge of the subject feltcould not be treated without knowing the identity of the study vaccine.

GSK Biologicals� policy (incorporating ICH E2A guidance, EU Clinical TrialDirective and US Federal Regulations) was to unblind any serious adverse event(SAE) report associated with the use of the investigational product, which wasunexpected and attributable/suspected, prior to regulatory reporting. The ClinicalSafety physician was responsible for unblinding the treatment assignment inaccordance with specified time frames for expedited reporting of SAEs.

3.8 Study procedures of the active phase periodAn outline of study procedures during the active phase of the study is summarized inTable 5.




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Table 5: Outline of study procedures during the active phase of the studyAge 12-24 months

Vaccination DOSE 1 DOSE 2Visit VISIT 1 VISIT 2 VISIT 3

Timing Day 0 Week 6 Week 12Sampling timepoint Pre Vacc

42-56 dayinterval Post Vacc 1

42-56 dayinterval Post Vacc 2

Informed consent ●

Check of inclusion/ exclusioncriteria

●

Check elimination criteria ● ●

Medical history and prior (30 dayspre-vaccination) concomitantmedication/ vaccination

●

Physical examination ○ ○ ○#Pre-vaccination body temperature ● ●

Randomization ●

Blood sampling (4 ml) ●●●●●●●●

(before dose 2) ●

Vaccination ● ●●●●

Recording of solicited localsymptoms on the diary cards by theparents/guardians of the subject

● (Day 0)

●(Days 1-3)

●(Day 0)

●(Days 1-3)

Recording of solicited generalsymptoms & unsolicited adverseevents on the diary cards by theparents/guardians of the subject

●(Day 0)

●(Days 1-42)

●(Day 0)

●(Days 1-42)

Recording of concomitantmedication on the diary cards bythe parents/guardians of the subject

● (Day 0)

●(Days 1-42)

●(Day 0)

●(Days 1-42)

Reporting of all serious adverseevents (SAEs) by theparents/guardians of the subject tothe investigator.

Day 0 to Week 12 (Visit 3)

Return of diary cards by theparents/ guardians ● ●

Diary card verification &transcription by the investigator ● ●

Reporting of all SAEs to GSKBiologicals by the investigator Day 0 to Week 12 (Visit 3)

Study Conclusion ●

If parents/guardians agree to have their child participate in long-term follow-up:Informed consent for long-term follow-up ●Check of inclusion/exclusion criteria ●

Distribution of postcards to parents/guardians of the vaccinees -Parents/guardians of the vaccinees are instructed to fill one of the postcards andmail it to the study personnel in case his/her child experiences a breakthroughcase (confirmed by a physician) of measles, mumps, rubella and/or varicella orcontact with measles, mumps, rubella and/or varicella/herpes zoster diseases afterVisit 3/Week 12

●

Source: Study protocol and sample CRF presented in Appendices: Study Information� was used to indicate a study procedure that required documentation in the individual eCRF/ diary cards.○ procedure performed by investigators but not recorded on subject's eCRF/diary cards.# was to be performed if deemed necessary based on interim medical history.




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3.9 Subject completion and withdrawal

3.9.1 Subject completion

A subject who returned for the concluding visit of the active phase of the studyforeseen in the protocol (i.e., Visit 3/Week 12) was considered to have completed theactive phase of the study.

3.9.2 Subject withdrawal from the study

From an analysis perspective, a 'withdrawal' or a 'drop-out' from the study wasdefined as any subject who did not come back for the concluding visit or who wasnot available for the concluding contact foreseen in the protocol. A subject qualifiesas a 'withdrawal' from the study when no study procedure occurred, no follow-upwas performed and no further information was collected for this subject from thedate of withdrawal/last contact. The investigators were to attempt to contact thosesubjects who did not return for scheduled visits or follow-up. Information relative tothe withdrawal was to be documented on the Study Conclusion page of the CRF. Theinvestigator was to document whether the decision to withdraw from the study wasmade by the subject�s parent or guardian or the investigator and which of thefollowing possible reasons was responsible for withdrawal:

� Serious adverse event

� Non-serious adverse event

� Protocol violation (specific reason was to be recorded)

� Consent withdrawal, not due to an adverse event

� Migration from the study area

� Lost to follow-up

� Others (any other reason was to be specified)

3.9.3 Subject withdrawal from investigational product

A �withdrawal� from the investigational product was defined as any subject who didnot receive the complete treatment, i.e. when no further planned dose wasadministered from the date of withdrawal. A subject withdrawn from theinvestigational product may not necessarily be withdrawn from the study as furtherstudy procedures or follow-up may be performed (safety or immunogenicity) ifplanned in the study protocol.

Information relative to premature discontinuation of the investigational product wasto be documented on the Vaccine Administration page of the CRF. The investigatorwas to document whether the decision to discontinue further vaccination was madeby the subject�s parent or guardian or the investigator and which of the following




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possible reasons was responsible for withdrawal:

• serious adverse event,

• non-serious adverse event,

• other (specify).

3.10 Assessment of immunogenicity variables (active phase)

Serum titres of antibodies against measles, mumps, rubella and varicella weremeasured in pre-vaccination blood samples taken at Visit 1 (Day 0) and in post-vaccination blood samples taken at Visit 2 (Day 42: 42−56 days after the first dose),and at Visit 3 (Week 12: 42−56 days after the second dose).

3.10.1 Intervals between study visits

To adequately assess the immune responses elicited by the vaccines, the time intervalbetween visits for each vaccination/blood sampling was specified in the protocol.Visit 2 and Visit 3 were scheduled to take place 42 days after each vaccination(i.e., 42-56 days interval). However, this interval was only indicative for theinvestigator and a less restrictive 35-77 day interval was utilized as criterion forinclusion or exclusion of subjects in the according-to-protocol (ATP)immunogenicity analysis (see Sections 3.4.3 and 3.13.4, respectively, for details ofcriteria for evaluability and cohorts for analysis).

3.10.2 Laboratory assays and time points

Table 6 summarizes the overall laboratory assays for serological and biologicalsamples.

For all subjects, 4 mL of whole venous blood was collected at Visit 1(pre-vaccination), Visit 2 (post-vaccination 1) and Visit 3 (post-vaccination 2) usingtubes with serum separator. After blood centrifugation and serum separation, thealiquots of serum were stored at -20°C until assays were performed at GSKBiologicals� laboratory in Rixensart, Belgium. The samples were tested in a blindedfashion for the presence of antibodies to measles-mumps-rubella and varicella.

Measles, mumps and rubella antibody titres were determined by commercialimmunoassay kit. The tests were carried out according to the manufacturer�sinstructions. Varicella antibodies were measured by an indirect immunofluorescenceassay (IFA). Varicella titres were expressed as the reciprocal of the last dilutionconsidered as positive.

Vesicular fluid samples were to be collected in those subjects who developed avesicular rash. Collection of samples was to be performed aseptically using a fine




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bore needle by capillary action. Polymerase chain reaction (PCR) was to beperformed for virus identification and characterization.

Similarly in subjects with suspected case of parotitis, samples were to be collected byswabbing the buccal area after palpation of the salivary glands. The samples were tobe tested by PCR for mumps virus detection and strain identification.

In case of febrile convulsions or suspected signs of meningism, lumbar puncture wasto be performed at the discretion of the testing physician. The cerebral spinal fluid(CSF) was to be tested at the centre�s laboratory for cell count, proteins, glucose andother microbiological assays. In addition to these tests, a sample of CSF was to besaved for analysis of mumps antigen by PCR at GSK Biologicals, Rixensart,Belgium.

Table 6: Laboratory assaysBiologicalsample

Timepoint Identification Assay

MethodTest Kit/

ManufacturerAssayunit

Assaycut-off

Anti-measlesvirus/IgG ELISA Enzygnost/

Behring mIU/ml 150

Anti-mumpsvirus/IgG ELISA Enzygnost/

Behring U/ml 231

Anti-rubellavirus/IgG ELISA Enzygnost/

Behring IU/ml 4Serum

(1) Pre Vacc 1Day 0(2) Post Vacc 1Week 6

(3) Post Vacc 2Week 12 Anti-varicella

virus/IgG IFA* Virgo/ HemagenDiagnostics Dilution-1 4

Vesicular fluidNo pre-specified

timepoint Varicella virus PCR - - -

Saliva No pre-specifiedtimepoint Mumps virus PCR - - -

Cerebrospinalfluid

No pre-specifiedtimepoint Mumps virus PCR - - -

* IFA with buffer-modified technique

In case of insufficient blood sample volume to perform assays for all antibodies, theywere analyzed for the following ranking: measles-mumps-rubella and varicella.

Any additional serology on antigens contained in the study vaccines was to beperformed if deemed necessary by GlaxoSmithKline Biologicals if any findings inthe present study or in other studies necessitate investigation of the immunogenicityof the vaccine. In this case, the ranking above may also be changed.

All laboratory assays described in Table 6 were performed at GSK Biologicals,Rixensart, Belgium.




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3.10.3 Endpoints for sub-optimal response

Subjects who did not seroconvert to any of the four antigens were to be offered anadditional dose of GSK Biologicals� measles-mumps-rubella vaccine (Priorix)and/or GSK Biologicals� varicella vaccine (Varilrix).

3.11 Assessment of safety variables

The investigator was responsible for the detection and documentation of eventsmeeting the criteria and definition of an adverse event (AE) or serious adverse event(SAE) as provided in the protocol.

An AE was any untoward medical occurrence in a clinical investigation subject,temporally associated with the use of a medicinal product, whether or not consideredrelated to the medicinal product.

A serious adverse event (SAE) was any untoward medical occurrence whichincluded the following: death, life-threatening event, hospitalization or prolongationof existing hospitalization, disability/incapacity, congenital anomaly/birth defect inthe offspring of a study subject, any important medical events that may not beimmediately life-threatening or result in death or hospitalization but may jeopardizethe subject or may require medical or surgical intervention (e.g. cancer).

Each subject�s parents/guardians were instructed to contact the investigatorimmediately should the subject manifest any signs or symptoms they perceived asserious.

3.11.1 Non-serious adverse events

Parents/guardians were provided with diary cards and were given instructions onhow to record symptoms as well as any other reactions after each vaccination. Thesedata were verified and transcribed into the appropriate sections of the eCRFs.

Solicited local (injection site) symptoms

The following local signs and symptoms were to be recorded from the day of eachvaccination and the subsequent 3 days.

• Redness and swelling at injection site were measured in millimetres and theintensity was scored as follows:

0: Absent1: ≤5 mm diameter2: >5 - ≥20 mm diameter3: >20 mm diameter

• Pain at injection site on digital pressure, was to be recorded and the intensitywere scored as follows:




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0 = Absent1 = Minor reaction to touch2 = Cries/protests on touch3 = Cries when limb is moved/spontaneously painful.

General adverse events

The following general signs and symptoms were to be recorded from the day of eachvaccination and the subsequent 42 days:

• Temperature/ fever: Every day from Day 0 to 14, parents/guardians were askedto record the child�s body temperature measured by axillary route. The intensityof temperature/fever were graded as follows:

Rectal temperature:0: <38°C1: ≥ 38.0°C � ≤ 38.5°C2: >38.5°C � ≤ 39.5°C3: >39.5°C

Axillary temperature:0: <37.5°C1: ≥ 37.5°C � ≤ 38.0°C2: >38.0°C � ≤ 39.0°C3: >39.0°C

After this period, from Day 15 to Day 42, the child�s temperature was to be screenedeach evening at bedtime for signs of fever by means of either a thermometer or atemperature sensitive pad (placed on the child's forehead). If the sensitive padindicated fever (i.e. internal temperature ≥ 38.0°C) or if the parents/guardianssuspected any possible fever, an accurate temperature measurement was to beperformed using the thermometer supplied (axillary route) and the measurement wasto be recorded on the diary card. If additional temperature measurements wereperformed at another time of day, the highest temperature was to be recorded.Subjects� parents/guardians were also requested to record on the diary card ifmedical advice was sought for any fever episode. The causality was to be assessed bythe investigator(s).

Rash/ exanthem: Subjects who developed any kind of skin eruption - even mild -were to be examined as soon as possible by the investigator to record the followingassessments:

- Exanthem: to be described and classified as

(1) Measles/ rubella rashes (macular or maculo-papular rashes):presence of macules, discolored small patches or spots of the skin,neither elevated nor depressed below the skin's surface




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(2) varicella rash (maculo-papulo-vesicular): simultaneous presenceof macules, papules and vesicles raised above the skin's surface

(3) Or other types of rash (heat rash, diaper rash etc�)

- causality

- date of onset and end of eruption were to be indicated, as well as the localityof the rash (injection site or non-injection site)

- intensity of rash as follows: 0: no lesion

1: 1-50 lesions

2: 51-150 lesions

3: > 150 lesions.

- outcome

In the presence of rash, parents/guardians of the subject were encouraged tocontact the study site and come for a visit. If vesicles were present, an attempt tocollect vesicular fluid for varicella virus identification by PCR was to be carriedout (see Section 3.10.2 for details).

• Parotid/salivary gland swelling: Should parotitis be clinically suspected(swelling / tenderness in the mandibular/submandibular region), the child was tobe examined by the investigator as soon as possible for an additional visit. Atthat visit the investigator was to assess the symptom as follows:

- swelling without difficulty moving the jaw

- swelling with difficulty moving the jaw

- swelling with accompanying general symptoms

A saliva sample was to be collected for mumps virus detection and strainidentification by PCR (see Section 3.10.2 for details).

• Any suspected signs of meningism, including febrile convulsions:Parents/guardians were instructed that should the child exhibit febrileconvulsions or any other neurological signs or symptoms indicative ofmeningism (e.g. vomiting, neck stiffness, photophobia) between Day 0 and thefollow-up visit, the child should undergo neurological examination according tocurrent local medical practice including (at the discretion of the treatingphysician) a lumbar puncture. The local monitor - in collaboration with theinvestigator - was to make sure that all relevant and supportive information(clinical, biological, etc) was made available to fully document the case.

The investigator was to make an assessment of intensity for all other AEs, i.e.




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unsolicited symptoms, including SAEs reported during the study. The assessmentwas based on the investigator�s clinical judgement. The intensity of each AE andSAE recorded in the CRF or SAE Report Form, as applicable, were assigned to oneof the following categories:

1 (mild) = Easily tolerated by the subject, causing minimal discomfortand not interfering with everyday activities.

2 (moderate) = Sufficiently discomforting to interfere with normal everydayactivities.

3 (severe) = Prevents normal, everyday activities. (e.g., a childpreventing attendance at school/ kindergarten/ a day-carecentre and causing the parents/ guardians to seek medicaladvice.

An AE that was assessed as Grade 3 (severe) should not be confused with aSAE. Grade 3 is a category utilised for rating the intensity of an event; and bothAEs and SAEs can be assessed as Grade 3.

Assessment of causality

The investigator was obliged to assess the relationship between investigationalproduct and the occurrence of each AE/SAE by using his/her clinical judgement todetermine the relationship. Alternative causes, such as natural history of theunderlying diseases, concomitant therapy, other risk factors and the temporalrelationship of the event to the investigational product was to be considered andinvestigated.

In case of concomitant administration of multiple vaccines, the investigator shouldassess whether the AE could be causally related to vaccination rather than to theindividual vaccines.

All solicited local (injection site) reactions were considered causally related tovaccination. Causality of all other AEs was assessed by the investigator by answeringthe following question:

In your opinion, did the vaccine(s) possibly contribute to the adverse event?

NO: The AE was not causally related to administration of the studyvaccine(s). There are other, more likely causes and administration ofthe study vaccine(s) was not suspected to have contributed to the AE.

YES: There was a reasonable possibility that the vaccine contributed to theAE.

Non-serious and serious AEs were evaluated as two distinct events. If an event metthe criteria to be determined �serious�, it was to be examined by the investigator to




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be able to determine ALL contributing factors applicable to each serious adverseevent. Other possible contributors included:

• Medical history• Other medication• Protocol required procedure• Other procedure not required by the protocol• Lack of efficacy of the vaccine, if applicable• Erroneous administration• Other cause (specify)

3.11.2 Serious adverse events

The time period for collecting and recording SAEs in this study began atrandomization or the first receipt of vaccine/ comparator (Day 0) up to 84 days foreach subject during the active phase period.

3.11.3 Post study adverse events and serious adverse events

A post-study AE/SAE was defined as any event that occurs outside of the AE/SAEdetection period defined in the protocol. Investigators were not obliged to activelyseek AEs or SAEs in former study participants. However, if the investigator learnedof any SAE, including a death, at any time after a subject had been discharged fromthe study, and he/she was considering the event reasonably related to theinvestigational product, the investigator was to promptly notify the Study Contact forReporting SAEs.

3.11.4 Prior and concomitant medication

All concomitant medication, with the exception of vitamins and/or dietarysupplements, administered at ANY time during the period starting withadministration of the first dose (Day 0) up to 84 days (Day 84) were to be recordedwith generic name of the medication, medical indication, total daily dose, route ofadministration, start and end dates of treatment.

Any treatments and/or medications specifically contraindicated, e.g., anyimmunoglobulins, other blood products and any immune modifying drugsadministered since birth or at any time until Visit 3 (Day 84) were to be recordedwith generic name of the medication, medical indication, total daily dose, route ofadministration, start and end dates of treatment.

Any vaccine not foreseen in the study protocol administered in the period beginning30 days preceding the first dose (Day 0) up to the entire active phase period (Day0-84) was to be recorded with trade name, route of administration and date(s) ofadministration.

Any concomitant medication administered prophylactically in anticipation of




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reaction to the vaccination was to be recorded in the CRF with generic name of themedication, total daily dose, route of administration, start and end dates of treatmentand was to be coded as �Prophylactic�.

Concomitant medication administered for the treatment of an AE or SAE was to berecorded in the CRF with generic name of the medication, medical indication(including which AE/SAE), total daily dose, route of administration, start and enddates of treatment.

3.12 Data quality assurance

To ensure that study procedures conformed across all investigator sites, the protocol,case report form and safety reporting were reviewed with the investigator and his/herpersonnel responsible for the conduct of the study by the Company representative(s)at the investigator site.

Adherence to the protocol requirements and verification of data generation accuracywas achieved through monitoring visits to each investigator site. All procedures wereperformed according to methodologies detailed in GlaxoSmithKline StandardOperating Procedures (SOPs).

3.13 Statistical Analyses

3.13.1 Primary endpoint

• Measles, mumps, rubella and varicella seroconversion, 42-56 days after thesecond dose (i.e., 42-56 days after the second vaccination time point given thatVarilrix vaccine was only administered as a single dose in the control group).

3.13.2 Secondary endpoints

Immunogenicity

• Measles, mumps, rubella and varicella antibody titres, 42-56 days after the firstdose and 42-56 days after the second dose.

• Measles, mumps, rubella and varicella seroconversion and antibody titres, 42-56days after the first dose.




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Safety

• Occurrence of any fever and grade 3 fever (defined as axillary: >39.0°C/rectaltemperature >39.5°C) within 15 days after each vaccination (Day 0-14).

• Occurrence of any and grade 3 solicited local symptoms within 4 days after eachvaccination (Day 0-3).

• Occurrence of any and grade 3 solicited general symptoms (fever, rash, any signof meningitis including febrile convulsion, parotitis gland swelling) within 43days after each vaccination (Day 0-42).

• Occurrence, intensity and relationship to vaccination of unsolicited symptomswithin 43 days after each vaccination (Day 0-42).

• Occurrence of SAEs throughout the entire study up to and including 42 days aftervaccination.

3.13.3 Target sample size

The study planned to enroll 480 subjects in order to reach 400 evaluable subjects forthe analysis of immunogenicity (100 subjects to be equally distributed in each studygroup).

3.13.4 Study cohorts/data sets analysed

The following subject cohorts were evaluated:

Total Vaccinated Cohort (Total cohort)

The Total Vaccinated Cohort included all vaccinated subjects for whom data wereavailable. For the total analysis of safety, this included all vaccinated subjects with atleast one vaccine administration documented. For the total cohort analysis ofimmunogenicity, this included vaccinated subjects for whom data concerningimmunogenicity were available.

Protocol defined or According To Protocol (ATP) cohort for analysis of safety

The protocol-defined cohort for analysis of safety included subjects:

• who received complete dosing of study vaccine according to the randomizationlist,

• with sufficient data to perform an analysis of safety,

• who only received vaccine specified or allowed in the protocol,

• for whom the administration site, side and route of study vaccine(s) was/were




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known.

Protocol defined or According To Protocol (ATP) cohort for analysis ofimmunogenicity

The protocol-defined cohort for analysis of immunogenicity included eligiblesubjects in the protocol-defined cohort for safety:

• with blood samples available,

• who complied with all protocol procedures,

• who were seronegative for all four antigens (i.e., measles, mumps, rubella andvaricella) at baseline, and

• whose post-vaccination serology data were available for at least one of thevaccine antigens.

3.13.5 Derived and transformed data

Immunogenicity:

For a given subject and the analysis of a given measurement, missing or unevaluablemeasurements were not replaced. Therefore, an analysis excluded subjects withmissing or with unevaluable measurements (e.g. total analysis of mumps antibodytitre included all vaccinated subjects with mumps antibody titre results aftervaccination).

For the analysis of immunogenicity, the following definitions were applied:

• A seronegative subject was a subject whose titre was below the cut-off value.

• A seropositive subject was a subject whose titre was greater than or equal to thecut-off value.

• Seroconversion was defined as the appearance of antibodies (i.e. titre greater thanor equal to the cut-off value) in the serum of subjects seronegative beforevaccination.

• The Geometric Mean Titres (GMTs) calculations were performed by taking theanti-log of the mean of the log titre transformations. Antibody titre below the cut-off of the assay were given an arbitrary value of half the cut-off for the purposeof GMT calculation.

Safety:

Subjects who missed reporting symptoms (i.e. solicited/unsolicited/concomitantmedication) were treated as subjects without symptoms (i.e.




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solicited/unsolicited/concomitant medication).

3.13.6 Analysis of demographics

Demographic characteristics (age, race and gender) and distribution of subjectsenrolled in all study centres were tabulated by group and overall.

3.13.7 Analysis of efficacy

To control the impact of multiple primary objectives on the Type I and Type II errorrate, the study primary objectives during the active phase period were evaluatedsequentially (i.e. the subsequent objective was to be evaluated in a confirmatorymanner only if the previous objective was reached).

To demonstrate the consistency of three MeMuRu-OKA lots, the pair wisestandardized asymptotic 90% CIs for seroconversion rate difference betweenMeMuRu-OKA lots were computed for each antigen (measles, mumps, rubella andvaricella) after the second dose. The three MeMuRu-OKA lots were to be consideredconsistent if, for each antigen and each pair wise comparison, the 90% CI wasincluded between [-10%, +10%].

To demonstrate the non-inferiority of Group MeMuRu-OKA when compared toGroup Priorix+Varilrix, the standardized asymptotic 95% CIs for seroconversionrate difference between vaccine groups (Group MeMuRu-OKA pooled lots minusGroup Priorix+Varilrix) were computed for each antigen (measles, mumps, rubellaand varicella) after the second dose. The objective was achieved if the lower limit ofthe standardized asymptotic 95% CI was [-10%] or higher.

To support these analyses, the following descriptive analyses were also performedfor each group and each antigen (measles, mumps, rubella and varicella):

• seroconversion/seropositivity rates and their exact 95% CIs were tabulated aftereach dose;

• antibody titres distribution were displayed as reverse cumulative curves (RCCs)for each antigen and each treatment group after each dose;

• antibody titres were summarised by GMTs with their 95% CIs after each dose.

The 90% CI for the GMT ratios between MeMuRu-OKA vaccine lots after thesecond dose and the 95% CI for the GMT ratios between vaccine groups (GroupMeMuRu-OKA pooled lots over Group Priorix+Varilrix) after each dose was alsocomputed by using a one-way ANOVA model on the logarithm10 transformation ofthe titres.

Finally, exploratory analysis was also performed on the 95% CI for GMT ratios




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between doses (Post dose 2 over Post dose 1) for all vaccine components in subjectswho seroconverted after Dose 1.

3.13.8 Analysis of safety

For each group, the following results were tabulated, after each vaccine dose:

• the number and percentage of subjects (with exact 95% CIs) with at least onelocal, general, and any adverse event (solicited and/ or unsolicited) aftervaccination and during the 43-day follow-up period;

• the number and percentage of subjects (with exact 95% CIs) reporting each localsolicited symptom, during the 4-day follow-up period (Day 0-3);

• the number and percentage of subjects (with exact 95% CIs) reporting grade 3fever and any fever during the first 15 days after vaccination (Day 0-14);

• the number and percentage of subjects (with exact 95% CIs) reporting eachgeneral solicited symptom during the follow-up period (Day 0-42). Similartabulations were performed for grade 3 general solicited adverse events and forgeneral solicited adverse events with causal relationship to vaccination. Inaddition, the prevalence of fever were also presented graphically by intensityover time;

• the number and percentage of subjects with exact 95% CIs for whom unsolicitedadverse events were reported within 42 days after vaccination (Day 0-42). Theverbatim reports of unsolicited symptoms were reviewed by a physician and thesigns and symptoms were coded according to World Health Organisation (WHO)body system or WHO preferred terms. Similar tabulations were performed forgrade 3 unsolicited adverse events and for unsolicited adverse events with apossibility of having a relationship to vaccination.

• the number and percentage of subjects who received at least one concomitantmedication after vaccination were calculated by group. Additionally, the numberand percentage of subjects who received antipyretic drugs (assumed due to fever)were also calculated by group.

Finally, subjects who experienced at least one SAE during the active phase periodwere reported with their associated Clinical Narratives.

3.14 Changes in the conduct of the study

The protocol planned to exclude subjects who were administered immunoglobulinsand/or any blood products since birth.

Subjects were to have been between 12-18




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months of age at enrolment. Three subjects who were 1 to 5 days younger than 12months were enrolled but have not been eliminated for analyses.

In addition, the protocol also requested that temperature measurements during thefollow-up period after vaccination were to be collected by axillary route. However, ahigher percentage of parents in this study recorded temperature with rectal route(62% versus 37% with axillary route). These subjects were not excluded for theanalysis of safety.

3.15 Changes in planned analyses

The protocol planned to include all subjects in the Total cohort. For statisticalanalyses, the Total cohort included all subjects enrolled and vaccinated (Totalvaccinated cohort). Hence, subjects who did not receive any vaccine dose were notincluded in safety nor immunogenicity analyses. It should be noted that all subjectsenrolled in this study were vaccinated. For the total analysis of safety, it includedsubjects with at least one vaccine administration documented rather than subjectswith safety data available. Doses administered without any documentation of safetydata were considered as doses not followed by any symptoms (see Table 9 forcompliance in documenting safety).

The World Health Organization (WHO) Dictionary was used rather than the MedRA(Medical Dictionary for Regulatory Authorities) for the coding of unsolicitedsymptoms to allow comparison of results to other previous studies with MeMuRu-OKA.

Finally, exploratory analyses were performed for the GMT ratios (i.e. GMT Postdose 2 over GMT Post dose 1) for all vaccine components in subjects whoseroconverted after Dose 1.

4. Study Population

4.1 Study dates

The first subject was enrolled in the study on 16 July 2003 and the last subjectreturned for the concluding visit on 09 January 2004.

See Appendix Table ICi for source data.

4.2 Subject eligibility and attrition from study

4.2.1 Number and distribution of subjects

Enrolment marginally exceeded the protocol-planned 480 subjects as a result of the20% over-randomization (Section 3.6).




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A total of 494 subjects (see Supplement 2) in 45 different study centres in Germanyand Austria were enrolled. One hundred twenty five subjects were allocated to GroupMeMuRu-OKA Lot MJRV159A48, 122 subjects to Group MeMuRu-OKA LotMJRV160A48, 124 subjects to Group MeMuRu-OKA Lot MJRV163A48 and 123subjects to Group Priorix+Varilrix.

4.2.2 Study completion and drop-out

Table 7 summarizes the number of subjects enrolled, who completed the study andwho were withdrawn and reasons for withdrawal from the study.

Table 7: Number of subjects withdrawn from the study and reasons for withdrawal –Total vaccinated cohort

No. of Subjects Reason for withdrawalEnrolled Completed Withdrawn A B C D E F G H

MeMuRu-OKA LotMJRV159A48

125 122 3 0 0 0 1 0 1 1 0


122 120 2 0 0 0 0 0 1 1 0


124 120 4 0 1 0 1 0 2 0 0

MeMuRu-OKAPooled lots

371 362 9 0 1 0 2 0 4 2 0

Priorix+Varilrix 123 122 1 0 0 0 0 1 0 0 0Total 494 484 10 0 1 0 2 1 4 2 0

Enrolled = number of subjects who were enrolled in the studyCompleted = number of subjects who completed last study visitWithdrawn = number of subjects who did not come for the last visitA - Serious Adverse EventB - Non-Serious Adverse EventC - Protocol Violation (not related to any adverse event)D - Consent WithdrawalE - Migration from study areaF - Lost to Follow-up (subject with incomplete vaccination course)G - Lost to Follow-up (subject with complete vaccination course)H - Others (not related to any adverse event)Individual subjects data can be found in Appendix table IEi

From the 494 subjects enrolled in the study, 484 subjects were returned to the studysite for the last visit. These subjects were considered to have completed the study.Ten subjects were not returned for the last study visit. By definition, these 10subjects were considered withdrawn from the study. The following were the reasonsfor withdrawal of subjects as recorded by the investigators/study personnel on theindividual CRFs:

•

The subject had high fever (no exact temperaturevalue was recorded) at Visit 2. The second dose of the vaccine was notadministered during this time. This subject was in good health at the last contactwith the investigator. The investigator indicated "non-serious adverse event" asthe reason for withdrawal from the study for this subject.




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•

The parents withdrew consent to further continue in the studyat Visit 2. A blood sample was taken at that visit, but Dose 2 was notadministered. No adverse events aside from low-grade fever were reported forthis subject following Dose 1.

No safety data was available for thissubject after Dose 1 (no symptom sheets returned to the sponsor).Immunogenicity data was also not available as blood sample from this subjectwas not collected at 42 days after vaccination.

•

This subject only received the firstdose of the vaccine. The child was in good health during the last contact.

•

These subjects were unable to return for the studyconclusion at Visit 3. All of these subjects were in good health at their lastcontact with the investigators.

None of the subjects in the study were withdrawn due to serious adverse events or toprotocol violations.

Refer to source data: Appendix Table IEi Study Conclusion.

4.2.3 Eligibility for analysis

Subjects who were eligible for the Total analysis of immunogenicity had received atleast one dose of the study vaccine and had immunogenicity data available. Allsubjects with at least one dose administered were considered for the analysis ofsafety. See Section 3.13.4 for definitions of study cohorts identified for analyses.

Table 8 presents the number of subjects enrolled, subjects who were eliminated andsubjects who were included for the ATP analyses performed. Subjects may have oneor more elimination code(s) assigned in which case the lowest code number is listedin the Table 8. Codes were given based on a ranking order. The code number listedin this table is presented in the order of ranking (e.g., code 1010 was assignedpreferentially to 1030 when the subject was eligible for elimination on both counts).Appendix Table IA lists all codes attributed to the subjects. Elimination codes(Clintrial Eligibility Codes) are defined at the end of the Supplement Section 10.




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Table 8: Number of subjects enrolled in the study as well as the number of subjectsexcluded from the ATP analyses with reasons for exclusion

MeMuRu-OKA lotTotal % MJRV

159A48MJRV160A48

MJRV163A48

MeMuRu-OKA

Pooled lots

Priorix+

VarilrixNumber of vaccines prepared 840 210 210 210 630 210Subjects or vaccine number notallocated (code 1010 )

346 85 88 86 259 87

Total enrolled cohort 494 - 125 122 124 371 123Total vaccinated cohort 494 100 125 122 124 371 123Administration of vaccine(s)forbidden in the protocol(code 1040 )

2 0 0 1 1 1

Randomisation code broken at theinvestigator site (code 1060 )

1 1 0 0 1 0

Study vaccine dose notadministered according to protocol(code 1070 )

18 3 5 5 13 5

Others (reacto) (code 1500 ) 1 0 0 0 0 1ATP safety cohort 472 95.5 121 117 118 356 116Protocol violation(inclusion/exclusion criteria)(code 2010 )

0(1) 0 (0) 0 (1) 0 (0) 0 (1) 0 (0)

Initially seropositive or initiallyunknown antibody status(code 2020 )

50(51) 12 (12) 13 (14) 17 (17) 42 (43) 8 (8)

Non compliance with bloodsampling schedule ( includingwrong and unknown dates(code 2090 )

1(1) 0 (0) 0 (0) 1 (1) 1 (1) 0 (0)

Essential serological data missing(code 2100 )

2(8) 1 (2) 1 (2) 0 (3) 2 (7) 0 (1)

ATP immunogenicity cohort 419 84.8 108 103 100 311 108% = percentage of subjects in the considered ATP cohort relative to the Total vaccinated cohortSubjects may have more than one elimination code assigned, therefore for each elimination reason n ( x ) is provided, where: n = number of subjects with the elimination code assigned excluding subjects who have been assigned a lower elimination code number. x = number of subjects with the elimination code assignedElimination codes are defined at the end of Supplement Section 10.Individual subjects data can be found in Appendix table IA

All of 494 subjects enrolled in the study were eligible for the Total vaccinated cohort(125 subjects in Group MeMuRu-OKA Lot MJRV159A48, 122 subjects in GroupMeMuRu-OKA Lot MJRV160A48, 124 subjects in Group MeMuRu-OKA LotMJRV163A48 and 123 subjects in Group Priorix + Varilrix.

From the subjects included in the Total vaccinated cohort, 22 were eliminated forATP analysis of safety for the following reasons:

•

•




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• Code 1070 was assigned for 18 subjects for the following reasons:

•

From the 472 subjects included in the analysis of ATP safety cohort, additional 53subjects were eliminated for ATP analysis of immunogenicity. The following werethe reasons for elimination of these subjects:

• Fifty subjects were seropositive (for at least one antigen) or with unknownserological status before Dose 1.

•

• Two subjects had serological data missing (post-dose 1 and post-dose 2 resultsmissing).

4.2.4 Compliance with protocol specified procedures

Table 9 presents the number and percentage of local and general symptom sheetscompleted. The overall compliance in terms of reactogenicity and general symptomsreporting was 99.1% in all groups.




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Table 9: Compliance with respect to documenting safety - Total vaccinated cohort

DosesNumber NOT* Number Compliance Number Compliance

of according of % of %Group Doses to protocol general SS general local SS LocalDose 1MeMuRu-OKA Lot MJRV159A48 125 4 125 100 125 100MeMuRu-OKA Lot MJRV160A48 122 2 122 100 122 100MeMuRu-OKA Lot MJRV163A48 124 1 120 96.8 120 96.8MeMuRu-OKA (pooled lots) 371 7 367 98.9 367 98.9Priorix+Varilrix 123 5 123 100 123 100Dose 2MeMuRu-OKA Lot MJRV159A48 123 3 123 100 123 100MeMuRu-OKA Lot MJRV160A48 121 5 120 99.2 120 99.2MeMuRu-OKA Lot MJRV163A48 120 4 119 99.2 119 99.2MeMuRu-OKA (pooled lots) 364 12 362 99.5 362 99.5Priorix+Varilrix 122 4 119 97.5 119 97.5TotalMeMuRu-OKA Lot MJRV159A48 248 7 248 100 248 100MeMuRu-OKA Lot MJRV160A48 243 7 242 99.6 242 99.6MeMuRu-OKA Lot MJRV163A48 244 5 239 98.0 239 98.0MeMuRu-OKA (pooled lots) 735 19 729 99.2 729 99.2Priorix+Varilrix 245 9 242 98.8 242 98.8* The number of doses not given according to protocol was based on the question in the vaccine administration sheet of the eCRF:"Has the study vaccine been administered according to protocol?"SS = Symptom sheetCompliance % = (number of SS / number of doses) * 100

4.3 Demographic characteristics

Table 10 presents the demographic characteristics of subjects included in the Totalvaccinated cohort in terms of age, gender and race.

Demographic characteristics of subjects included in the ATP immunogenicity andsafety cohorts are presented in Supplement 3 and Supplement 4, respectively.




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Table 10: Summary of demographic characteristics – Total vaccinated cohort

MeMuRu-OKAMJRV159A48 MJRV160A48 MJRV163A48

N= 125 N= 122 N= 124

Priorix+VarilrixN= 123

TotalN= 494Characteristics

ParametersorCategories Value

or n % Valueor n % Value


or n %

Age(M) Mean 14.1 - 14.4 - 14.5 - 14.5 - 14.4 -SD 2.10 - 2.26 - 2.35 - 2.44 - 2.30 -Median 14 - 14 - 14 - 14 - 14 -Minimum* 11 - 11 - 12 - 12 - 11 -Maximum 21 - 23 - 23 - 23 - 23 -

Gender Female 55 44.0 59 48.4 61 49.2 61 49.6 236 47.8Male 70 56.0 63 51.6 63 50.8 62 50.4 258 52.2

Race Black 1 0.8 1 0.8 2 1.6 1 0.8 5 1.0White 121 96.8 114 93.4 121 97.6 120 97.6 476 96.4Oriental 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0Arabic/NA 0 0.0 3 2.5 0 0.0 1 0.8 4 0.8East & SEA 0 0.0 2 1.6 1 0.8 1 0.8 4 0.8Other 3 2.4 2 1.6 0 0.0 0 0.0 5 1.0

N = total number of subjectsn = number of subjects in a given categoryValue = value of the considered parameter% = n / Number of subjects with available results x 100SD= standard deviationAge(M)= age expressed in monthsNA = North African; SEA = South East AsianIndividual subjects data can be found in Appendix table IB

5. Analysis of immunogenicity

Individual immunogenicity data can be found in Appendix Table IIIA.

5.1 Data sets analysed

Since more than 5% of subjects enrolled were excluded from the ATPimmunogenicity cohort, a secondary analysis was performed on the Total vaccinatedcohort. Since the results of the analysis from the Total vaccinated cohort wereconsistent with the results obtained from the ATP immunogenicity cohort, only theATP immunogenicity cohort will be presented in this report.

Subjects who were initially seropositive or for whom the pre-vaccination status wasunknown for at least one antigen were eliminated from the ATP immunogenicitycohort. Therefore, all subjects in ATP immunogenicity cohort were initiallyseronegative for all antigens. However, in order to show the number of subjects whowere initially seropositive and those with unknown serological status beforevaccination, Total vaccinated cohort is used to present initial serological status ofsubjects.




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5.2 Consistency between MeMuRu-OKA lots

5.2.1 Pre-vaccination serological status

Table 11 summarises the serological status of subjects in MeMuRu-OKA groupsbefore the first vaccine dose was given.

Table 11: Initial serological status of subjects in MeMuRu-OKA groups – TotalVaccinated Cohort

Group MeMuRu-OKAN = 371

Lot MJRV159A48N=125

Lot MJRV160A48N=122

Lot MJRV163A48N=124

AntibodyInitial

serologicalstatus before

Dose 1n % n % n %

Measles S- 121 97.6 119 98.3 118 97.5S+ 3 2.4 2 1.7 3 2.5Unknown 1 - 1 - 3 -

Mumps S- 121 97.6 119 98.3 119 98.3S+ 3 2.4 2 1.7 2 1.7Unknown 1 - 1 - 3 -

Rubella S- 121 97.6 118 97.5 119 98.3S+ 3 2.4 3 2.5 2 1.7Unknown 1 - 1 - 3 -

Varicella S- 114 93.4 110 90.9 109 92.4S+ 8 6.6 11 9.1 9 7.6Unknown 3 - 1 - 6 -

S- = seronegative subjects at pre-vaccination.S+ = seropositive subjects at pre-vaccination.N = number of subjects in a group who were S-, S+ and those with unknown serological status before Dose 1.n = number of subjects with the considered pre-vaccination serological status.% = proportion of subjects who were seronegative or seropositive before Dose 1.Cut-off values: measles: 150 mIU/ml, mumps: 231 U/ml, rubella: 4 IU/ml, varicella: 4 [dilution-1]Individual subjects data can be found in Appendix table IIIA

For subjects included in the Total vaccinated cohort, 8, 7, 8 and 28 of subjects inMeMuRu-OKA groups were initially seropositive for antibodies to measles, mumps,rubella or varicella, respectively.

5.2.2 Seroconversion rates and GMTs - MeMuRu-OKA lots

Table 12 presents the seroconversion rates and GMTs for measles, mumps, rubellaand varicella for subjects in MeMuRu-OKA groups.




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Table 12: Seroconversion rates and GMTs for all antigens in MeMuRu-OKA groupsfor initially seronegative subjects – ATP immunogenicity cohort

Seroconversion/seropositivity GMTs

95% CI 95% CIGroup

MeMuRu-OKAlot

Timepoint N n % LL UL Value LL UL MIN MAX

Measles (150 mIU/ml)MJRV159A48 PRE 108 0 0.0 0.0 3.4 75.0 75.0 75.0 <150.0 <150.0

PI(D42) 106 103 97.2 92.0 99.4 3848.7 3199.6 4629.6 <150.0 13758.0PII(D84) 106 106 100 96.6 100 5840.4 5138.4 6638.3 550.0 14899.0

MJRV160A48 PRE 103 0 0.0 0.0 3.5 75.0 75.0 75.0 <150.0 <150.0PI(D42) 100 99 99.0 94.6 100 4605.8 3979.2 5331.1 <150.0 15856.0PII(D84) 102 102 100 96.4 100 6872.4 6047.6 7809.7 965.0 26481.0

MJRV163A48 PRE 100 0 0.0 0.0 3.6 75.0 75.0 75.0 <150.0 <150.0PI(D42) 100 97 97.0 91.5 99.4 3713.6 3054.5 4514.9 <150.0 11796.0PII(D84) 99 99 100 96.3 100 5663.1 4842.1 6623.3 225.0 25097.0PRE 311 0 0.0 0.0 1.2 75.0 75.0 75.0 <150.0 <150.0PI(D42) 306 299 97.7 95.3 99.1 4034.0 3644.0 4465.6 <150.0 15856.0


PII(D84) 307 307 100 98.8 100 6103.9 5639.6 6606.4 225.0 26481.0Mumps (231 U/ml)

MJRV159A48 PRE 108 0 0.0 0.0 3.4 115.5 115.5 115.5 <231.0 <231.0PI(D42) 105 96 91.4 84.4 96.0 968.2 799.8 1172.0 <231.0 12832.0PII(D84) 106 106 100 96.6 100 1525.3 1346.3 1728.0 333.0 10237.0

MJRV160A48 PRE 103 0 0.0 0.0 3.5 115.5 115.5 115.5 <231.0 <231.0PI(D42) 98 84 85.7 77.2 92.0 832.1 679.7 1018.6 <231.0 10085.0PII(D84) 102 97 95.1 88.9 98.4 1398.5 1178.6 1659.4 <231.0 20159.0

MJRV163A48 PRE 100 0 0.0 0.0 3.6 115.5 115.5 115.5 <231.0 <231.0PI(D42) 99 92 92.9 86.0 97.1 953.0 788.4 1152.0 <231.0 15123.0PII(D84) 99 98 99.0 94.5 100 1473.2 1258.8 1724.1 <231.0 13449.0PRE 311 0 0.0 0.0 1.2 115.5 115.5 115.5 <231.0 <231.0PI(D42) 302 272 90.1 86.1 93.2 917.0 820.5 1024.8 <231.0 15123.0


PII(D84) 307 301 98.0 95.8 99.3 1465.4 1343.8 1598.0 <231.0 20159.0Rubella (4 IU/mL)

MJRV159A48 PRE 108 0 0.0 0.0 3.4 2.0 2.0 2.0 <4.0 <4.0PI(D42) 106 103 97.2 92.0 99.4 56.6 46.5 68.8 <4.0 270.0PII(D84) 106 106 100 96.6 100 98.3 87.3 110.6 17.0 297.0

MJRV160A48 PRE 103 0 0.0 0.0 3.5 2.0 2.0 2.0 <4.0 <4.0PI(D42) 100 100 100 96.4 100 62.1 52.7 73.3 6.0 383.0PII(D84) 102 102 100 96.4 100 104.8 91.4 120.1 5.0 351.0

MJRV163A48 PRE 100 0 0.0 0.0 3.6 2.0 2.0 2.0 <4.0 <4.0PI(D42) 100 100 100 96.4 100 56.9 48.5 66.8 6.0 311.0PII(D84) 99 99 100 96.3 100 101.7 91.1 113.5 18.0 371.0PRE 311 0 0.0 0.0 1.2 2.0 2.0 2.0 <4.0 <4.0PI(D42) 306 303 99.0 97.2 99.8 58.5 52.9 64.6 <4.0 383.0


PII(D84) 307 307 100 98.8 100 101.5 94.6 108.8 5.0 371.0(continued)




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Table 12: Seroconversion rates and GMTs for all antigens in MeMuRu-OKA groupsfor initially seronegative subjects – ATP immunogenicity cohort (cont)

Seroconversion/seropositivity GMT

95% CI 95% CI

GroupMeMuRu-OKA

lotTimepoint N

n % LL UL Value LL UL

MIN MAX

Varicella (4 [dilution-1])MJRV159A48 PRE 108 0 0.0 0.0 3.4 2.0 2.0 2.0 <4.0 <4.0

PI(D42) 105 104 99.0 94.8 100 194.0 152.1 247.5 <4.0 2048.0PII(D84) 106 106 100 96.6 100 5082.5 3903.1 6618.2 8.0 65536.0

MJRV160A48 PRE 103 0 0.0 0.0 3.5 2.0 2.0 2.0 <4.0 <4.0PI(D42) 99 99 100 96.3 100 233.7 181.3 301.4 8.0 16384.0PII(D84) 102 102 100 96.4 100 5449.0 3988.2 7444.8 8.0 131072.0

MJRV163A48 PRE 100 0 0.0 0.0 3.6 2.0 2.0 2.0 <4.0 <4.0PI(D42) 100 100 100 96.4 100 224.4 183.7 274.1 8.0 2048.0PII(D84) 98 98 100 96.3 100 4303.9 3383.9 5474.0 32.0 32768.0PRE 311 0 0.0 0.0 1.2 2.0 2.0 2.0 <4.0 <4.0PI(D42) 304 303 99.7 98.2 100 216.3 189.1 247.2 <4.0 16384.0


PII(D84) 306 306 100 98.8 100 4932.1 4215.1 5771.0 8.0 131072.0N = number of subjects with available resultsn/% = number/percentage of subjects with titre within the specified rangeGMT = geometric mean titre calculated on all subjects with an arbitrary value of half the cut-off for seronegative titres95% CI = 95% confidence interval; LL = Lower Limit; UL = Upper LimitMIN/MAX = Minimum/MaximumPRE = Pre-vaccination time point at Day 0PI(D42)= Post-vaccination time point at Day 42PII(D84) = Post-vaccination time point at Day 84Cut-off values: measles: 150 mIU/ml, mumps: 231 U/ml, rubella: 4 IU/ml, varicella: 4 [dilution-1]Individual subject data can be found in Appendix table IIIA

After the first dose, the seroconversion rates were 97.2%, 99.0%, 97.0% for measles,91.4%, 85.7%, 92.9% for mumps, 97.2%, 100%, 100% for rubella and 99.0%, 100%,100% for varicella for the three respective MeMuRu-OKA lots. The observed GMTsin MeMuRu-OKA groups 42 days after the first dose ranged from 3713.6 to 4605.8mIU/mL for measles, 832.1 to 968.2 U/mL for mumps, 56.6 to 62.1 IU/mL forrubella and 194.0 to 233.7 dil-1 for varicella.

After the second dose, all subjects seroconverted for measles, rubella and varicellafor the three MeMuRu-OKA lots. The mumps seroconversion rates were 100%,95.1% and 99.0% for the three respective lots of MeMuRu-OKA. The observedGMTs in MeMuRu-OKA groups 42 days after the second dose ranged from 5663.1to 6872.4 mIU/mL for measles, 1398.5 to 1525.3 U/mL for mumps, 98.3 to 104.8IU/mL for rubella and 4303.9 to 5449.0 dil-1 for varicella.

For subjects included in the ATP immunogenicity cohort, the distribution ofantibody titres and the Reverse Cumulative Curve (RCC) are presented respectivelyin Supplement 6 and Supplement 7 for measles, Supplement 8 and Supplement 9 formumps, Supplement 10 and Supplement 11 for rubella, and Supplement 12 andSupplement 13 for varicella.




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5.2.3 Lot-to-lot consistency evaluation

Table 13 presents the differences in seroconversion rates for all antigens betweenMeMuRu-OKA lots after the second dose.

Table 13: Measles, mumps, rubella and varicella seroconversion rate differencebetween MeMuRu-OKA lots at 42 days after the second dose – ATP

immunogenicity cohort

90% CIMeMuRu-OKA

lot N SC %MeMuRu-OKA

lot N SC %

SC difference betweenMeMuRu-OKA vaccine

lotValue

% LL ULmeasles

MJRV159A48 106 100 MJRV160A48 102 100 MJRV160A48 - MJRV159A48 0.0 -2.6 2.5MJRV159A48 106 100 MJRV163A48 99 100 MJRV163A48 - MJRV159A48 0.0 -2.7 2.5MJRV160A48 102 100 MJRV163A48 99 100 MJRV163A48 - MJRV160A48 0.0 -2.7 2.6

mumpsMJRV159A48 106 100 MJRV160A48 102 95.1 MJRV160A48 - MJRV159A48 -4.9 -9.7 -2.4MJRV159A48 106 100 MJRV163A48 99 99.0 MJRV163A48 - MJRV159A48 -1.0 -4.4 1.5MJRV160A48 102 95.1 MJRV163A48 99 99.0 MJRV163A48 - MJRV160A48 3.9 -0.1 8.8

rubellaMJRV159A48 106 100 MJRV160A48 102 100 MJRV160A48 - MJRV159A48 0.0 -2.6 2.5MJRV159A48 106 100 MJRV163A48 99 100 MJRV163A48 - MJRV159A48 0.0 -2.7 2.5MJRV160A48 102 100 MJRV163A48 99 100 MJRV163A48 - MJRV160A48 0.0 -2.7 2.6

varicellaMJRV159A48 106 100 MJRV160A48 102 100 MJRV160A48 - MJRV159A48 0.0 -2.6 2.5MJRV159A48 106 100 MJRV163A48 98 100 MJRV163A48 - MJRV159A48 0.0 -2.7 2.5MJRV160A48 102 100 MJRV163A48 98 100 MJRV163A48 - MJRV160A48 0.0 -2.7 2.6

N = number of subjects with available resultsSC (%) = Seroconversion rate (percentage of initially seronegative subjects before Dose 1 with titre ≥ assay cut-off)CI = Standardized asymptotic confidence interval LL/UL =lower/upper limit of CIAssay cut-off values: measles: 150 mIU/ml, mumps: 231 U/ml, rubella: 4 IU/ml, varicella: 4 [dilution-1]Lot-to-lot consistency criteria = 90% CI of SC rate difference between lot was within [-10%, +10%]Individual subject data can be found in Appendix table IIIA

For all antigens and each pair wise comparison, the 90% CIs for the difference inseroconversion rates between MeMuRu-OKA lots were within [-10%, +10%],thereby demonstrating the consistency between the three MeMuRu-OKA lots (Table13).

Exploratory analysis on GMT ratios between MeMuRu-OKA lots after the seconddose was performed as part of the study's secondary objectives. Table 14 presents theGMT ratios between MeMuRu-OKA lots for all antigens.




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Table 14: GMT ratios between MeMuRu-OKA lots after the second dose in initiallyseronegative subjects before Dose 1– ATP immunogenicity cohort

Value 90% CIMeMuRu-OKAvaccine lot N GMT

MeMuRu-OKAvaccine lot N GMT

GMT ratio betweenMeMuRu-OKA lots % LL UL

measlesMJRV159A48 106 5840.4 MJRV160A48 102 6872.4 MJRV159A48 over MJRV160A48 0.85 0.72 1.00MJRV159A48 106 5840.4 MJRV163A48 99 5663.1 MJRV159A48 over MJRV163A48 1.03 0.88 1.21MJRV160A48 102 6872.4 MJRV163A48 99 5663.1 MJRV160A48 over MJRV163A48 1.21 1.03 1.43

mumpsMJRV159A48 106 1525.3 MJRV160A48 102 1398.5 MJRV159A48 over MJRV160A48 1.09 0.91 1.30MJRV159A48 106 1525.3 MJRV163A48 99 1473.2 MJRV159A48 over MJRV163A48 1.04 0.87 1.24MJRV160A48 102 1398.5 MJRV163A48 99 1473.2 MJRV160A48 over MJRV163A48 0.95 0.79 1.14

rubellaMJRV159A48 106 98.3 MJRV160A48 102 104.8 MJRV159A48 over MJRV160A48 0.94 0.81 1.08MJRV159A48 106 98.3 MJRV163A48 99 101.7 MJRV159A48 over MJRV163A48 0.97 0.84 1.12MJRV160A48 102 104.8 MJRV163A48 99 101.7 MJRV160A48 over MJRV163A48 1.03 0.89 1.19

varicellaMJRV159A48 106 5082.5 MJRV160A48 102 5449.0 MJRV159A48 over MJRV160A48 0.93 0.68 1.28MJRV159A48 106 5082.5 MJRV163A48 98 4303.9 MJRV159A48 over MJRV163A48 1.18 0.85 1.63MJRV160A48 102 5449.0 MJRV163A48 98 4303.9 MJRV160A48 over MJRV163A48 1.27 0.91 1.75

N: Number of subjects with available resultsCI = confidence interval LL/UL =lower/upper limit of CI (ANOVA model - pooled variance with more than 2 groups)Assay cut-off values: measles: 150 mIU/ml, mumps: 231 U/ml, rubella: 4 IU/ml, varicella: 4 [dilution-1]Individual subjects data can be found in Appendix table IIIA

5.3 Non-inferiority of MeMuRu-OKA candidate vaccine

5.3.1 Pre-vaccination serological status

Table 15 summarizes the initial serological status of subjects in the Total vaccinatedcohort before Dose 1.




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Table 15: Initial serological status of subjects in Group MeMuRu-OKA (pooled lots)and Group Priorix+Varilrix – Total Vaccinated Cohort

GroupMeMuRu-OKA(pooled lots)

(N = 371)

GroupPriorix + Varilrix

(N = 123)Total

(N = 494)Antibody

Initialserologicalstatus beforeDose 1 n % n % n %

Measles S- 358 97.8 122 100 480 98.4S+ 8 2.2 0 0.0 8 1.6Unknown 5 - 1 - 6 -

Mumps S- 359 98.1 121 99.2 480 98.4S+ 7 1.9 1 0.8 8 1.6Unknown 5 - 1 - 6 -

Rubella S- 358 97.8 122 100 480 98.4S+ 8 2.2 0 0.0 8 1.6Unknown 5 - 1 - 6 -

Varicella S- 333 92.2 115 95.8 448 93.1S+ 28 7.8 5 4.2 33 6.9Unknown 10 - 3 - 13 -

S- = seronegative subjects at pre-vaccination.S+ = seropositive subjects at pre-vaccination.N = number of subjects in a group regardless of whether the result is or not available (i.e. including subjects withunknown initially serological status).n = Number of subjects with the considered pre-vaccination serological status.% = Proportion of subjects who were seronegative or seropositive before Dose 1.Cut-off values: measles: 150 mIU/ml, mumps: 231 U/ml, rubella: 4 IU/ml, varicella: 4 [dilution-1]Individual subjects data can be found in Appendix table IIIA

In the control group, no subject was initially seropositive to measles and rubellaantibodies but one and five subjects were initially seropositive for mumps andvaricella antibodies, respectively. Very few subjects had unknown serological statusbefore the first vaccine dose. In Group MeMuRu-OKA pooled lots, around 2% ofsubjects were initially seropositive for measles, mumps and rubella and 7.8% ofsubjects were initially seropositive for varicella antibodies before the first vaccinedose.

5.3.2 Seroconversion rates and GMTs between vaccine groups

Table 16 presents the seroconversion rates and GMTs for measles, mumps, rubellaand varicella between Group MeMuRu-OKA pooled lots and GroupPriorix+Varilrix.




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Table 16: Seroconversion rates and GMTs for all antigens in Group MeMuRu-OKApooled lots and Group Priorix+Varilrix in initially seronegative subjects – ATP

immunogenicity cohort

N Seroconversion/seropositivity GMT MIN MAX

95% CI Value 95% CIGroup Timepoint

n % LL UL LL ULMeasles (150 mIU/ml)

PRE 311 0 0.0 0.0 1.2 75.0 75.0 75.0 <150.0 <150.0PI(D42) 306 299 97.7 95.3 99.1 4034.0 3644.0 4465.6 <150.0 15856.0


PII(D84) 307 307 100 98.8 100 6103.9 5639.6 6606.4 225.0 26481.0PRE 108 0 0.0 0.0 3.4 75.0 75.0 75.0 <150.0 <150.0PI(D42) 106 106 100 96.6 100 2567.3 2143.6 3074.7 215.0 13879.0

Priorix+Varilrix

PII(D84) 108 108 100 96.6 100 3719.2 3183.7 4344.7 324.0 31826.0Mumps (231 U/ml)

PRE 311 0 0.0 0.0 1.2 115.5 115.5 115.5 <231.0 <231.0PI(D42) 302 272 90.1 86.1 93.2 917.0 820.5 1024.8 <231.0 15123.0


PII(D84) 307 301 98.0 95.8 99.3 1465.4 1343.8 1598.0 <231.0 20159.0PRE 108 0 0.0 0.0 3.4 115.5 115.5 115.5 <231.0 <231.0PI(D42) 106 101 95.3 89.3 98.5 993.2 848.0 1163.2 <231.0 4175.0

Priorix+Varilrix

PII(D84) 108 107 99.1 94.9 100 1667.8 1441.7 1929.3 <231.0 10142.0Rubella (4 IU/ml)

PRE 311 0 0.0 0.0 1.2 2.0 2.0 2.0 <4.0 <4.0PI(D42) 306 303 99.0 97.2 99.8 58.5 52.9 64.6 <4.0 383.0


PII(D84) 307 307 100 98.8 100 101.5 94.6 108.8 5.0 371.0PRE 108 0 0.0 0.0 3.4 2.0 2.0 2.0 <4.0 <4.0PI(D42) 106 106 100 96.6 100 69.0 59.4 80.3 6.0 416.0

Priorix+Varilrix

PII(D84) 108 108 100 96.6 100 107.0 95.3 120.2 21.0 341.0Varicella (4 [dilution-1])

PRE 311 0 0.0 0.0 1.2 2.0 2.0 2.0 <4.0 <4.0PI(D42) 304 303 99.7 98.2 100 216.3 189.1 247.2 <4.0 16384.0


PII(D84) 306 306 100 98.8 100 4932.1 4215.1 5771.0 8.0 131072.0PRE 108 0 0.0 0.0 3.4 2.0 2.0 2.0 <4.0 <4.0PI(D42) 106 106 100 96.6 100 216.0 177.7 262.4 8.0 1024.0

Priorix+Varilrix

PII(D84) 108 108 100 96.6 100 155.2 126.4 190.5 8.0 4096.0N = number of subjects with available resultsn/% = number/percentage of subjects with titre within the specified rangeGMT = geometric mean titre calculated on all subjects with an arbitrary value of half the cut-off for seronegative titres95% CI = 95% confidence interval; LL = Lower Limit; UL = Upper LimitMIN/MAX = Minimum/MaximumPRE = Pre-vaccination time point at Day 0PI(D42)= Post-vaccination time point at Day 42PII(D84) = Post-vaccination time point at Day 84Individual subject data can be found in Appendix table IIIA

After the first dose, the observed seroconversion rates in Group MeMuRu-OKApooled lots were 97.7%, 90.1%, 99.0% and 99.7% for measles, mumps, rubella andvaricella, respectively. In the control Group Priorix+Varilrix, all subjectsseroconverted for measles, rubella and varicella and 95.3% of subjects in this groupseroconverted for the mumps component. The observed GMTs in Group MeMuRu-OKA pooled lots 42 days after the first dose were 4034.0 mIU/mL, 917.0 U/mL, 58.5IU/mL and 216.3 dil-1 for measles, mumps, rubella and varicella, respectively. Theobserved GMTs in Group Priorix+Varilrix 42 days after the first dose were 2567.3mIU/mL, 993.2 U/mL, 69.0 IU/mL and 216.0 dil-1 for measles, mumps, rubella and




Page 54

varicella, respectively (Table 16).

After the second dose, all subjects in both the MeMuRu-OKA pooled lots andPriorix+Varilrix groups seroconverted for measles and rubella. For the mumpscomponent of the vaccine, the seroconversion rate was 98.0% in Group MeMuRu-OKA pooled lots and 99.1% in Group Priorix+Varilrix. All subjects in GroupMeMuRu-OKA pooled lots seroconverted for varicella after the second dose. Theobserved GMTs in Group MeMuRu-OKA pooled lots 42 days after the second dosewere 6103.9 mIU/mL, 1465.4 U/mL, 101.5 IU/mL and 4932.1 dil-1 for measles,mumps, rubella and varicella, respectively. The observed GMTs in GroupPriorix+Varilrix 42 days after the second dose were 3719.2 mIU/mL, 1667.8 U/mL,and 107.0 IU/mL for measles, mumps and rubella, respectively. It should be notedthat for subjects in Group Priorix+Varilrix who received only one dose of Varilrix atDay 0, all subjects who seroconverted for varicella at 42 days after the first doseremained seropositive after 84 days. The varicella GMTs observed in this group was155.2 dil-1 84 days after a single dose (Table 16).

For subjects included in the ATP immunogenicity cohort, the distribution ofantibody titres and the Reverse Cumulative Curve (RCC) are presented respectivelyin Supplement 6 and Supplement 7 for measles, Supplement 8 and Supplement 9 formumps, Supplement 10 and Supplement 11 for rubella, and Supplement 12 andSupplement 13 for varicella.

5.3.3 Non-inferiority evaluation of MeMuRu-OKA vaccine

Table 17 presents the difference in seroconversion rats between Group MeMuRu-OKA and Group Priorix+Varilrix after the second dose.




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Table 17: Seroconversion rate difference between Group MeMuRu-OKA and GroupPriorix+Varilrix after the second dose – ATP immunogenicity cohort

Difference in SC rateMeMuRu-OKA (pooled lots)

minusPriorix+Varilrix

Priorix+VarilrixMeMuRu-OKA(pooled lots) 95% CI

N SC (%) N SC (%) Value (%) LL ULNon-

inferiorityAnti-measles 108 100 307 100 0.0 -1.2 3.4 *Anti-mumps 108 99.1 307 98.0 -1.0 -3.5 3.2 *Anti-rubella 108 100 307 100 0.0 -1.2 3.4 *Anti-varicella 108 100 306 100 0.0 -1.2 3.4 *N = number of subjects with available resultsSC = seroconversion (subjects with titre ≥ cut-off)% = percentage of subjects with titre for anti-measles ≥ 150 mIU/mL, anti-mumps ≥ 231 U/mL, anti-rubella ≥ 4 IU/mL and anti-varicella ≥ 4 dilution-1

CI = Standardized asymptotic confidence intervalLL/UL = lower/upper limit of 95% CIAn asterix (*) indicates non-inferiority of MeMuRu-OKA versus Priorix+Varilrix based on endpoints (the non-inferiority criterion isachieved when the LL of 95% CI is ≥ -10%)Individual subjects data can be found in Appendix table IIIA

For each antigen, the lower limit of the 95% CI of the difference in seroconversionrate was above the pre-defined limit for non-inferiority of -10%, thereby reaching theco-primary objective of the study.

Exploratory analyses:

For all antigens, exploratory analyses were performed for the GMT ratios betweengroups after the second dose and the difference in seroconversion rates as well as theGMT ratios between groups after the first dose. No pre-defined criteria were plannedin this study for these comparisons.

Table 18 presents the GMT ratios for all antigens between Group MeMuRu-OKApooled lots and Group Priorix+Varilrix after the second dose.




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Table 18: GMT ratios between MeMuRu-OKA pooled lots and Priorix + Varilrixafter the second dose in subjects who were initially seronegative before Dose 1 -

ATP immunogenicity cohort

GMT ratio

MeMuRu-OKA(pooled lots) Priorix+Varilrix

MeMuRu-OKA (pooled lots)over

Priorix+VarilrixN GMT N GMT value 95% CI

LL ULAnti-measles 307 6103.9 108 3719.2 1.64 1.40 1.93Anti-mumps 307 1465.4 108 1667.8 0.88 0.74 1.04Anti-rubella 307 101.5 108 107.0 0.95 0.83 1.09Anti-varicella 306 4932.1 108 155.2 31.78 23.77 42.50N: Number of subjects with available results95% CI LL, UL: 95% lower and upper confidence interval limits (ANOVA model )Individual subjects data can be found in Appendix table IIIA

The GMT ratios (MeMuRu-OKA pooled lots over Priorix+Varilrix) for measles,mumps and rubella after the second dose were 1.64, 0.88 and 0.95, respectively(Table 18).

For the varicella component at Day 84 time point, the GMT for subjects in GroupMeMuRu-OKA pooled lots was 4932.1 dil-1 after two doses of MeMuRu-OKA and155.2 dil-1 for subjects in Group Priorix+Varilrix after one dose of Varilrix. TheGMT ratio between Group MeMuRu-OKA pooled lots and Group Priorix+Varilrixwas 31.78 (Table 18).

Table 19 presents the difference in seroconversion rates between Group MeMuRu-OKA pooled lots and Group Priorix+Varilrix after the first dose.

Table 19: Seroconversion rate difference between Group MeMuRu-OKA and GroupPriorix+Varilrix after the first dose – ATP immunogenicity cohort

Difference in SC rateMeMuRu-OKA (pooled lots)

minusPriorix+Varilrix

Priorix+VarilrixMeMuRu-OKA(pooled lots) 95% CI

N SC (%) N SC (%) Value (%) LL ULAnti-measles 106 100 306 97.7 -2.3 -4.6 1.2Anti-mumps 106 95.3 302 90.1 -5.2 -10.1 1.2Anti-rubella 106 100 306 99.0 -1.0 -2.8 2.5Anti-varicella 106 100 304 99.7 -0.3 -1.8 3.2N = number of subjects with available resultsSC = seroconversion (subjects with titre ≥ cut-off)% = percentage of subjects with titre for anti-measles ≥ 150 mIU/mL, anti-mumps ≥ 231 U/mL, anti-rubella ≥ 4 IU/mLand anti-varicella ≥ 4 dilution-1

CI = Standardized asymptotic confidence intervalLL/UL = lower/upper limit of 95% CIIndividual subjects data can be found in Appendix table IIIA

At Day 42 after the first dose in this study, no evidence of differences in




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seroconversion rates between groups was observed, since the 95% CIs around thedifference in seroconversion rates for all antigens included the value of 0 (Table 19).

Table 20: GMT ratios between MeMuRu-OKA pooled lots and Priorix+Varilrixafter the first dose in subjects who were initially seronegative before vaccination -

ATP immunogenicity cohort

GMT ratio


MeMuRu-OKA (pooled lots)over

Priorix+VarilrixN GMT N GMT value 95% CI

LL ULAnti-measles 306 4034.0 106 2567.3 1.57 1.28 1.92Anti-mumps 302 917.0 106 993.2 0.92 0.75 1.14Anti-rubella 306 58.5 106 69.0 0.85 0.70 1.03Anti-varicella 304 216.3 106 216.0 1.00 0.78 1.29N: Number of subjects with available results95% CI LL, UL: 95% lower and upper confidence interval limits (ANOVA model )Individual subjects data can be found in Appendix table IIIA

The GMT ratios (MeMuRu-OKA pooled lots over Priorix+Varilrix) for measles,mumps, rubella and varicella after the first dose were 1.57, 0.92, 0.85 and 1.00,respectively (Table 20).

Exploratory analysis was also performed on the GMT ratios (GMT post-dose 2 overGMT post-dose 1) for all antigens in subjects who seroconverted after dose 1 (seeTable 21).




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Table 21: GMT ratio of post-dose 2 over post-dose 1 titer in subjects whoseroconverted after dose 1 for each antigens - ATP immunogenicity cohort

Antibody Group NDose 2 GMT

overDose 1 GMT

Value 95% CILL UL

MEASLES MeMuRu-OKA pooled lots 295 1.4 1.4 1.5Priorix+Varilrix 106 1.4 1.3 1.6

MUMPS MeMuRu-OKA pooled lots 269 1.4 1.3 1.5Priorix+Varilrix 101 1.6 1.4 1.9

RUBELLA MeMuRu-OKA pooled lots 299 1.7 1.5 1.8Priorix+Varilrix 106 1.5 1.4 1.7

VARICELLA MeMuRu-OKA pooled lots 298 23.2 19.8 27.2Priorix+Varilrix 106 0.7 0.6 0.8

N: Number of subjects with available results95% CI LL, UL: 95% lower and upper confidence interval limitsIndividual subjects data can be found in Appendix table IIIA

In both vaccine groups, the measles, mumps and rubella GMTs increased after twodoses as shown by the GMT ratios (range: 1.4 to 1.7). For varicella, 2 doses ofMeMuRu-OKA significantly increased the observed GMTs by approximately 23times (Table 21).

6. Analysis of safety

Data concerning solicited and unsolicited signs and symptoms following eachvaccination were documented on symptom sheets by the investigator. Symptomsheets are the specific pages in the individual CRFs onto which the investigatortranscribed diary card documentation and any other symptom(s) reported for thesubject.

Local injection site symptoms (pain, redness and swelling) were solicited during the4-day (Days 0 to 3) follow-up period after each vaccination. Evidence of fever, rash(local and generalized), parotid/salivary gland swelling and signs of meningism weresolicited during the 43-day (Days 0 to 42) follow-up period after each vaccination.Any unsolicited symptoms and serious adverse event occurring within 43 days aftereach vaccination were also recorded.

Individual subject data regarding the occurrence and severity of solicited local andgeneral symptoms and unsolicited symptoms after each vaccination are presented inAppendix Tables II A-C.

Safety results between groups (i.e. Group MeMuRu-OKA pooled lots and GroupPriorix+Varilrix) are presented in this section of the core report while the results ofsafety (i.e. solicited and unsolicited symptoms) between MeMuRu-OKA lots arepresented in the Supplement section.




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6.1 Overall incidence of symptoms

Table 22 summarizes the incidence of both solicited (local and general) andunsolicited adverse events reported over the 43-day follow-up (Day 0-42) after eachvaccination.

Table 22: Incidence and nature of (solicited and unsolicited) symptoms reportedduring the 43 days of follow-up after each dose – Total vaccinated cohort

Any symptoms General symptoms Local symptomsGroup N n % 95% CI N n % 95% CI N n % 95% CI

LL UL LL UL LL ULPost-Dose 1

MeMuRU-OKA(pooled lots)

371 312 84.1 80.0 87.7 371 293 79.0 74.5 83.0 371 135 36.4 31.5 41.5

Priorix+Varilrix 123 90 73.2 64.4 80.8 123 82 66.7 57.6 74.9 123 33 26.8 19.2 35.6Post-Dose 2

MeMuRU-OKA(pooled lots)

364 286 78.6 74.0 82.7 364 257 70.6 65.6 75.2 364 142 39.0 34.0 44.2

Priorix+Varilrix 122 89 73.0 64.2 80.6 122 78 63.9 54.7 72.4 122 28 23.0 15.8 31.4Any symptoms = included solicited (general/local symptoms) or unsolicited symptomsGeneral symptoms = fever, rash, any signs of meningism including febrile convulsions, parotid salivary gland swellingLocal symptoms: pain, redness and swelling at injection sitesN = number of subjects having received the considered dosen/% = number/percentage of subjects reporting at least one type of symptom during the 43 days of follow-up (Day 0-42) for the considered dose95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit

The percentage of subjects reporting at least one solicited (local/general) orunsolicited symptom (referred to "Any symptom" in Table 22) was 84.1% in GroupMeMuRu-OKA pooled lots and 73.2% in Group Priorix+Varilrix after the first dose,and 78.6% and 73.0% in the respective groups after the second dose.

6.2 Solicited local signs and symptoms

Table 23 gives a summary of the incidence of any and grade 3 solicited localsymptoms (pain, redness, swelling, and local rash) within the 4 days of follow-up(Day 0 to 3) after each vaccination. Individual subject data can be found in AppendixTable IIA.




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Table 23: Incidence of solicited local symptoms during the follow-up period aftereach dose– Total vaccinated cohort

Group MeMuRu-OKA (pooled lots) Group Priorix+VarilrixSymptom Injection site Intensity N n % 95% CI N n % 95% CI

LL UL LL ULPost-Dose 1

PAIN ANY site Any 371 45 12.1 9.0 15.9 123 8 6.5 2.8 12.4(Day 0-3) Grade 3 371 0 0.0 0.0 1.0 123 0 0.0 0.0 3.0

Priorix Any - - - - - 123 7 5.7 2.3 11.4Grade 3 - - - - - 123 0 0.0 0.0 3.0

MeMuRu-OKA Any 371 45 12.1 9.0 15.9 - - - - -Grade 3 371 0 0.0 0.0 1.0 - - - - -

Varilrix Any - - - - - 122 8 6.6 2.9 12.5Grade 3 - - - - - 122 0 0.0 0.0 3.0

REDNESS ANY site Any 371 113 30.5 25.8 35.4 123 30 24.4 17.1 33.0(Day 0-3) Grade 3 371 3 0.8 0.2 2.3 123 0 0.0 0.0 3.0




SWELLING ANY site Any 371 37 10.0 7.1 13.5 123 14 11.4 6.4 18.4(Day 0-3) Grade 3 371 2 0.5 0.1 1.9 123 0 0.0 0.0 3.0




LOCAL RASH ANY site Any 371 0 0.0 0.0 1.0 123 0 0.0 0.0 3.0(Day 0-42) Priorix Any - - - - - 123 0 0.0 0.0 3.0

MeMuRu-OKA Any 371 0 0.0 0.0 1.0 - - - - -Varilrix Any - - - - - 122 0 0.0 0.0 3.0

Post-Dose 2PAIN Priorix Any - - - - - 122 5 4.1 1.3 9.3(Day 0-3) Grade 3 - - - - - 122 0 0.0 0.0 3.0


REDNESS Priorix Any - - - - - 122 27 22.1 15.1 30.5(Day 0-3) Grade 3 - - - - - 122 0 0.0 0.0 3.0


SWELLING Priorix Any - - - - - 122 11 9.0 4.6 15.6(Day 0-3) Grade 3 - - - - - 122 0 0.0 0.0 3.0


LOCAL RASH Priorix Any - - - - - 122 0 0.0 0.0 3.0(Day 0-42) MeMuRu-OKA Any 364 0 0.0 0.0 1.0 - - - -For each dose: N = number of subjects having received at least one dose n/% = number/percentage of subjects reporting a specified symptom

95%CI = Exact 95% confidence interval Grade 3 redness and swelling = >20mm in diameterGrade 3 pain = subject cried when limb was moved/spontaneously painful *Local rashes were solicited during the 43-day follow-up period

A single dose of Varilrix was co-administered with Priorix only at Visit 1.Individual subjects data can be found in Appendix table IIA & IIBiii




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All local injection site symptoms were considered causally related to vaccination.

Within the 4 days of follow-up after the first dose, redness at any injection site wasthe most frequently reported local symptom with similar incidence in both vaccinegroups (30.5% in Group MeMuRu-OKA and 24.4% in Group Priorix+Varilrix). Theincidence of other solicited local symptoms (any pain and swelling) was also similarin both groups. Grade 3 intensity of redness and swelling (> 20mm in diameter) wasrarely observed in MeMuRu-OKA group (less than 1%) after Dose 1. No subject ineither group reported grade 3 pain in this study.

Within the 4 days of follow-up after the second dose of MeMuRu-OKA and Priorix(Group Priorix+Varilrix), redness at injection site was also the most frequentlyreported local symptom with a higher incidence observed in Group MeMuRu-OKApooled lots (33.8%) than in Group Priorix+Varilrix (22.1%). Post-Dose 2 pain atinjection site was observed in 14.6% of subjects in Group MeMuRu-OKA pooledlots and in 4.1% of subjects in the control group. The observed incidence of swellingappeared to be similar in both groups. In Group MeMuRu-OKA, grade 3 redness wasreported in 5.5% of subjects and grade 3 swelling was reported in 2.5% of subjectsafter Dose 2.

No subject in any group reported local rash (i.e. injection site rash) after any dose inthis study.

6.3 Solicited general signs and symptoms

Individual data for solicited general symptoms are listed in Appendix Table IIB.

6.3.1 Fever

Table 24 presents the incidence of any types of fever between Group MeMuRu-OKApooled lots and Group Priorix+Varilrix occurring within 15 days of each vaccination(Day 0-14).




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Table 24: Incidence of fever within 15 days (Day 0−14) of follow-up after eachvaccination - Total vaccinated cohort

MeMuRu-OKA (pooled lots)(N=371)

Priorix+Varilrix(N=123)

n % 95% CI n % 95% CITypes of fever after Dose 1

LL UL LL ULAny fever (≥38.0°C rectal temperature; ≥37.5°C axillary temperature)Any fever 251 67.7 62.6 72.4 60 48.8 39.7 58.0Any fever causally related to vaccination 107 28.8 24.3 33.7 26 21.1 14.3 29.4Medical advice sought due to any fever 54 14.6 11.1 18.6 11 8.9 4.5 15.4Grade 3 fever (>39.5°C rectal temperature; >39.0°C axillary temperature)Grade 3 fever 43 11.6 8.5 15.3 13 10.6 5.7 17.4Grade 3 fever causally related to vaccination 12 3.2 1.7 5.6 5 4.1 1.3 9.2Medical advice sought due to grade 3 fever 17 4.6 2.7 7.2 6 4.9 1.8 10.3




LL UL LL ULAny fever (≥38.0°C rectal temperature; ≥37.5°C axillary temperature)Any fever 157 43.1 38.0 48.4 58 47.5 38.4 56.8Any fever causally related to vaccination 48 13.2 9.9 17.1 19 15.6 9.6 23.2Medical advice sought due to any fever 18 4.9 3.0 7.7 5 4.1 1.3 9.3Grade 3 fever (>39.5°C rectal temperature; >39.0°C axillary temperature)Grade 3 fever 22 6.0 3.8 9.0 7 5.7 2.3 11.5Grade 3 fever causally related to vaccination 10 2.7 1.3 5.0 2 1.6 0.2 5.8Medical advice sought due to grade 3 fever 9 2.5 1.1 4.6 3 2.5 0.5 7.0N = number of subjects having received the considered dosen/% = number/percentage of subjects reporting at least one symptom for the considered dose95%CI = Exact 95% confidence interval, LL = Lower Limit, UL = Upper LimitVarilrix only administered as a single dose at Day 0Causality of fever was assessed by investigatorsIndividual subjects data can be found in Appendix table IIBi

During the 15 days of follow-up after Dose 1, a higher incidence of any fever wasobserved in Group MeMuRu-OKA (67.7%) when compared to GroupPriorix+Varilrix (48.8%) (Table 24). In both groups, the incidence of grade 3 feverafter Dose 1 was similar (about 11%).

During the 15 days of follow-up after Dose 2, similar incidence of any and grade 3fever was observed in both groups.




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Table 25: Incidence of fever within 43 days (Day 0−42) of follow-up after each dose- Total vaccinated cohort




LL UL LL ULAny fever (≥38.0°C rectal temperature; ≥37.5°C axillary temperature)Any fever 272 73.3 68.5 77.7 70 56.9 47.7 65.8Any fever causally related to vaccination 108 29.1 24.5 34.0 26 21.1 14.3 29.4Medical advice sought due to any fever 76 20.5 16.5 25.0 20 16.3 10.2 24.0Grade 3 fever (>39.5°C rectal temperature; >39.0°C axillary temperature)Grade 3 fever 67 18.1 14.3 22.4 22 17.9 11.6 25.8Grade 3 fever causally related to vaccination 15 4.0 2.3 6.6 5 4.1 1.3 9.2Medical advice sought due to grade 3 fever 26 7.0 4.6 10.1 12 9.8 5.1 16.4




LL UL LL ULAny fever (≥38.0°C rectal temperature; ≥37.5°C axillary temperature)Any fever 209 57.4 52.2 62.6 68 55.7 46.5 64.7Any fever causally related to vaccination 49 13.5 10.1 17.4 19 15.6 9.6 23.2Medical advice sought due to any fever 37 10.2 7.3 13.7 12 9.8 5.2 16.6Grade 3 fever (>39.5°C rectal temperature; >39.0°C axillary temperature)Grade 3 fever 41 11.3 8.2 15.0 14 11.5 6.4 18.5Grade 3 fever causally related to vaccination 10 2.7 1.3 5.0 2 1.6 0.2 5.8Medical advice sought due to grade 3 fever 16 4.4 2.5 7.0 7 5.7 2.3 11.5N = number of subjects having received the considered dosen/% = number/percentage of subjects reporting at least one symptom for the considered dose95%CI = Exact 95% confidence interval, LL = Lower Limit, UL = Upper LimitAny fever = ≥38.0°C rectal temperature; ≥37.5°C axillary temperatureGrade 3 fever = >39.5°C rectal temperature; >39.0°C axillary temperatureIndividual subjects data can be found in Appendix table IIBi

During the 43 days of follow-up after Dose 1, the observed incidence of any feverwas higher in Group MeMuRu-OKA (73.3%) when compared to GroupPriorix+Varilrix (56.9%) (Table 25). Both vaccine groups presented a similarpattern for fever prevalence with a peak between Day 4 and Day 10 after vaccination.However, for any fever, the peak was higher in Group MeMuRu-OKA pooled lots(Supplement 14), while the peaks were equal between groups for grade 3 fever(Supplement 15).

Following Dose 2, no differences between groups were found for the incidence ofboth any and grade 3 fever, and no patterns were identified on prevalence curvesover the 43 days of follow-up (Supplement 14 and Supplement 15).

Supplement 16 presents the mean number of days with any fever in both groupswithin the 43 days of follow-up. In both groups, about 18% of subjects reportedgrade 3 fever with a mean duration of approximately two days (Supplement 17).

6.3.2 Rash

Table 26 presents the incidence of rash within the 43 days (Day 0-42) of follow-up




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after each vaccination.

Table 26: Incidence of general rash within 43 days (Day 0−42) of follow-up aftereach dose - Total vaccinated cohort


(N=371) (N=123)95% CI 95% CI

Rash type after Dose 1 n % LL UL n % LL ULGeneral rash* 61 16.4 12.82 20.61 16 13.0 7.62 20.26Rash causally related to vaccination 17 4.6 2.7 7.2 1 0.8 0.0 4.4Rash with fever 44 11.9 8.75 15.59 10 8.1 3.97 14.44Grade 3 rash 4 1.1 0.3 2.7 0 0.0 0.0 3.0Measles/rubella-like rash 13 3.5 1.88 5.92 2 1.6 0.20 5.75Varicella-like rash 4 1.1 0.29 2.74 0 0.0 0.00 2.95


(N=364) (N=122)95% CI 95% CI

Rash type after Dose 2 n % LL UL n % LL ULGeneral rash* 22 6.0 3.83 9.01 7 5.7 2.34 11.46Rash causally related to vaccination 2 0.5 0.1 2.0 0 0.0 0.0 3.0Rash with fever 9 2.5 1.14 4.64 2 1.6 0.20 5.80Grade 3 rash 2 0.5 0.1 2.0 0 0.0 0.0 3.0Measles/rubella-like rash 1 0.3 0.01 1.52 0 0.0 0.00 2.98Varicella-like rash 0 0 0 1.01 0 0 0 2.98N = number of subjects having received the considered dosen/% = number/percentage of subjects reporting at least one specified symptom after the considered dose95%CI = Exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit* General rash was a type of rash occurring at any site other than the site of injectionCausality of rash was assessed by the investigatorsGrade 3 rash = a type of rash with > 150 lesionsIndividual subjects data can be found in Appendix table IIBii

During the 43 days of follow-up, the observed incidence of any type of rash (generalrash in Table 26) was similar in both vaccine groups after Dose 1 (16.4% and 13.0%in Group MeMuRu-OKA pooled lots and Group Priorix+Varilrix, respectively).Measles/rubella-like rashes were reported for 15 subjects (13 in Group MeMuRu-OKA pooled lots and 2 in Group Priorix+Varilrix) and varicella-like rashes wasreported for four subjects in Group MeMuRu-OKA pooled lots alone.

No varicella virus of any type was detected from thissample.

Rash during the 43 days of follow-up after Dose 2 was observed in approximately6% of subjects in both groups. Only two subjects in Group MeMuRu-OKA pooledlots reported rash episode that was assessed with causal relationship to vaccination.Measles/rubella-like rashes was reported for only one subject in Group MeMuRu-OKA pooled lots after Dose 2.




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6.3.3 Parotid/salivary gland swelling

Parotid/salivary gland swelling was reported for one subject in GroupPriorix+Varilrix.

The investigator assessed this case to have a causal relationship to studyvaccination (see Appendix Bvi).

6.3.4 Signs of meningism including febrile convulsions

Signs of meningism including febrile convulsions were reported for three subjects inthis study (see Appendix Bv):

The investigator assessed thiscase to have a causal relationship to study vaccination. This subject recovered fromthis episode.

The child was nothospitalised, but the investigator considered the event medically important, for whichreason he reported it as Serious Adverse Event (See Section 6.6 for deatils).

This subjectrecovered from this event. The investigator assessed this case to have no causalrelationship to vaccination.

Cerebrospinal fluid was not collected from these three subjects for virusidentification. These three subjects were not withdrawn from the study.




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6.4 Unsolicited symptoms

Individual data for unsolicited symptoms are listed in Appendix Table IIC.

The verbatim reports of unsolicited symptoms were reviewed by a physician and thesigns and symptoms were coded according to WHO body system or WHO preferredterms. Every verbatim term was matched with the appropriate Preferred Term.Similar tabulations were performed for grade 3 unsolicited adverse events and forunsolicited adverse events identified by the investigators as having a possiblerelationship to vaccination.

Table 27 summarizes the percentage of subjects who reported unsolicited symptomsduring the follow-up period after the first dose.




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Table 27: Percentage of subjects who reported unsolicited symptoms during the 43-days of follow-up (Day 0-42) after dose 1 - Total Vaccinated Cohort

WHO Body System(CODE)

WHO Preferred Term(CODE)

MeMuRu-OKA(pooled lots)

N = 371Priorix+Varilrix

N = 12395% CI 95% CI

s % LL UL s % LL ULAt least one symptom 162 43.7 38.6 48.9 41 33.3 25.1 42.4Application site (1820) Injection site reaction �

(0058)1 0.3 0 1.5 0 0.0 0 3

Body as a whole Crying abnormal (1162) 4 1.1 0.3 2.7 1 0.8 0 4.4general (1810) Fatigue (0724) 3 0.8 0.2 2.3 1 0.8 0 4.4

Influenza-like symptoms(1222)

10 2.7 1.3 4.9 4 3.3 0.9 8.1

Injury (9001) 10 2.7 1.3 4.9 1 0.8 0 4.4Pain (0730) 1 0.3 0 1.5 0 0.0 0 3

Central and peripheralnervous system (410)

Headache (0109) 1 0.3 0 1.5 0 0.0 0 3

Gastrointestinal Abdominal pain (0268) 0 0.0 0 1 1 0.8 0 4.4system (600) Anorexia (0165) 3 0.8 0.2 2.3 4 3.3 0.9 8.1

Constipation (0204) 0 0.0 0 1 1 0.8 0 4.4Diarrhea (0205) 15 4.0 2.3 6.6 3 2.4 0.5 7Enteritis (0282) 9 2.4 1.1 4.6 3 2.4 0.5 7

Flatulence (0285) 2 0.5 0.1 1.9 0 0.0 0 3Gastroenteritis (0293) 17 4.6 2.7 7.2 3 2.4 0.5 7

Gastrointestinal disorder nos(1262)

1 0.3 0 1.5 0 0.0 0 3

Stomatitis (0327) 4 1.1 0.3 2.7 2 1.6 0.2 5.8Stomatitis aphthous (0751) 2 0.5 0.1 1.9 1 0.8 0 4.4

Tooth ache (1376) 7 1.9 0.8 3.8 2 1.6 0.2 5.8Vomiting (0228) 6 1.6 0.6 3.5 1 0.8 0 4.4

Hearing and vestibular(432)

Earache (0260) 0 0.0 0 1 1 0.8 0 4.4

Psychiatric (500) Anxiety (0166) 0 0.0 0 1 1 0.8 0 4.4Emotional lability (0177) 1 0.3 0 1.5 0 0.0 0 3

Insomnia (0183) 1 0.3 0 1.5 1 0.8 0 4.4Nervousness (0188) 7 1.9 0.8 3.8 4 3.3 0.9 8.1Somnolence (0197) 2 0.5 0.1 1.9 3 2.4 0.5 7

Reproductive female(1420)

Vaginitis (0669) 1 0.3 0 1.5 0 0.0 0 3

Reproductive male(1410)

Penis disorder (1142) 1 0.3 0 1.5 0 0.0 0 3

Resistance Infection (0736) 5 1.3 0.4 3.1 1 0.8 0 4.4mechanism (1830) Infection bacterial (0738) 1 0.3 0 1.5 0 0.0 0 3

Infection fungal (0739) 3 0.8 0.2 2.3 1 0.8 0 4.4Resistancemechanism (1830)

Infection viral (0740) 4 1.1 0.3 2.7 2 1.6 0.2 5.8

Moniliasis (0741) 6 1.6 0.6 3.5 2 1.6 0.2 5.8Otitis media (0750) 10 2.7 1.3 4.9 2 1.6 0.2 5.8

Upper respiratory tractinfection (0543)

43 11.6 8.5 15.3 12 9.8 5.1 16.4

(continued)




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Table 27: Percentage of subjects who reported unsolicited symptoms during the 43-days of follow-up (Day 0-42) after dose 1 - Total Vaccinated Cohort (cont)





N = 123Respiratory system Bronchitis (0805) 11 3.0 1.5 5.2 2 1.6 0.2 5.8(1100) Coughing (0513) 11 3.0 1.5 5.2 2 1.6 0.2 5.8

Epistaxis (0515) 1 0.3 0 1.5 0 0.0 0 3Laryngitis (0521) 3 0.8 0.2 2.3 0 0.0 0 3

Respiratory system Pharyngitis (0523) 12 3.2 1.7 5.6 1 0.8 0 4.4(1100) Rhinitis (0539) 20 5.4 3.3 8.2 5 4.1 1.3 9.2

Stridor (0542) 4 1.1 0.3 2.7 0 0.0 0 3Tracheitis (1468) 1 0.3 0 1.5 1 0.8 0 4.4

Skin and Dermatitis (0007) 3 0.8 0.2 2.3 0 0.0 0 3appendages (100) Rash erythematous * (0028) 0 0.0 0 1 1 0.8 0 4.4Vision (431) Blepharitis (1007) 1 0.3 0 1.5 0 0.0 0 3

Conjunctivitis (0238) 5 1.3 0.4 3.1 1 0.8 0 4.4White cell andreticuloendothelialsyste (1220)

Lymphadenopathy (0577) 1 0.3 0 1.5 0 0.0 0 3

At least one symptom = at least one symptom was experienced regardless of the WHO Preferred TermN = number of subjects having received the considered doses/% = number/percentage of subjects reporting at least once a specified symptom within 43 days (Day 0-42) after vaccination95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit� redness at injection site with onset on Day 39.*

Individual subjects data can be found in Appendix table IIC

During the follow-up period after Dose 1, 43.7% of subjects in Group MeMuRu-OKA pooled lots and 33.3% of subjects in Group Priorix + Varilrix reported at leastone unsolicited symptom. Among the unsolicited symptoms, the most frequentlyreported symptom was upper respiratory tract infection (11.6% in Group MeMuRu-OKA pooled lots and 9.8% in Group Priorix + Varilrix). No evidence of differencesbetween groups was observed for the percentage of subjects who reported at leastone unsolicited symptom with grade 3 intensity (3.5% of subjects in GroupMeMuRu-OKA pooled lots and 1.6% of subjects in Group Priorix + Varilrix)(Supplement 19). There were 3.8% of subjects in Group MeMuRu-OKA pooled lotsand 2.4% of subjects in Group Priorix+Varilrix who reported unsolicited symptomsconsidered by the investigators to have a causal relationship to vaccination(Supplement 20).

Table 28 summarizes the percentage of subjects who reported unsolicited symptomsduring the 43 days of follow-up after the second dose.




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Table 28: Percentage of subjects who reported unsolicited symptoms during the 43days (Day 0-42) of follow-up after dose 2 - Total Vaccinated Cohort





N = 12295% CI 95% CI

s % LL UL s % LL ULAt least one symptom 154 42.3 37.2 47.6 49 40.2 31.4 49.4Application site (1820) Injection site reaction �(0058) 0 0.0 0 1 1 0.8 0 4.5Body as a whole Edema genital (1092) 0 0.0 0 1 1 0.8 0 4.5general (1810) Influenza-like symptoms

(1222)8 2.2 1 4.3 2 1.6 0.2 5.8

Injury (9001) 9 2.5 1.1 4.6 2 1.6 0.2 5.8Pain (0730) 1 0.3 0 1.5 0 0.0 0 3

Central and peripheralnervous system (410)

Fever convulsions* (1357) 1 0.3 0 1.5 0 0.0 0 3

Fetal (1500) Hernia congenital (0885) 1 0.3 0 1.5 0 0.0 0 3Gastrointestinal Abdominal pain (0268) 0 0.0 0 1 2 1.6 0.2 5.8system (600) Constipation (0204) 3 0.8 0.2 2.4 2 1.6 0.2 5.8

Diarrhea (0205) 5 1.4 0.4 3.2 2 1.6 0.2 5.8Enteritis (0282) 9 2.5 1.1 4.6 2 1.6 0.2 5.8

Gastroenteritis (0293) 16 4.4 2.5 7 2 1.6 0.2 5.8Stomatitis (0327) 2 0.5 0.1 2 1 0.8 0 4.5

Stomatitis aphthous (0751) 2 0.5 0.1 2 1 0.8 0 4.5Tooth ache (1376) 4 1.1 0.3 2.8 3 2.5 0.5 7

Vomiting (0228) 5 1.4 0.4 3.2 1 0.8 0 4.5Earache (0260) 1 0.3 0 1.5 0 0.0 0 3Hearing and vestibular

(432)Metabolic andnutritional (800)

Dehydration (0370) 1 0.3 0 1.5 0 0.0 0 3

Psychiatric (500) Insomnia (0183) 2 0.5 0.1 2 1 0.8 0 4.5Nervousness (0188) 2 0.5 0.1 2 0 0.0 0 3


Balanoposthitis (0630) 0 0.0 0 1 1 0.8 0 4.5

Resistance Abscess (0887) 1 0.3 0 1.5 0 0.0 0 3mechanism (1830) Infection (0736) 4 1.1 0.3 2.8 1 0.8 0 4.5

Infection fungal (0739) 1 0.3 0 1.5 0 0.0 0 3Infection viral (0740) 4 1.1 0.3 2.8 1 0.8 0 4.5

Moniliasis (0741) 5 1.4 0.4 3.2 4 3.3 0.9 8.2Otitis media (0750) 17 4.7 2.7 7.4 4 3.3 0.9 8.2

Upper respiratory tractinfection (0543)

49 13.5 10.1 17.4 19 15.6 9.6 23.2

Respiratory system Asthma (1367) 1 0.3 0 1.5 0 0.0 0 3(1100) Bronchitis (0805) 13 3.6 1.9 6 1 0.8 0 4.5

Bronchospasm (0511) 3 0.8 0.2 2.4 0 0.0 0 3Coughing (0513) 5 1.4 0.4 3.2 2 1.6 0.2 5.8Laryngitis (0521) 1 0.3 0 1.5 2 1.6 0.2 5.8

Pharyngitis (0523) 6 1.6 0.6 3.6 2 1.6 0.2 5.8Respiratory disorder (0536) 1 0.3 0 1.5 0 0.0 0 3

Rhinitis (0539) 24 6.6 4.3 9.7 3 2.5 0.5 7Sinusitis (0540) 1 0.3 0 1.5 0 0.0 0 3

Sputum increased (0541) 1 0.3 0 1.5 1 0.8 0 4.5Stridor (0542) 2 0.5 0.1 2 1 0.8 0 4.5

Tracheitis (1468) 1 0.3 0 1.5 0 0.0 0 3(continued)




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Table 28: Percentage of subjects who reported unsolicited symptoms during the 43days (Day 0-42) of follow-up after dose 2 - Total Vaccinated Cohort (cont)





N = 122Skin and Dermatitis (0007) 3 0.8 0.2 2.4 1 0.8 0 4.5appendages (100) Dermatitis lichenoid (0010) 1 0.3 0 1.5 0 0.0 0 3

Nail disorder (0020) 1 0.3 0 1.5 0 0.0 0 3Skin ulceration (0041) 1 0.3 0 1.5 0 0.0 0 3

Vision (431) Conjunctivitis (0238) 5 1.4 0.4 3.2 1 0.8 0 4.5White cell andreticuloendothelialsystem (1220)

Lymphadenopathy (0577) 1 0.3 0 1.5 0 0.0 0 3

At least one symptom = at least one symptom experienced regardless of the Preferred TermN = number of subjects having received the considered doses/% = number/percentage of subjects reporting at least once a specified symptom within 43 days after vaccination day 0 to day 4295% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit�

* Febrile convulsions reported in detail in the solicited symptom section 6.3.4Individual subjects data can be found in Appendix table IICi

During the follow-up period after Dose 2, 42.3% of subjects in the Group MeMuRu-OKA pooled lots and 40.2% of subjects in Group Priorix + Varilrix reported at leastone unsolicited symptom. Among the unsolicited symptoms, the most frequentlyreported symptom was upper respiratory tract infection (13.5% in Group MeMuRu-OKA pooled lots and 15.6% in Group Priorix + Varilrix). No evidence ofdifferences between groups was observed for the percentage of subjects who reportedat least one unsolicited symptom with grade 3 intensity (3.3% of subject in GroupMeMuRu-OKA pooled lots and 2.5% of subjects in Group Priorix + Varilrix)(Supplement 19). There were 1.4% of subjects in Group MeMuRu-OKA pooled lotsand 0.8% of subjects in Group Priorix+Varilrix who reported unsolicited symptomsconsidered by the investigators to have a causal relationship to vaccination(Supplement 20).

6.5 Concomitant medications/vaccinations

Individual data for concomitant medications/vaccinations are listed in AppendixTable IIDi. Table 29 presents the number and percentage of subjects who wereadministered concomitant medication during the follow-up period after each dose.




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Table 29: Number and percentage of subjects who took at least one concomitantmedication within 43 days (Day 0-42) after each dose - Total Vaccinated Cohort

Post-Dose 1MeMuRu-OKA (pooled lots)

N=371Priorix+Varilrix

N=123n % 95% CI n % 95% CI

Type LL UL LL ULAny medication 139 37.5 32.5 42.6 43 35.0 26.6 44.1Any antipyretic 92 24.8 20.5 29.5 26 21.1 14.3 29.4Prophylactic antipyretic 1 0.3 0.0 1.5 0 0.0 0.0 3.0Any antibiotic 25 6.7 4.4 9.8 5 4.1 1.3 9.2

Post-Dose 2MeMuRu-OKA (pooled lots)

N=364Priorix+Varilrix

N=122n % 95% CI n % 95% CI

Type LL UL LL ULAny medication 137 37.6 32.6 42.8 40 32.8 24.6 41.9Any antipyretic 64 17.6 13.8 21.9 17 13.9 8.3 21.4Prophylactic antipyretic 1 0.3 0.0 1.5 0 0.0 0.0 3.0Any antibiotic 31 8.5 5.9 11.9 9 7.4 3.4 13.5N = number of subjects having received the considered dosen/% = number/percentage of subjects who started to take the specified concomitant medication at least once during the mentionedperiod95%CI = Exact 95% confidence interval, LL = Lower Limit, UL = Upper LimitIndividual subjects data can be found in Appendix table IIDi

The percentage of subjects who were administered concomitant medication aftereach dose was similar between groups (37.5% of subjects in Group MeMuRu-OKApooled lots vs 35.0% of subjects in Group Priorix + Varilrix after Dose 1 and 37.6%of subjects in Group MeMuRu-OKA pooled lots vs 32.8% of subjects in GroupPriorix+Varilrix after Dose 2) (Table 29).

The number of subjects who were administered medication before vaccination was31 out of 371 subjects in Group MeMuRu-OKA pooled lots and 12 out of 123subjects in Group Priorix+Varilrix.

6.6 Serious adverse events

SAEs Table and Clinical Narratives are included in the Appendix section of thisreport.

Table 30 summarizes the 12 serious adverse events (SAEs) reported during thefollow-up period after each vaccination.




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Table 30: Serious adverse events reported during the follow-up period after eachdose

Source: Appendices on Clinical narratives

After the first dose, a total of six SAEs were reported (three SAEs for three subjectsin Group MeMuRu-OKA pooled lots and three SAEs for three subjects in the controlgroup). No subject was withdrawn from the study due to serious adverse event (seeTable 7). None of these events were related to vaccination as assessed by theinvestigators. All of these SAEs resolved.

After the second dose, a total of six SAEs were reported (one SAE for one subject inthe control group and five SAEs for five subjects in Group MeMuRu-OKA pooledlots). All of these SAEs resolved. From these six SAEs, one was considered by theinvestigator to have a causal relationship to vaccination. Details of this event aredescribed below:




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There were no clinical signs ofan underlying neurological pathology. Laboratory tests were notperformed. This event has been considered by the investigator to bemedically important. The investigator reported this event to have apossible causal relationship to the vaccination. For this reason, anExpedited Investigator Safety Report (EISR) letter was sent toinvestigators involved in active MeMuRu-OKA vaccine studies inaccordance with GSK policy.

7. Discussion

This study enrolled and vaccinated 494 subjects in multiple study sites in Germanyand Austria. Subjects were equally randomized to receive one of three productionlots of MeMuRu-OKA candidate vaccine (371 subjects) or separate administration ofthe licensed Priorix and Varilrix vaccines (123 subjects). Two vaccinations wereperformed 6-8 weeks apart. A single dose of MeMuRu-OKA vaccine wasadministered at the first and second study visits. For the control group, a single doseof Priorix was administered at the first and second study visits, and a single dose ofVarilrix was administered once at the first study visit.

This study had multiple primary objectives. In order to control the impact of themultiplicity of the objectives on the global type I error rate, the co-primary objectiveswere evaluated in a pre-determined sequential order. The subsequent objective wasto be evaluated in a confirmatory manner only if the first objective was reached.

The first co-primary objective of this study was to demonstrate the lot-to-lotconsistency of MeMuRu-OKA vaccine in terms of seroconversion to each of thevaccine antigens after the second dose. The consistency criteria were fulfilled for allvaccine antigens after the second dose (i.e., the 90% CI for the difference inseroconversion rates between MeMuRu-OKA lots was within the pre-defined limitsof equivalence of [-10% and +10%]).

The second co-primary objective of this study was to demonstrate the non-inferiorityof MeMuRu-OKA pooled lots to the separate administration of Priorix and Varilrixafter the second dose. The criteria of non-inferiority were fulfilled for all vaccineantigens after the second dose.

The secondary objectives of this study included the immunogenicity of studyvaccines after the first dose and safety of study vaccines after each vaccination.




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Regarding the immune response following the first dose of MeMuRu-OKA (pooledlots), more than 97% of subjects seroconverted to measles, rubella and varicella andmore than 90% of subjects seroconverted for mumps antibodies. Following the firstdose of Priorix and Varilrix (administered in separate injections), all subjectsseroconverted to measles, rubella and varicella and more than 95% of subjectsseroconverted to mumps antibodies.

As for the safety evaluation of the study vaccines in this study, redness at injectionsite was the most frequently reported local symptom following each vaccination.Both groups had similar incidence of all solicited local symptoms (any and grade 3)after the first dose while higher incidence of pain (any) and redness (any and grade 3)was observed in Group MeMuRu-OKA pooled lots after the second dose.

After Dose 1, the incidence of any fever during the 15 days and 43 days of follow-upwas observed to be higher in Group MeMuRu-OKA pooled lots when compared toGroup Priorix+Varilrix. Both vaccine groups presented a similar pattern for feverprevalence with a peak between Day 4 and Day 10 after vaccination. However, forany fever, the observed peak was higher in Group MeMuRu-OKA pooled lots, whilethe peaks were similar between groups for grade 3 fever. Following Dose 2, nodifferences between groups were found for the incidence of both any and grade 3fever, and no patterns were identified on prevalence curves over the 43 days offollow-up (see Supplement 14 and Supplement 15).

The observed incidence of any types of rash was similar in both groups after eachvaccination. Four subjects reported rare adverse events in this study (1 case ofparotid/salivary gland swelling, 2 cases of febrile convulsions and 1 case indicativeof meningism i.e., neck stiffness). Serious adverse events were reported for 12subjects and only one case (febrile convulsions) was considered to have a causalrelationship to vaccination.

8. Conclusions

This study met the primary objectives related to the demonstration of lot-to lotconsistency of MeMuRu-OKA candidate vaccine as well as the non-inferiority ofMeMuRu-OKA pooled lots to separate injections of Priorix and Varilrix for allvaccine components:

• The seroconversion rates after the second dose did not vary by more than 10%from one MeMuRu-OKA lot to another for all antigens.

• The seroconversion rates after the second dose in Group MeMuRu-OKA pooledlots did not decrease by more than 10% when compared to GroupPriorix+Varilrix for all antigens.




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The incidence of grade 3 fever was similar between MeMuRu-OKA andPriorix+Varilrix groups after each dose. For this reason, the observed higherincidence of low-grade fever (reflecting a peak between Day 4 and Day 10, morepronounced in the MeMuRu-OKA group than in the Priorix+Varilrix group)following the first dose was considered of limited clinical relevance. Therefore, thisstudy provides evidence that the candidate MeMuRu-OKA vaccine was shown to beas safe and as well tolerated as the separate injections of Priorix and Varilrix.




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9. References

[1] Recommendation of the Standing Committee on Immunization(STIKO) at Robert Koch Institute. Epidemiologisches Bulletin 2002,28: 227-242.

[2] Gershon A. A. Varicella vaccine-Are two doses better than one?(Editorials). The New England Journal of Medicine 2002, 347 (24):1962-1963.

[3] Galil K. et. al. Outbreak of varicella at a day-care centre despitevaccination. The New England Journal of Medicine 2002, 347 (24):1909-1915.

[4] White S.J., Freedman L.S. Allocation of patients to treatment groups ina controlled clinical study. Br. J. Cancer 1978, 37: 849-857




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10. Supplements

Supplement 1: Investigators, study centres and investigational sites

Investigators Centreno. Investigational site

Germany:Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med. Dr. med.

Dr. med. Dr. med. Dr. med. Dr. med. Prof. Dr. med. Dr. med. Dr. med. Dr. med. Austria:Dr. Dr. Dr. Dr.




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Supplement 2: Number of subjects enrolled and vaccinated in the study - Totalvaccinated cohort

Centre MeMuRu-OKA Priorix+Varilrix TotalLot MJRV159A48

Lot MJRV160A48

Lot MJRV163A48

n n n n n %Germany

8 8 8 8 32 6.52 2 2 2 8 1.63 3 3 3 12 2.43 3 3 3 12 2.40 1 1 0 2 0.46 6 5 6 23 4.70 0 1 1 2 0.43 3 3 3 12 2.41 2 1 2 6 1.23 3 3 3 12 2.41 0 1 1 3 0.63 3 3 2 11 2.22 2 2 2 8 1.61 0 0 1 2 0.41 0 0 1 2 0.44 4 4 4 16 3.24 3 4 3 14 2.89 9 9 9 36 7.31 2 2 2 7 1.41 1 0 0 2 0.41 0 1 0 2 0.41 2 1 2 6 1.24 4 4 5 17 3.40 1 0 0 1 0.20 1 1 1 3 0.66 6 6 6 24 4.93 2 2 2 9 1.82 2 2 3 9 1.8

11 11 11 11 44 8.94 4 4 4 16 3.21 0 0 0 1 0.26 6 7 5 24 4.90 0 1 0 1 0.21 1 1 0 3 0.61 1 1 1 4 0.82 2 2 2 8 1.61 1 1 1 4 0.86 6 6 6 24 4.94 5 5 4 18 3.61 1 1 1 4 0.82 1 2 2 7 1.4

Austria4 3 3 4 14 2.83 2 2 2 9 1.83 3 3 3 12 2.42 2 2 2 8 1.6

All 125 122 124 123 494 100n = number of subjects included in each group or in total for a given centre or for all centres.All = sum of all subjects in each group or in total (sum of all groups).% = n/All*100Centre = GSK-assigned centre number.Individual subjects data can be found in Appendix table IB




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Supplement 3: Summary of demographic characteristics – ATP Safety cohortMeMuRu-OKA

MJRV159A48 MJRV160A48 MJRV163A48Priorix

+Varilrix TotalN= 121 N= 117 N= 118 N= 116 N= 472Characteristics Parameters or

Categories Valueor n % Value


or n % Valueor n %



Race Black 1 0.8 1 0.9 2 1.7 1 0.9 5 1.1White 118 97.5 109 93.2 115 97.5 113 97.4 455 96.4Oriental 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0Arabic/north 0 0.0 3 2.6 0 0.0 1 0.9 4 0.8East/south ea 0 0.0 2 1.7 1 0.8 1 0.9 4 0.8Other 2 1.7 2 1.7 0 0.0 0 0.0 4 0.8

N = total number of subjectsn = number of subjects in a given categoryValue = value of the considered parameter% = n / Number of subjects with available results x 100SD= standard deviationAge(M)= age expressed in months* The protocol included subjects from 12-18 months of age. The study finally included 3 subjects who were 3 or 5 days younger than 12months. Therefore, the minimum age that was considered in this table was 11 months.Individual subjects data can be found in Appendix table IB




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Supplement 4 Summary of demographic characteristics – ATP Immunogenicitycohort

MeMuRu-OKAMJRV159A48 MJRV160A48 MJRV163A48

Priorix+Varilrix Total

N= 108 N= 103 N= 100 N= 108 N= 419CharacteristicsParameters

orCategories Value


or n % Valueor n % Value or

n %



Race Black 1 0.9 0 0.0 2 2.0 1 0.9 4 1.0White 106 98.1 98 95.1 98 98.0 105 97.2 407 97.1Oriental 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0Arabic/north 0 0.0 3 2.9 0 0.0 1 0.9 4 1.0East/south ea 0 0.0 1 1.0 0 0.0 1 0.9 2 0.5Other 1 0.9 1 1.0 0 0.0 0 0.0 2 0.5

N = total number of subjectsn = number of subjects in a given categoryValue = value of the considered parameter% = n / Number of subjects with available results x 100SD= standard deviationAge(M)= age expressed in months* The protocol included subjects from 12-18 months of age. The study finally included 3 subjects who were 3 or 5 days younger than 12months. Therefore, the minimum age that was considered in this table was 11 months.Individual subjects data can be found in Appendix table IB




Page 81

Supplement 5: Duration of follow-up (days) - Total vaccinated cohort

From Visit 1 to Visit 2

Class Group MeMuRu-OKApooled lots Group Priorix+Varilrix

(N=371) (N=123)n % LL UL n % LL UL

Unknown 5 1.3 0.44 3.12 1 0.8 0.02 4.45[30;40[ 1 0.3 0.01 1.49 0 0.0 0.00 2.95[40;50[ 286 77.1 72.47 81.27 93 75.6 67.05 82.90[50;60[ 72 19.4 15.51 23.80 23 18.7 12.24 26.72[60; [ 7 1.9 0.76 3.85 6 4.9 1.81 10.32N=Number of subjects having received the considered dosen/%=Number / percentage of subjects with follow duration in the specified class95% CI=exact 95% confidence interval, LL=Lower Limit, UL=Upper Limit

From Visit 2 to Visit 3

Class Group MeMuRu-OKApooled lots Group Priorix+Varilrix

(N=371) (N=123)n % LL UL n % LL UL

Unknown 9 2.4 1.12 4.55 1 0.8 0.02 4.45[0;30[ 1 0.3 0.01 1.49 0 0.0 0.00 2.95[30;40[ 4 1.1 0.29 2.74 2 1.6 0.20 5.75[40;50[ 308 83.0 78.80 86.70 106 86.2 78.80 91.74[50;60[ 46 12.4 9.22 16.19 13 10.6 5.75 17.40[60; [ 3 0.8 0.17 2.34 1 0.8 0.02 4.45N=Number of subjects having received the considered dosen/%=Number / percentage of subjects with follow duration in the specified class95% CI=exact 95% confidence interval, LL=Lower Limit, UL=Upper Limit




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Supplement 6: Distribution of anti-Measles antibody titres - ATP ImmunogenicityCohort

Group Timepoint N <150

mIU/mL≥≥≥≥150

mIU/mL≥≥≥≥300

mIU/mL≥≥≥≥600

mIU/mL≥≥≥≥1200

mIU/mLn % n % n % n % n %

PRE 108 108 100 0 0.0 0 0.0 0 0.0 0 0.0PI(D42) 106 3 2.8 103 97.2 102 96.2 102 96.2 99 93.4

MeMuRu-OKAlot MJRV159A48

PII(D84) 106 0 0.0 106 100 106 100 105 99.1 104 98.1PRE 103 103 100 0 0.0 0 0.0 0 0.0 0 0.0PI(D42) 100 1 1.0 99 99.0 99 99.0 98 98.0 96 96.0


PII(D84) 102 0 0.0 102 100 102 100 102 100 101 99.0PRE 100 100 100 0 0.0 0 0.0 0 0.0 0 0.0PI(D42) 100 3 3.0 97 97.0 96 96.0 96 96.0 91 91.0


PII(D84) 99 0 0.0 99 100 97 98.0 96 97.0 94 94.9PRE 311 311 100 0 0.0 0 0.0 0 0.0 0 0.0PI(D42) 306 7 2.3 299 97.7 297 97.1 296 96.7 286 93.5


PII(D84) 307 0 0.0 307 100 305 99.3 303 98.7 299 97.4PRE 108 108 100 0 0.0 0 0.0 0 0.0 0 0.0PI(D42) 106 0 0.0 106 100 105 99.1 99 93.4 81 76.4

Priorix+Varilrix

PII(D84) 108 0 0.0 108 100 108 100 106 98.1 99 91.7PRE = pre-vaccination time point at Day 0PI(D42) = post-vaccination time point at Day 42PII(D84) = post-vaccination time point at Day 84N = number of subjects with available results.n/% = number/percentage of subjects with titres within the specified range.Individual subjects data can be found in Appendix table IIIA




Page 83

Supplement 7: Reverse Cumulative Curve of anti-Measles antibody titres - ATPImmunogenicity Cohort

Post-dose 1

Groups:MMRV_1 : MeMuRu-OKA vaccine Lot MJRV159A48MMRV_2 : MeMuRu-OKA vaccine Lot MJRV160A48MMRV_3 : MeMuRu-OKA vaccine Lot MJRV163A48

GroupsMMRV = Pooled MeMuRu-OKA lotsMMR_V = Priorix+ Varilrix

Source: Appendix Table IIIA




Page 84

Supplement 7 continuedPost-dose 2


Groups:MMRV = Pooled MeMuRu-OKA lotsMMR_V = Priorix+ Varilrix





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Supplement 8: Distribution of anti-Mumps antibody titres - ATP ImmunogenicityCohort

Group Time point N <231 U/mL ≥≥≥≥231 U/mL ≥≥≥≥460 U/mL ≥≥≥≥920 U/mLn % n % n % n %

PRE 108 108 100 0 0.0 0 0.0 0 0.0PI(D42) 105 9 8.6 96 91.4 81 77.1 60 57.1


PII(D84) 106 0 0.0 106 100 101 95.3 85 80.2PRE 103 103 100 0 0.0 0 0.0 0 0.0PI(D42) 98 14 14.3 84 85.7 77 78.6 52 53.1


PII(D84) 102 5 4.9 97 95.1 94 92.2 79 77.5PRE 100 100 100 0 0.0 0 0.0 0 0.0PI(D42) 99 7 7.1 92 92.9 79 79.8 52 52.5


PII(D84) 99 1 1.0 98 99.0 93 93.9 72 72.7PRE 311 311 100 0 0.0 0 0.0 0 0.0PI(D42) 302 30 9.9 272 90.1 237 78.5 164 54.3


PII(D84) 307 6 2.0 301 98.0 288 93.8 236 76.9PRE 108 108 100 0 0.0 0 0.0 0 0.0PI(D42) 106 5 4.7 101 95.3 90 84.9 61 57.5

Priorix+Varilrix

PII(D84) 108 1 0.9 107 99.1 103 95.4 87 80.6PRE = pre-vaccination time point at Day 0PI(D42) = post-vaccination time point at Day 42PII(D84) = post-vaccination time point at Day 84N = number of subjects with available results.n/% = number/percentage of subjects with titres within the specified range.Individual subjects data can be found in Appendix table IIIA




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Supplement 9: Reverse Cumulative Curve of anti-Mumps antibody titres - ATPImmunogenicity Cohort

Post-Dose 1







Page 87

Supplement 9 continuedPost-Dose 2







Page 88

Supplement 10: Distribution of anti-Rubella antibody titres - ATP ImmunogenicityCohort

Group Timepoint N <4 IU/mL ≥≥≥≥4 IU/mL ≥≥≥≥10 IU/mL ≥≥≥≥16 IU/mL ≥≥≥≥32 IU/mL ≥≥≥≥64 IU/mL

n % n % n % n % n % n %PRE 108 108 100 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0PI(D42) 106 3 2.8 103 97.2 101 95.3 96 90.6 82 77.4 54 50.9


PII(D84) 106 0 0.0 106 100 106 100 106 100 102 96.2 80 75.5PRE 103 103 100 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0PI(D42) 100 0 0.0 100 100 98 98.0 92 92.0 78 78.0 56 56.0


PII(D84) 102 0 0.0 102 100 101 99.0 101 99.0 96 94.1 82 80.4PRE 100 100 100 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0PI(D42) 100 0 0.0 100 100 98 98.0 92 92.0 77 77.0 48 48.0


PII(D84) 99 0 0.0 99 100 99 100 99 100 96 97.0 79 79.8PRE 311 311 100 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0PI(D42) 306 3 1.0 303 99.0 297 97.1 280 91.5 237 77.5 158 51.6


PII(D84) 307 0 0.0 307 100 306 99.7 306 99.7 294 95.8 241 78.5PRE 108 108 100 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0PI(D42) 106 0 0.0 106 100 105 99.1 102 96.2 89 84.0 61 57.5

Priorix+Varilrix

PII(D84) 108 0 0.0 108 100 108 100 108 100 105 97.2 86 79.6PRE = pre-vaccination time point at Day 0PI(D42) = post-vaccination time point at Day 42PII(D84) = post-vaccination time point at Day 84N = number of subjects with available results.n/% = number/percentage of subjects with titres within the specified range.Individual subjects data can be found in Appendix table IIIA




Page 89

Supplement 11: Reverse Cumulative Curve of anti-Rubella antibody titres - ATPImmunogenicity Cohort

Post-Dose 1



Source: Appendix Table III.a




Page 90

Supplement 11 continuedPost-Dose 2







Page 91

Supplement 12: Distribution of anti-Varicella antibody titres - ATP ImmunogenicityCohort

Group Timepoint N <4 dil-1 ≥≥≥≥4 dil-1 ≥≥≥≥8 dil-1 ≥≥≥≥16 dil-1 ≥≥≥≥32 dil-1 ≥≥≥≥64 dil-1 ≥≥≥≥128 dil-1

n % n % n % n % n % n % n %PRE 108 108 100 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0PI(D42) 105 1 1.0 104 99.0 104 99.0 103 98.1 99 94.3 93 88.6 79 75.2


PII(D84) 106 0 0.0 106 100 106 100 105 99.1 105 99.1 104 98.1 103 97.2PRE 103 103 100 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0PI(D42) 99 0 0.0 99 100 99 100 98 99.0 95 96.0 89 89.9 81 81.8


PII(D84) 102 0 0.0 102 100 102 100 101 99.0 101 99.0 99 97.1 99 97.1PRE 100 100 100 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0PI(D42) 100 0 0.0 100 100 100 100 99 99.0 98 98.0 95 95.0 86 86.0


PII(D84) 98 0 0.0 98 100 98 100 98 100 98 100 97 99.0 96 98.0PRE 311 311 100 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0PI(D42) 304 1 0.3 303 99.7 303 99.7 300 98.7 292 96.1 277 91.1 246 80.9


PII(D84) 306 0 0.0 306 100 306 100 304 99.3 304 99.3 300 98.0 298 97.4PRE 108 108 100 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0PI(D42) 106 0 0.0 106 100 106 100 105 99.1 102 96.2 101 95.3 87 82.1

Priorix+Varilrix

PII(D84) 108 0 0.0 108 100 108 100 104 96.3 103 95.4 97 89.8 83 76.9PRE = pre-vaccination time point at Day 0PI(D42) = post-vaccination time point at Day 42PII(D84) = post-vaccination time point at Day 84N = number of subjects with available results.n/% = number/percentage of subjects with titres within the specified range.Individual subjects data can be found in Appendix table IIIA




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Supplement 13: Reverse Cumulative Curve of anti-Varicella antibody titres - ATPImmunogenicity Cohort

Post-Dose 1







Page 93

Supplement 13 continued

Post-Dose 2







Page 94

Supplement 14: Prevalence of any fever from Day 0 to Day 42 after each dose -Total vaccinated cohort

Post-Dose 1

Post-Dose 2

Groups:MMR_V = Priorix + VarilrixMMRV = MeMuRu-OKA pooled lotsSource: Appendix Table IIBi




Page 95

Supplement 15: Prevalence of grade 3 fever from Day 0 to Day 42 after each dose -Total vaccinated cohort l

Post-Dose 1

Post-Dose 2





Page 96

Supplement 16: Number of days with any fever (Day 0-42) after each dose - Totalvaccinated cohort

Post Dose 1

Post-Dose 2





Page 97

Supplement 17: Number of days with grade 3 fever (Day 0-42) after each dose - ATPSafety Cohort

Post-Dose 1

Post-Dose 2





Page 98

Supplement 18: Number of days with generalized rash (Day 0-42) after each dose -Total vaccinated cohort

Post-Dose 1

Post-Dose 2

Groups:MMR_V = Priorix + VarilrixMMRV = Pooled MeMuRu-OKA lotsSource: Appendix Table IIBii




Page 99

Supplement 19: Percentage of subjects with grade 3 unsolicited symptoms within 43days (Day 0-42) of follow-up after each dose - Total vaccinated Cohort

Body System(CODE)

Preferred Term(CODE)



N = 12395% CI 95% CI

Post-Dose 1 s % LL UL s % LL ULAt least one symptom 13 3.5 1.9 5.9 2 1.6 0.2 5.8Central and peripheralnervous system (410)

Headache (0109) 1 0.3 0 1.5 0 0.0 0 3

Gastrointestinal Anorexia (0165) 0 0.0 0 1 1 0.8 0 4.4system (600) Diarrhea (0205) 1 0.3 0 1.5 0 0.0 0 3

Gastroenteritis (0293) 1 0.3 0 1.5 0 0.0 0 3Vomiting (0228) 1 0.3 0 1.5 0 0.0 0 3

Psychiatric (500) Somnolence (0197) 0 0.0 0 1 1 0.8 0 4.4Reproductive female(1420)

Vaginitis (0669) 1 0.3 0 1.5 0 0.0 0 3

Resistance Infection viral (0740) 1 0.3 0 1.5 0 0.0 0 3mechanism (1830) Otitis media (0750) 3 0.8 0.2 2.3 0 0.0 0 3

Upper resp tract infection(0543)

1 0.3 0 1.5 1 0.8 0 4.4

Respiratory system Bronchitis (0805) 2 0.5 0.1 1.9 0 0.0 0 3(1100) Pharyngitis (0523) 1 0.3 0 1.5 0 0.0 0 3Vision (431) Conjunctivitis (0238) 2 0.5 0.1 1.9 0 0.0 0 3



N = 12295% CI 95% CI

Post-Dose 2 s % LL UL s % LL ULAt least one symptom 12 3.3 1.7 5.7 3 2.5 0.5 7Body as a wholegeneral (1810)


1 0.3 0 1.5 0 0.0 0 3

Gastrointestinal Gastroenteritis (0293) 2 0.5 0.1 2 0 0.0 0 3system (600) Stomatitis (0327) 0 0.0 0 1 1 0.8 0 4.5

Stomatitis aphthous (0751) 1 0.3 0 1.5 0 0.0 0 3Tooth ache (1376) 0 0.0 0 1 1 0.8 0 4.5

Resistance Infection (0736) 1 0.3 0 1.5 0 0.0 0 3mechanism (1830) Otitis media (0750) 1 0.3 0 1.5 0 0.0 0 3


1 0.3 0 1.5 1 0.8 0 4.5

Respiratory system Asthma (1367) 1 0.3 0 1.5 0 0.0 0 3(1100) Bronchitis (0805) 3 0.8 0.2 2.4 0 0.0 0 3

Rhinitis (0539) 1 0.3 0 1.5 0 0.0 0 3At least one symptom = at least one symptom experienced regardless of the Preferred TermN = number of subjects having received the considered doses/% = number/percentage of subjects reporting at least once a specified symptom within 43 days (Day 0-42) aftervaccination95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper LimitIndividual subjects data can be found in Appendix table IICi




Page 100

Supplement 20: Percentage of subjects who reported unsolicited symptomsconsidered to have a causal relationship to vaccination within 43 days after each

dose - Total Vaccinated CohortMeMuRu-OKA(pooled lots)


N = 12395% CI 95% CIWHO Body System

(CODE)WHO Preferred Term

(CODE) s % LL UL s % LL ULPost-Dose 1At least one symptom 14 3.8 2.1 6.3 3 2.4 0.5 7Application site (1820) Injection site reaction � (0058) 1 0.3 0 1.5 0 0.0 0 3Body as a whole Crying abnormal (1162) 2 0.5 0.1 1.9 0 0.0 0 3general (1810) Fatigue (0724) 2 0.5 0.1 1.9 1 0.8 0 4.4Gastrointestinal Anorexia (0165) 0 0.0 0 1 1 0.8 0 4.4system (600) Diarrhea (0205) 1 0.3 0 1.5 0 0.0 0 3

Enteritis (0282) 1 0.3 0 1.5 0 0.0 0 3Gastroenteritis (0293) 1 0.3 0 1.5 0 0.0 0 3

Stomatitis (0327) 1 0.3 0 1.5 0 0.0 0 3Psychiatric (500) Anxiety (0166) 0 0.0 0 1 1 0.8 0 4.4

Emotional lability (0177) 1 0.3 0 1.5 0 0.0 0 3Insomnia (0183) 1 0.3 0 1.5 0 0.0 0 3

Nervousness (0188) 2 0.5 0.1 1.9 1 0.8 0 4.4Somnolence (0197) 2 0.5 0.1 1.9 2 1.6 0.2 5.8

Resistance Infection viral (0740) 1 0.3 0 1.5 0 0.0 0 3mechanism (1830) Upper respiratory tract

infection (0543)2 0.5 0.1 1.9 0 0.0 0 3

Respiratory system Bronchitis (0805) 1 0.3 0 1.5 0 0.0 0 3(1100) Epistaxis (0515) 1 0.3 0 1.5 0 0.0 0 3

Rhinitis (0539) 1 0.3 0 1.5 0 0.0 0 3MeMuRu-OKA(pooled lots)


N = 12295% CI 95% CI

s % LL UL s % LL ULPost-Dose 2At least one symptom 5 1.4 0.4 3.2 1 0.8 0 4.5Application site (1820) Injection site reaction �(0058) 0 0.0 0 1 1 0.8 0 4.5Central and peripheralnervous system (410)

Fever convulsions * (1357) 1 0.3 0 1.5 0 0.0 0 3

Gastrointestinalsystem (600)

Diarrhea (0205) 1 0.3 0 1.5 0 0.0 0 3

Psychiatric (500) Insomnia (0183) 1 0.3 0 1.5 0 0.0 0 3Nervousness (0188) 2 0.5 0.1 2 0 0.0 0 3

Respiratory system(1100)

Respiratory disorder (0536) 1 0.3 0 1.5 0 0.0 0 3

At least one symptom = at least one symptom experienced regardless of the WHO Preferred TermN = number of subjects having received the considered doses/% = number/percentage of subjects reporting at least once a specified symptom within 43 days (Day 0-42) aftervaccination95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit� redness at injection site with onset on Day 39.�

* Febrile convulsions reported in detail in the solicited symptom section 6.3.4Individual subjects data can be found in Appendix table IICi




Page 101

Note: The following Supplement tables present the results of MeMuRu-OKAconsistency lots in terms of safety.

Supplement 21: Incidence of local symptoms during the follow-up period after eachvaccination with MeMuRu-OKA vaccine - Total vaccinated cohort

MeMuRu-OKA lotMJRV159A48



N n % 95% CI N n % 95% CI N n % 95% CISymptom atinjection site Intensity

LL UL LL UL LL ULPost-dose 1

Any 125 12 9.6 5.1 16.2 122 18 14.8 9.0 22.3 124 15 12.1 6.9 19.2Pain(Day 0-3) Grade 3 125 0 0.0 0.0 2.9 122 0 0.0 0.0 3.0 124 0 0.0 0.0 2.9

Any 125 0 0.0 0.0 2.9 122 0 0.0 0.0 3.0 124 0 0.0 0.0 2.9Local rash(Day 0-42) Grade 3 125 0 0.0 0.0 2.9 122 0 0.0 0.0 3.0 124 0 0.0 0.0 2.9

Any 125 34 27.2 19.6 35.9 122 39 32.0 23.8 41.0 124 40 32.3 24.1 41.2Redness(Day 0-3) Grade 3 125 1 0.8 0.0 4.4 122 1 0.8 0.0 4.5 124 1 0.8 0.0 4.4

Any 125 4 3.2 0.9 8.0 122 21 17.2 11.0 25.1 124 12 9.7 5.1 16.3Swelling(Day 0-3) Grade 3 125 0 0.0 0.0 2.9 122 1 0.8 0.0 4.5 124 1 0.8 0.0 4.4

Post-dose 2Any 123 15 12.2 7.0 19.3 121 20 16.5 10.4 24.4 120 18 15.0 9.1 22.7Pain

(Day 0-3) Grade 3 123 0 0.0 0.0 3.0 121 0 0.0 0.0 3.0 120 0 0.0 0.0 3.0Any 123 0 0.0 0.0 3.0 121 0 0.0 0.0 3.0 120 0 0.0 0.0 3.0Local rash

(Day 0-42) Grade 3 123 0 0.0 0.0 3.0 121 0 0.0 0.0 3.0 120 0 0.0 0.0 3.0Any 123 41 33.3 25.1 42.4 121 43 35.5 27.0 44.8 120 39 32.5 24.2 41.7Redness

(Day 0-3) Grade 3 123 8 6.5 2.8 12.4 121 5 4.1 1.4 9.4 120 7 5.8 2.4 11.6Any 123 15 12.2 7.0 19.3 121 22 18.2 11.8 26.2 120 15 12.5 7.2 19.8Swelling

(Day 0-3) Grade 3 123 4 3.3 0.9 8.1 121 4 3.3 0.9 8.2 120 1 0.8 0.0 4.6For each dose :N = number of subjects having received at least one dosen/% = number/percentage of subjects reporting a specified symptom95%CI = Exact 95% confidence intervalIndividual subjects data can be found in Appendix table IIA & IIBiii




Page 102

Supplement 22: Incidence of fever during the 15-day follow-up (Day 014) after eachvaccination with MeMuRu-OKA - Total vaccinated cohortMeMuRu-OKA lot

MJRV159A48(N=125)


(N=122)


(N=124)n % 95% CI n % 95% CI n % 95% CI

Types of fever

LL UL LL UL LL ULPost-dose 1Any fever (≥38.0°C rectal temperature; ≥37.5°C axillary temperature)Any fever 88 70.4 61.6 78.2 78 63.9 54.7 72.4 85 68.5 59.6 76.6Any fever causallyrelated to vaccination

35 28.0 20.3 36.7 36 29.5 21.6 38.4 36 29.0 21.2 37.9

Medical advice soughtdue to any fever

22 17.6 11.4 25.4 12 9.8 5.2 16.6 20 16.1 10.1 23.8

Grade 3 fever (>39.5°C rectal temperature; >39.0°C axillary temperature)Grade 3 fever 17 13.6 8.1 20.9 12 9.8 5.2 16.6 14 11.3 6.3 18.2Grade 3 fever causallyrelated to vaccination

5 4.0 1.3 9.1 4 3.3 0.9 8.2 3 2.4 0.5 6.9

Medical advice soughtdue to grade 3 fever

7 5.6 2.3 11.2 6 4.9 1.8 10.4 4 3.2 0.9 8.1


(N=123)


(N=121)


(N=120)n % 95% CI n % 95% CI n % 95% CI

Types of fever

LL UL LL UL LL ULPost-dose 2Any fever (≥38.0°C rectal temperature; ≥37.5°C axillary temperature)Any fever 56 45.5 36.5 54.8 52 43.0 34.0 52.3 49 40.8 32.0 50.2Any fever causallyrelated to vaccination

19 15.4 9.6 23.1 17 14.0 8.4 21.5 12 10.0 5.3 16.8

Medical advice soughtdue to any fever

8 6.5 2.8 12.4 5 4.1 1.4 9.4 5 4.2 1.4 9.5

Grade 3 fever (>39.5°C rectal temperature; >39.0°C axillary temperature)Grade 3 fever 9 7.3 3.4 13.4 6 5.0 1.8 10.5 7 5.8 2.4 11.6Grade 3 fever causallyrelated to vaccination

5 4.1 1.3 9.2 3 2.5 0.5 7.1 2 1.7 0.2 5.9

Medical advice soughtdue to grade 3 fever

4 3.3 0.9 8.1 3 2.5 0.5 7.1 2 1.7 0.2 5.9

N = number of subjects having received the considered dosen/% = number/percentage of subjects reporting at least one symptom for the considered dose95%CI = Exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit




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Supplement 23: Incidence of general rash in MeMuRu-OKA groups during the 43-day (Day 0-42) follow-up after each dose - Total vaccinated cohort


(N=125)


(N=122)


(N=124)n % 95% CI n % 95% CI n % 95% CI

Types of rash

LL UL LL UL LL ULPost-dose 1Any rash* 22 17.6 11.4 25.4 17 13.9 8.3 21.4 22 17.7 11.5 25.6Any rash with fever 13 10.4 5.65 17.13 13 10.7 5.80 17.53 18 14.5 8.84 21.97Any rash with grade 3intensity

1 0.8 0.0 4.4 1 0.8 0.0 4.5 2 1.6 0.2 5.7

Any rash with causalrelationship to vaccination

7 5.6 2.3 11.2 5 4.1 1.3 9.3 5 4.0 1.3 9.2

Measles/rubella-like rash 4 3.2 0.88 7.99 5 4.1 1.34 9.31 4 3.2 0.89 8.05Varicella-like rash 1 0.8 0.02 4.38 2 1.6 0.20 5.80 1 0.8 0.02 4.41


(N=123)


(N=121)


(N=120)n % 95% CI n % 95% CI n % 95% CI

Types of rash

LL UL LL UL LL ULPost-dose 2Any rash* 6 4.9 1.8 10.3 12 9.9 5.2 16.7 4 3.3 0.9 8.3Any rash with fever 3 2.4 0.51 6.96 4 3.3 0.91 8.25 2 1.7 0.20 5.89Any rash with grade 3intensity

1 0.8 0.0 4.4 1 0.8 0.0 4.5 0 0.0 0.0 3.0

Any rash with causalrelationship to vaccination

1 0.8 0.0 4.4 0 0.0 0.0 3.0 1 0.8 0.0 4.6

Measles/rubella-like rash 0 0.0 0.00 2.95 0 0.0 0.00 3.00 1 0.8 0.02 4.56Varicella-like rash 0 0 0 2.95 0 0 0 3.00 0 0 0 3.03N = number of subjects having received the considered dosen/% = number/percentage of subjects reporting at least one specified symptom for the considered dose95%CI = Exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit* Any rash was a generalised rash occurring at any site other than the site of injectionGrade 3 rash = rash reported with more than 150 lesionsIndividual subjects data can be found in Appendix table IIBi




Page 104

Supplement 24: Number and percentage of subjects in MeMuRu-OKA groups whotook at least one concomitant medication during the 43 days of follow-up (Day 0-42)

- Total Vaccinated CohortMeMuRu-OKA lot

MJRV159A48(N=125)


(N=122)


(N=124)n % 95% CI n % 95% CI n % 95% CI

LL UL LL UL LL ULPost-dose 1Any medication 53 42.4 33.6 51.6 44 36.1 27.6 45.3 42 33.9 25.6 42.9Any antipyretic 36 28.8 21.1 37.6 28 23.0 15.8 31.4 28 22.6 15.6 31.0Prophylactic antipyretic 1 0.8 0.0 4.4 0 0.0 0.0 3.0 0 0.0 0.0 2.9Any antibiotic 6 4.8 1.8 10.2 10 8.2 4.0 14.6 9 7.3 3.4 13.3


(N=123)


(N=121)


(N=120)n % 95% CI n % 95% CI n % 95% CI

LL UL LL UL LL ULPost-dose 2Any medication 44 35.8 27.3 44.9 43 35.5 27.0 44.8 50 41.7 32.7 51.0Any antipyretic 24 19.5 12.9 27.6 19 15.7 9.7 23.4 21 17.5 11.2 25.5Prophylactic antipyretic 1 0.8 0.0 4.4 0 0.0 0.0 3.0 0 0.0 0.0 3.0Any antibiotic 9 7.3 3.4 13.4 10 8.3 4.0 14.7 12 10.0 5.3 16.8N = number of subjects having received the considered dosen/% = number/percentage of subjects who started to take the specified concomitant medication at least once during the mentioned period95%CI = Exact 95% confidence interval, LL = Lower Limit, UL = Upper LimitIndividual subjects data can be found in Appendix table IIDi




Page 105

Supplement 25: Percentage of subjects with unsolicited symptoms classified by WHOBody System and Preferred Term for adverse events within 43 days after dose 1 -

Total Vaccinated CohortMeMuRu-OKA lot

MJRV159A48(N = 125)


(N = 122)


(N = 124)95% CI 95% CI 95% CIBody System

(CODE)Preferred Term

(CODE) s % LL UL s % LL UL s % LL ULAt least onesymptom

58 46.4 37.4 55.5 55 45.1 36.1 54.3 49 39.5 30.9 48.7

Application site(1820)

Injection site reaction(0058)

0 0.0 0 2.9 1 0.8 0 4.5 0 0.0 0 2.9

Body as a whole Crying abnormal (1162) 2 1.6 0.2 5.7 1 0.8 0 4.5 1 0.8 0 4.4general (1810) Fatigue (0724) 2 1.6 0.2 5.7 0 0.0 0 3 1 0.8 0 4.4


4 3.2 0.9 8 2 1.6 0.2 5.8 4 3.2 0.9 8.1

Injury (9001) 3 2.4 0.5 6.9 2 1.6 0.2 5.8 5 4.0 1.3 9.2Pain (0730) 0 0.0 0 2.9 0 0.0 0 3 1 0.8 0 4.4

Central andperipheral nervoussystem (410)

Headache (0109) 1 0.8 0 4.4 0 0.0 0 3 0 0.0 0 2.9

Gastrointestinal Abdominal pain (0268) 0 0.0 0 2.9 0 0.0 0 3 0 0.0 0 2.9system (600) Anorexia (0165) 2 1.6 0.2 5.7 1 0.8 0 4.5 0 0.0 0 2.9

Constipation (0204) 0 0.0 0 2.9 0 0.0 0 3 0 0.0 0 2.9Diarrhea (0205) 8 6.4 2.8 12.2 5 4.1 1.3 9.3 2 1.6 0.2 5.7Enteritis (0282) 6 4.8 1.8 10.2 2 1.6 0.2 5.8 1 0.8 0 4.4

Flatulence (0285) 0 0.0 0 2.9 0 0.0 0 3 2 1.6 0.2 5.7Gastroenteritis (0293) 2 1.6 0.2 5.7 6 4.9 1.8 10.4 9 7.3 3.4 13.3

Gastrointestinal disordernos (1262)

0 0.0 0 2.9 0 0.0 0 3 1 0.8 0 4.4

Stomatitis (0327) 3 2.4 0.5 6.9 0 0.0 0 3 1 0.8 0 4.4Gastrointestinalsystem (600)

Stomatitis aphthous(0751)

1 0.8 0 4.4 1 0.8 0 4.5 0 0.0 0 2.9

Tooth ache (1376) 3 2.4 0.5 6.9 3 2.5 0.5 7 1 0.8 0 4.4Vomiting (0228) 1 0.8 0 4.4 3 2.5 0.5 7 2 1.6 0.2 5.7

Hearing andvestibular (432)

Earache (0260) 0 0.0 0 2.9 0 0.0 0 3 0 0.0 0 2.9

Psychiatric (500) Anxiety (0166) 0 0.0 0 2.9 0 0.0 0 3 0 0.0 0 2.9Emotional lability (0177) 0 0.0 0 2.9 0 0.0 0 3 1 0.8 0 4.4

Insomnia (0183) 1 0.8 0 4.4 0 0.0 0 3 0 0.0 0 2.9Nervousness (0188) 4 3.2 0.9 8 1 0.8 0 4.5 2 1.6 0.2 5.7Somnolence (0197) 1 0.8 0 4.4 0 0.0 0 3 1 0.8 0 4.4

Reproductivefemale (1420)

Vaginitis (0669) 1 0.8 0 4.4 0 0.0 0 3 0 0.0 0 2.9


Penis disorder (1142) 1 0.8 0 4.4 0 0.0 0 3 0 0.0 0 2.9

Resistance Infection (0736) 3 2.4 0.5 6.9 0 0.0 0 3 2 1.6 0.2 5.7mechanism (1830) Infection bacterial

(0738)0 0.0 0 2.9 1 0.8 0 4.5 0 0.0 0 2.9

Infection fungal (0739) 1 0.8 0 4.4 2 1.6 0.2 5.8 0 0.0 0 2.9Resistancemechanism (1830)

Infection viral (0740) 2 1.6 0.2 5.7 2 1.6 0.2 5.8 0 0.0 0 2.9

Moniliasis (0741) 2 1.6 0.2 5.7 2 1.6 0.2 5.8 2 1.6 0.2 5.7(continued)




Page 106

Supplement 25: Percentage of subjects with unsolicited symptoms classified by WHOBody System and Preferred Term for adverse events within 43 days after dose 1 -Total Vaccinated Cohort (cont)


(N = 125)


(N = 122)


(N = 124)95% CI 95% CI 95% CIBody System

(CODE)Preferred Term

(CODE) s % LL UL s % LL UL s % LL ULOtitis media (0750) 1 0.8 0 4.4 4 3.3 0.9 8.2 5 4.0 1.3 9.2

Upper resp tractinfection

(0543)

18 14.4 8.8 21.8 11 9.0 4.6 15.6 14 11.3 6.3 18.2

Respiratory system Bronchitis (0805) 5 4.0 1.3 9.1 4 3.3 0.9 8.2 2 1.6 0.2 5.7(1100) Coughing (0513) 4 3.2 0.9 8 4 3.3 0.9 8.2 3 2.4 0.5 6.9

Epistaxis (0515) 0 0.0 0 2.9 0 0.0 0 3 1 0.8 0 4.4Laryngitis (0521) 1 0.8 0 4.4 2 1.6 0.2 5.8 0 0.0 0 2.9

Respiratory system Pharyngitis (0523) 3 2.4 0.5 6.9 6 4.9 1.8 10.4 3 2.4 0.5 6.9(1100) Rhinitis (0539) 4 3.2 0.9 8 8 6.6 2.9 12.5 8 6.5 2.8 12.3

Stridor (0542) 1 0.8 0 4.4 2 1.6 0.2 5.8 1 0.8 0 4.4Tracheitis (1468) 0 0.0 0 2.9 1 0.8 0 4.5 0 0.0 0 2.9

Skin and Dermatitis (0007) 2 1.6 0.2 5.7 0 0.0 0 3 1 0.8 0 4.4appendages (100) Rash erythematous

(0028)0 0.0 0 2.9 0 0.0 0 3 0 0.0 0 2.9

Vision (431) Blepharitis (1007) 1 0.8 0 4.4 0 0.0 0 3 0 0.0 0 2.9Conjunctivitis (0238) 3 2.4 0.5 6.9 0 0.0 0 3 2 1.6 0.2 5.7

White cell andreticuloendothelialsyste (1220)

Lymphadenopathy(0577)

1 0.8 0 4.4 0 0.0 0 3 0 0.0 0 2.9

At least one symptom = at least one symptom experienced by the subject regardless of the WHO Preferred TermN = number of subjects having received the considered doses/% = number/percentage of subjects reporting at least once a specified symptom within 43 days after vaccination (Day 0-42)95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper LimitIndividual subjects data can be found in Appendix table IIC




Page 107

Supplement 26: Percentage of subjects with unsolicited symptoms classified by WHOBody System and Preferred Term for adverse events within 43 days after dose 2 -

Total Vaccinated CohortMeMuRu-OKA lot

MJRV159A48(N = 123)


(N = 121)


(N = 120)95% CI 95% CI 95% CI

Body System(CODE)


s % LL UL s % LL UL s % LL ULAt least onesymptom

50 40.7 31.9 49.9 45 37.2 28.6 46.4 59 49.2 39.9 58.4

Application site(1820)

Injection site reaction(0058)

0 0.0 0 3 0 0.0 0 3 0 0.0 0 3

Body as a whole Edema genital (1092) 0 0.0 0 3 0 0.0 0 3 0 0.0 0 3general (1810) Influenza-like symptoms

(1222)2 1.6 0.2 5.8 4 3.3 0.9 8.2 2 1.7 0.2 5.9

Injury (9001) 4 3.3 0.9 8.1 0 0.0 0 3 5 4.2 1.4 9.5Pain (0730) 0 0.0 0 3 0 0.0 0 3 1 0.8 0 4.6

Central andperipheral nervoussystem (410)

Fever convulsions* (1357) 1 0.8 0 4.4 0 0.0 0 3 0 0.0 0 3

Fetal (1500) Hernia congenital (0885) 0 0.0 0 3 1 0.8 0 4.5 0 0.0 0 3Gastrointestinal Abdominal pain (0268) 0 0.0 0 3 0 0.0 0 3 0 0.0 0 3system (600) Constipation (0204) 0 0.0 0 3 2 1.7 0.2 5.8 1 0.8 0 4.6

Diarrhea (0205) 1 0.8 0 4.4 2 1.7 0.2 5.8 2 1.7 0.2 5.9Enteritis (0282) 4 3.3 0.9 8.1 1 0.8 0 4.5 4 3.3 0.9 8.3

Gastroenteritis (0293) 5 4.1 1.3 9.2 3 2.5 0.5 7.1 8 6.7 2.9 12.7Stomatitis (0327) 1 0.8 0 4.4 0 0.0 0 3 1 0.8 0 4.6

Stomatitis aphthous(0751)

0 0.0 0 3 1 0.8 0 4.5 1 0.8 0 4.6

Tooth ache (1376) 2 1.6 0.2 5.8 1 0.8 0 4.5 1 0.8 0 4.6Vomiting (0228) 2 1.6 0.2 5.8 1 0.8 0 4.5 2 1.7 0.2 5.9

Metabolic andnutritional (800)

Dehydration (0370) 0 0.0 0 3 1 0.8 0 4.5 0 0.0 0 3

Psychiatric (500) Insomnia (0183) 1 0.8 0 4.4 0 0.0 0 3 1 0.8 0 4.6Nervousness (0188) 1 0.8 0 4.4 0 0.0 0 3 1 0.8 0 4.6


Balanoposthitis (0630) 0 0.0 0 3 0 0.0 0 3 0 0.0 0 3

Resistance Abscess (0887) 0 0.0 0 3 0 0.0 0 3 1 0.8 0 4.6mechanism (1830) Infection (0736) 2 1.6 0.2 5.8 2 1.7 0.2 5.8 0 0.0 0 3

Infection fungal (0739) 0 0.0 0 3 0 0.0 0 3 1 0.8 0 4.6Infection viral (0740) 2 1.6 0.2 5.8 0 0.0 0 3 2 1.7 0.2 5.9

Moniliasis (0741) 2 1.6 0.2 5.8 1 0.8 0 4.5 2 1.7 0.2 5.9Otitis media (0750) 5 4.1 1.3 9.2 4 3.3 0.9 8.2 8 6.7 2.9 12.7


16 13.0 7.6 20.3 14 11.6 6.5 18.7 19 15.8 9.8 23.6

Respiratory system Asthma (1367) 0 0.0 0 3 0 0.0 0 3 1 0.8 0 4.6(1100) Bronchitis (0805) 5 4.1 1.3 9.2 3 2.5 0.5 7.1 5 4.2 1.4 9.5

Bronchospasm (0511) 1 0.8 0 4.4 1 0.8 0 4.5 1 0.8 0 4.6Coughing (0513) 0 0.0 0 3 2 1.7 0.2 5.8 3 2.5 0.5 7.1Laryngitis (0521) 0 0.0 0 3 1 0.8 0 4.5 0 0.0 0 3

Pharyngitis (0523) 2 1.6 0.2 5.8 0 0.0 0 3 4 3.3 0.9 8.3Respiratory disorder

(0536)1 0.8 0 4.4 0 0.0 0 3 0 0.0 0 3

Rhinitis (0539) 6 4.9 1.8 10.3 8 6.6 2.9 12.6 10 8.3 4.1 14.8(continued)




Page 108

Supplement 26: Percentage of subjects with unsolicited symptoms classified by WHOBody System and Preferred Term for adverse events within 43 days after dose 2 -Total Vaccinated Cohort (cont)


(N = 123)


(N = 121)


(N = 120)95% CI 95% CI 95% CI

Body System(CODE)


s % LL UL s % LL UL s % LL ULSinusitis (0540) 0 0.0 0 3 1 0.8 0 4.5 0 0.0 0 3

Sputum increased (0541) 0 0.0 0 3 1 0.8 0 4.5 0 0.0 0 3Stridor (0542) 2 1.6 0.2 5.8 0 0.0 0 3 0 0.0 0 3

Tracheitis (1468) 0 0.0 0 3 0 0.0 0 3 1 0.8 0 4.6Skin and Dermatitis (0007) 2 1.6 0.2 5.8 0 0.0 0 3 1 0.8 0 4.6appendages (100) Dermatitis lichenoid

(0010)1 0.8 0 4.4 0 0.0 0 3 0 0.0 0 3

Nail disorder (0020) 1 0.8 0 4.4 0 0.0 0 3 0 0.0 0 3Skin ulceration (0041) 0 0.0 0 3 0 0.0 0 3 1 0.8 0 4.6

Vision (431) Conjunctivitis (0238) 0 0.0 0 3 1 0.8 0 4.5 4 3.3 0.9 8.3White cell andreticuloendothelialsyste (1220)

Lymphadenopathy (0577) 1 0.8 0 4.4 0 0.0 0 3 0 0.0 0 3

At least one symptom = at least one symptom experienced (regardless of the Preferred Term)N = number of subjects having received the considered doses/% = number/percentage of subjects reporting at least once a specified symptom within 43 days after vaccination day 0 to day 4295% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit* symptom already reported in the solicited symptom section .Individual subjects data can be found in Appendix table IIC




Page 109

Clintrial Eligibility Codes

Elimination from safety and immunogenicity analysis (ITT and ATP)1010 Subject or vaccine number not allocated

Vaccine not administered at allNo subject attributed for the number randomised or for the vaccine number

Elimination from safety and immunogenicity analysis (ATP)1030 Vaccine not administered at all but subject number allocated1040 Administration of vaccine not specified or forbidden in the protocol1050 Randomisation failure (subject not randomised in the correct group)1060 Randomisation code broken at the investigator site (only for blinded study)1070 Study vaccine dose not administered according to protocol:

One of planned multiple injections not administered and NOT due to drop out- Side, site or route of study vaccine administration wrong or unknown- Replacement vial used NOT corresponding to the correct randomization group- Subject number not in the randomization list and not requested by the sponsor (extra PID)Wrong vaccine vials given

1500 Others

Elimination from immunogenicity analysis (ATP)2010 Protocol violation (inclusion/exclusion criteria)

Demographics Too youngToo oldUnknown age

2020 Initially seropositive or unknown antibody status for at least one antigen2040 Administration of any medication forbidden by the protocol2050 Underlying medical condition2060 Concomitant infection related to the vaccine which may influence immune

response. Infection related to any of the vaccine component.2080 Non compliance with vaccination schedules (dates of vaccination not

corresponding to adapted protocol intervals or unknown vaccination dates)2090 Non compliance with blood sampling schedules (dates of BS not

corresponding to adapted protocol intervals or unknown BS dates)2100 Serological results not available for all antigens and ALL blood samples

POST vaccination (including BS lost, Not Done, unable to test, absence of parallelism)

2120 Obvious incoherence, abnormal serology evolution or error in data (incoherence between CRF and results, wrong labelling in BS)




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Notes to appendix tables

The following abbreviations are common throughout the Appendix tables:

Sub. No. subject numberElig /Elim (code) eligibility/ eliminated from analysis(es)

E eliminated from reactogenicity and immunogenicity analysesI eliminated from immunogenicity analysis

Ctr. Study site

Abbreviations which are unique to a particular appendix are presented below:

Appendix IBF: femaleM maleAppendix ICPre pre-vaccination blood samplingPI (D42 or W6) post-vaccination blood sampling at Day 42 or Week 6PI (D84 or W12) post-vaccination blood sampling at Day 84 or Week 12Appendix Iciii reason for visit not doneSAM same reason and decision as previous visitSAE serious adverse eventAEX non-serious adverse eventOTH othersAppendix IDStatus: Past medical historyCurrent present at the physical examinationBoth past and currentAppendix IIAM? Any medical advice sought: Y/N: Yes/NoL? Any local symptoms: Y/N: Yes/ NoMA Medical advice sought for the symptom: Y: Yes or BlankSite Site of vaccinationSide Left/ RightExp Symptom experienced: Y/N: Yes / NoPA Pain scored as Empty or from 0 to 3RE Redness in millimetre (greatest diameter)SW Swelling in millimetre (greatest diameter)Last day End day of symptom if it has continued after the solicited

follow-up periodCau Causality: relationship to investigational product (Y/N:

yes/no)VA vaccine (study/replacement vaccine)Adm? Has the vaccine been administered?

S: study vaccineR: Replacement vaccineW: Wrong vial numberN: not administered




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Appendix IIBi-IIBviM? Any medical advice sought: Y/N: Yes/NoG? Any general symptom: Y/N: Yes / NoExp Adverse event: Y/N: Yes / NoMA Medical advice sought for the symptom: Y: Yes or BlankSymptomsTE Temperature = Body temperature in °C or °FOther general symptoms (where applicable) scored as:

Empty / 0 = no adverse event1 = adverse event which is easily tolerated2 = adverse event sufficiently discomforting to interfere with daily activities3 = adverse event which prevents normal everyday activities.

RA RashRL Local rashRoute Route (for body temperature recording):

A = axillaryR = rectal

O? On going at the end of the solicited follow-up period Y/N:Yes/No

Last day End day of symptom if it has continued after the solicitedfollow-up period

FC febrile convulsions:Intensity (1: mild; 2: moderate and 3: severe)

Neur neurological test performed? (Yes or No)Lumbar lumbar puncture performed? (Yes or No)PS parotid salivary gland swellingTak saliva sample taken? Yes or no; date of collectionAdm sit Administration site (G/GEN:Generalised; L/LOC: Localised)

Appendix IIBii, IIBiii, IIBvi, IICiAenb subject�s adverse event numberVerbatim Description of experience as recorded in the case report formKeyword Specific identification terminology linked to WHO

classification codesWHO code Code for WHO preferred term, a WHO adverse reaction

classification systemL/G local or generalPrev. dose (Pr DO) previous vaccine dosePreferred term Medical term assigned to the keyword/ verbatimBody syst Numeric code in relation with the location of the adverse

event in the bodyPr. Do Dose given prior to the adverse eventStart date Date of onset of adverse eventDay onset Number of days since last vaccine doseEnd date Date of end of adverse eventDur (d) Duration (days)Max Fever maximum temperature during the period with rashVF Take vesicular fluid sample taken




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VF data vesicular fluid dateComm commentOut outcome 1 = recovered/resolved

2 = recovering/resolving3 = not recovered/not resolved4 = recovered with sequelae/resolved with sequelae

caus causality: Y/N: Yes/NoMA Medical advice soughtHO Hospitalisation occurred

Ser serious adverse event: Y/N: Yes/ NoCor corrective therapyInt. Intensity:

Empty /0 = no adverse event1 = adverse event which is easily tolerated2 = adverse event sufficiently discomforting to interfere with daily

activities3 = adverse event which prevents normal everyday activities.

Appendix IIDiPrev. dose previous vaccine doseRel. day of onset day of onset of medication, relative to day of previous

vaccinationStart date date when medication administration startedEnd date date of end of medicationDur (day) duration (days)Trade-Generic name trade and/or generic name of medicationMedical indic. medical indication for which medication was usedCode (P/T) Prophylactic medication Y (Yes) or blank/ TreatmentAntibiot antibioticAntipyr antipyreticProph prophylactic

Appendix IIDiiTrade name trade name of vaccine administeredStart date date of administration of concomitant vaccine

Appendix IIIAcut Cut-off of the laboratory assayAP Absence of parallelismBS ND Blood sampling not doneIR Invalid resultQNS Quantity of serum not sufficientTNR Test not requestedBlank Blood sample not available or test not requested

AppendicesIndividual Listings

This section contained data from each individual patient, rather than in aggregate. They have

been excluded to protect patient privacy. Anonymized data from each patient may be made

available subject to an approved research proposal. For further information please see the

Patient Level Data section of the GSK Clinical Study Register.

AppendicesSerious Adverse Events

SAE Narratives

SAE Table

This section contained patient narratives which are textual descriptions of medical history,

treatment and outcome for individual patients who experienced a clinically important adverse

event including serious adverse events during the trial. They have been excluded to protect

patient privacy. This data may be made available subject to an approved research proposal and

a determination of the ability to provide information from the specific narratives whilst protecting

the patient’s privacy. For further information please see the Patient Level Data section of

the GSK Clinical Study Register.

Appendices

Study Information

Protocol

GlaxoSmithKline BiologicalsRue de l'Institut 89

1330 Rixensart, BelgiumConfidential & Proprietary Information

This protocol was developed based on Version 12 of GlaxoSmithKline Biologicals’ Protocol DocumentStandard.

Study vaccine GlaxoSmithKline Biologicals’ live attenuated measles - mumps -rubella - varicella candidate vaccine (MeMuRu-OKA)

CPMS Nos. 208136/038 (MeMuRu-OKA-038) Active phase period208136/039 (MeMuRu-OKA-039) Year 1 Follow-up208136/040 (MeMuRu-OKA-040) Year 2 Follow-up208136/041 (MeMuRu-OKA-041) Year 3 Follow-up

Date of approval Final 25 March 2003

Title A phase III, randomised, controlled study to evaluate theimmunogenicity and safety of three production lots ofGlaxoSmithKline Biologicals’ combined measles-mumps-rubella-varicella (MeMuRu-OKA) candidate vaccine given on a two-doseschedule to healthy children in their second year of life, ascompared to separate administration of GlaxoSmithKlineBiologicals’ measles-mumps-rubella vaccine (Priorix®) andvaricella vaccine (Varilrix®).

Coordinating author Scientific writer

Contributing authors MD, Associate Director, Clinical R & DManager, Bio-statistics

Central Study Coordinator

Sponsor signatory approval

MDAssociate Director, ClinicalResearch & DevelopmentGlaxoSmithKline Biologicals

Date of signature

25 March 2003 GlaxoSmithKline BiologicalsConfidential and Proprietary InformationFinal Protocol 208136/038 (MeMuRu-OKA-038)

2

Investigator Agreement (Germany)

CPMS Study Number 208136/038 (MeMuRu-OKA-038)

Title A phase III, randomised, controlled study to evaluate theimmunogenicity and safety of three production lots ofGlaxoSmithKline Biologicals’ combined measles-mumps-rubella-varicella (MeMuRu-OKA) candidate vaccine given ona two-dose schedule to healthy children in their second year oflife, as compared to separate administration ofGlaxoSmithKline Biologicals’ measles-mumps-rubellavaccine (Priorix®) and varicella vaccine (Varilrix®).

I agree:• To assume responsibility for the proper conduct of the study at this site.

• To conduct the study in compliance with this protocol, any mutually agreed futureprotocol amendments, and with any other study conduct procedures provided byGlaxoSmithKline Biologicals (GSK Biologicals).

• Not to implement any changes to the protocol without agreement from the sponsorand prior review and written approval from the Institutional Review Board (IRB) orIndependent Ethics Committee (IEC), except where necessary to eliminate animmediate hazard to the subjects, or for administrative aspects of the study (wherepermitted by all applicable regulatory requirements).

• That I am thoroughly familiar with the appropriate use of the vaccine, as described inthis protocol, and any other information provided by the sponsor, including, but notlimited to, the following: the current Investigator’s Brochure (IB) or equivalentdocument, IB supplement (if applicable), prescribing information (in the case of amarketed vaccine) and/or Master Data Sheet (if the Master Data Sheet exists andserves as reference document for the vaccine in the case of a marketed vaccine).

• That I am aware of, and will comply with, “Good Clinical Practices” (GCP) and allapplicable regulatory requirements.

• That I have been informed that certain regulatory authorities require the sponsor toobtain and supply, as necessary, details about the investigator’s ownership interest inthe sponsor or the investigational product, and more generally about his/her financialties with the sponsor. GSK Biologicals will use and disclose the information solelyfor the purpose of complying with regulatory requirements.

Hence I:• Agree to supply GSK Biologicals with any necessary information regarding

ownership interest and financial ties (including those of my spouse and dependentchildren).

• Agree to promptly update this information if any relevant changes occur during thecourse of the study and for 1 year following completion of the study.


3

• Agree that GSK Biologicals may disclose any information it has about suchownership interests and financial ties to regulatory authorities.

• Agree to provide GSK Biologicals with an updated Curriculum Vitae and other FDArequired documents.

Principal Investigator:Signature Date

Prof. Dr.

“Leiter der klinischen Prüfung” (LKP)

Signature Date

Dr. med habil.


4

Investigator Agreement (Austria)













5

• Agree that GSK Biologicals may disclose any information it has about suchownership interests and financial ties to regulatory authorities.

• Agree to provide GSK Biologicals with an updated Curriculum Vitae and other FDArequired documents.

Principal Investigators:Signature Date

Dr.

Dr.

Dr.

Dr.


6

Synopsis

Title A phase III, randomised, controlled study to evaluate the immunogenicityand safety of three production lots of GlaxoSmithKline Biologicals’combined measles-mumps-rubella-varicella (MeMuRu-OKA) candidatevaccine given on a two-dose schedule to healthy children in their secondyear of life, as compared to separate administration of GlaxoSmithKlineBiologicals’ measles-mumps-rubella vaccine (Priorix®) and varicellavaccine (Varilrix®).

Indication/Studypopulation

Active immunization of healthy children during their second yearof life against measles, mumps, rubella and varicella diseases.

Rationale Many countries worldwide recommend two doses of MMR vaccine, thefirst dose generally in the second year of life and the second dose either at4-6 years or 11-12 years of age, depending on local recommendations.Because the vaccination coverage for the second dose is not alwaysoptimal, some countries like Germany now recommend to give both dosesof MMR vaccine in the second year of life1.

On the other hand, recent studies 2, 3 have reported that the currentvaccination strategy for varicella may not be appropriate because of theoccurrence of varicella breakthrough cases and outbreaks after routinevaccination. The need for a second dose of varicella vaccine to childrenhas been proposed as a strategy to enhance protection against anyvaricella disease. Because of the observation that the occurrence ofbreakthrough cases of varicella increases with the time since vaccination,the second dose of varicella should ideally be given in a reasonable timeframe after the first one.

Based on these considerations, the availability of a combined measles-mumps-rubella-varicella vaccine that could be given on a two-doseschedule in the second year of life may adequately address vaccinationneeds against measles, mumps, rubella (increased vaccination coveragefor the second dose of MMR) and varicella (increased protection againstany varicella disease, and decreased number of breakthrough cases ofvaricella after vaccination) as well as offering the convenience of lessinjections.

GSK Biologicals' MeMuRu-OKA candidate vaccine administered on atwo-dose schedule has been tested in a previous trial (study MeMuRu-OKA-018). In this study, the first dose was given at 9 months of age andthe second dose was given at 12 months of age. After two doses, thecandidate vaccine was shown to be immunogenic (100% seroconversion


7

to measles, mumps, rubella and varicella), safe and well tolerated.

The present study is proposed to evaluate the consistency of threeproduction lots of MeMuRu-OKA vaccine, as well as the immunogenicityand safety of MeMuRu-OKA vaccine administered on a two-doseschedule to healthy children in their second year of life, in comparison toGSK Biologicals' MMR vaccine (Priorix) given on a two-dose scheduleand one dose of GSK Biologicals' Varicella vaccine (Varilrix). The studywill also evaluate the antibody persistence for measles, mumps, rubellaand varicella and will assess the occurrence of varicella breakthroughcases for a three-year period after vaccination in a subset of subjects.

Objectives Active phase of the study

Co-primary (sequential):

• To demonstrate the consistency of three production lots of MeMuRu-OKA candidate vaccine in terms of measles, mumps, rubella andvaricella seroconversion, 42-56 days after the second dose.

• To demonstrate the non-inferiority of MeMuRu-OKA candidatevaccine to separate administration of Priorix and Varilrix vaccines interms of measles, mumps, rubella and varicella seroconversion, 42-56days after the second dose.

Secondary:

• To assess the immunogenicity of the study vaccines in terms ofantibody titres to each vaccine component, 42-56 days after thesecond dose.

• To assess the immunogenicity of the study vaccines in terms ofseroconversion and antibody titres to each vaccine component, 42-56days after the first dose.

• To assess the safety of the study vaccines after the first and the seconddose.

Long-term objectives

• To evaluate the persistence of measles, mumps, rubella and varicellaantibodies on a yearly basis for a period of three years aftervaccination.

• To assess the occurrence of breakthrough cases (confirmed by a


8

physician) of measles, mumps, rubella and/or varicella for a period ofthree years after vaccination.

• To assess the occurrence of contacts with measles, mumps, rubellaand/or varicella/herpes zoster for a period of three years aftervaccination.

Studydesign

• Phase III, randomised (1:1:1:1), controlled study with four parallelgroups:

Subjects in Group MeMuRu-OKA lot A will receive two doses ofGSK Biologicals’ MeMuRu-OKA vaccine lot A administered atVisit 1/Day 0 and Visit 2/Week 6

Subjects in Group MeMuRu-OKA lot B will receive two doses ofGSK Biologicals’ MeMuRu-OKA vaccine lot B administered atVisit 1/Day 0 and Visit 2/Week 6

Subjects in Group MeMuRu-OKA lot C will receive two doses ofGSK Biologicals’ MeMuRu-OKA vaccine lot C administered atVisit 1/Day 0 and Visit 2/Week 6

Subjects in Group Priorix + Varilrix will receive one dose ofGSK Biologicals’ licensed measles-mumps-rubella (Priorix)vaccine administered concomitantly with one dose of varicella(Varilrix) vaccine at Visit 1/Day 0 and a second dose of Priorixadministered at Visit 2/Week 6.

• All vaccines will be administered subcutaneously to healthy infants intheir second year of life (6-week apart).

• Blinding: The study will be conducted double-blind for GroupsMeMuRu-OKA lots A-B-C and open for Groups MeMuRu-OKA lotsA-B-C versus Group Priorix + Varilrix. Refer to Section 6.5 fordetails.

• Four millilitres (4 ml) of blood will be collected for all subjects ateach time point as follows: Pre-vaccination (Visit1/Day 0), post-dose1 (Visit 2/ Week 6) and post-dose 2 (Visit 3/Week 12). Threeadditional blood samples will also be collected during the 3-yearfollow-up period (4 ml of blood per year) in a subset of subjects forthe assessment of antibody persistence at Visit 4/Year 1, Visit 5/Year


9

2 and Visit 6/Year 3.

• The study duration for each subject will be approximately 12 weeksfor the active phase of the study and 3 years for the whole study,including the long-term follow-up. The long-term follow-up will beidentified by CPMS protocol numbers 208136/039 (MeMuRu-OKA-039) for Year 1, 208136/040 (MeMuRu-OKA-040) for Year 2 and208136/041 (MeMuRu-OKA-041) for Year 3.

• All subjects should be enrolled within a period of 8 weeks (seeAppendix C).

• Data Collection: Electronic Case Report Forms (eCRF) or RemoteData Entry (RDE).

• This study is self-contained.

Number of subjects A total of 480 eligible children will be enrolled in the study toachieve the target sample size of 400 evaluable subjects (100subjects per group) at the time of analysis for the according toprotocol (ATP) immunogenicity cohort at Week 12.

Endpoints Active phase of the study

Primary endpoint

• Measles, mumps, rubella and varicella seroconversion, 42-56 days after the second dose.

Secondary endpoints

Immunogenicity

• Measles, mumps, rubella and varicella antibody titres, 42-56 days after the first dose and 42-56 days after the seconddose.

• Measles, mumps, rubella and varicella seroconversion andantibody titres, 42-56 days after the first dose.

Safety

• Occurrence of any fever and grade 3 fever (defined asaxillary temperature >39.0°C) within 15 days after eachvaccination (Day 0-14).

• Occurrence of any and grade 3 solicited local symptoms


10

within 4 days after each vaccination (Day 0-3).

• Occurrence of any and grade 3 solicited general symptoms(fever, rash, any sign of meningitis including febrileconvulsion, parotitis) within 43 days after each vaccination(Day 0-42).

• Occurrence, intensity and relationship to vaccination ofunsolicited symptoms within 43 days after each vaccination(Day 0-42).

• Occurrence of SAEs throughout the entire study up to andincluding 42 days after vaccination.

Long-term endpoints

• Seroconversion/ seropositivity and antibody titres tomeasles, mumps, rubella and varicella at 1, 2 and 3 yearsafter vaccination.

• Occurence of breakthrough cases (confirmed by aphysician) of measles, mumps, rubella and/or varicelladuring the 3-year follow-up period after vaccination.

• Contacts with measles, mumps, rubella and/orvaricella/herpes zoster diseases during the 3-year follow-upperiod after vaccination.


11

Table of ContentsSynopsis..........................................................................................................................6Table of Contents .......................................................................................................... 11List of Abbreviations..................................................................................................... 14Glossary of Terms ......................................................................................................... 151 Introduction ............................................................................................................. 17

1.1 Background ................................................................................................... 171.2 Rationale for the study................................................................................... 17

2 Objective(s) ............................................................................................................. 182.1 Active phase of the study............................................................................... 18

2.1.1 Co-primary objectives (sequential) ......................................................... 182.1.2 Secondary objectives .............................................................................. 18

2.2 Long-term objectives..................................................................................... 193 Study Design Overview ........................................................................................... 194 Study Cohort ........................................................................................................... 21

4.1 Number of subjects / centres.......................................................................... 214.2 Inclusion criteria............................................................................................ 21

4.2.1 Inclusion criteria for the active phase of the study................................... 214.2.2 Inclusion criteria for the long-term follow-up.......................................... 21

4.3 Exclusion criteria for enrolment..................................................................... 224.3.1 Exclusion criteria for the active phase of the study.................................. 224.3.2 Exclusion criteria for the long-term follow-up ........................................ 23

4.4 Elimination criteria........................................................................................ 234.4.1 Elimination criteria for the active phase .................................................. 234.4.2 Elimination criteria for the long-term follow-up...................................... 24

4.5 Precautions to vaccination ............................................................................. 245 Conduct of Study..................................................................................................... 25

5.1 Ethics and regulatory considerations.............................................................. 255.1.1 Institutional Review Board/Independent Ethics Committee (IRB/IEC) ... 255.1.2 Informed consent .................................................................................... 26

5.2 General study aspects .................................................................................... 295.2.1 Outline of study procedures .................................................................... 30

5.3 Detailed description of study stages/visits...................................................... 325.4 Sample handling and analysis ........................................................................ 37

5.4.1 Treatment and storage of biological samples........................................... 375.4.2 Laboratory assays ................................................................................... 385.4.3 Serology plan.......................................................................................... 385.4.4 Endpoints for sub-optimal response ........................................................ 38

6 Investigational Products and Administration............................................................ 396.1 Study vaccines............................................................................................... 39


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6.2 Dosage and administration............................................................................. 406.3 Storage .......................................................................................................... 416.4 Treatment allocation and randomisation ........................................................ 41

6.4.1 Randomization of supplies...................................................................... 416.4.2 Randomization of subjects ...................................................................... 41

6.5 Method of blinding and breaking the study blind ........................................... 426.6 Replacement of unusable vaccine doses......................................................... 426.7 Packaging...................................................................................................... 436.8 Vaccine accountability................................................................................... 436.9 Concomitant medication/treatment ................................................................ 43

7 Adverse Events and Serious Adverse Events............................................................ 447.1 Definition of an adverse event ....................................................................... 447.2 Definition of a serious adverse event ............................................................. 457.3 Lack of efficacy............................................................................................. 467.4 Clinical laboratory parameters and other abnormal assessments qualifying as

adverse events and serious adverse events ..................................................... 467.5 Time period, frequency, and method of detecting adverse events and serious

adverse events ............................................................................................... 477.5.1 Solicited adverse events.......................................................................... 48

7.6 Evaluating adverse events and serious adverse events.................................... 517.6.1 Assessment of intensity........................................................................... 517.6.2 Assessment of causality .......................................................................... 53

7.7 Follow-up of adverse events and serious adverse events and assessment ofoutcome......................................................................................................... 54

7.8 Prompt reporting of serious adverse events to GSK Biologicals..................... 557.8.1 Time frames for submitting serious adverse event reports to GSK

Biologicals.............................................................................................. 557.8.2 Completion and transmission of serious adverse event reports to GSK

Biologicals.............................................................................................. 567.9 Regulatory reporting requirements for serious adverse events........................ 577.10 Post study adverse events and serious adverse events..................................... 587.11 Pregnancy...................................................................................................... 587.12 Treatment of adverse events .......................................................................... 58

8 Subject Completion and Withdrawal........................................................................ 588.1 Subject completion ........................................................................................ 588.2 Subject withdrawal ........................................................................................ 58

8.2.1 Subject withdrawal from the study.......................................................... 598.2.2 Subject withdrawal from investigational product .................................... 59

9 Data Evaluation: Criteria for Evaluation of Objectives............................................. 609.1 Active phase of the study............................................................................... 60

9.1.1 Co-primary endpoints ............................................................................. 60


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9.1.2 Secondary endpoints............................................................................... 609.2 Long-term endpoints ..................................................................................... 619.3 Estimated sample size.................................................................................... 619.4 Study cohorts to be evaluated ........................................................................ 629.5 Derived and transformed data........................................................................ 639.6 Final analyses................................................................................................ 64

9.6.1 Analysis of demographics/baseline characteristics .................................. 649.6.2 Analysis of immunogenicity ................................................................... 649.6.3 Analysis of safety ................................................................................... 65

9.7 Planned interim analysis ................................................................................ 6610 Administrative Matters ............................................................................................ 66APPENDICES

Appendix A: World Medical Association Declaration of HelsinkiAppendix B: Administrative MattersAppendix C: Overview of the Recruitment PlanAppendix D: Handling of Biological Samples Collected by the InvestigatorAppendix E: Shipment of Biological SamplesAppendix F: Laboratory AssaysAppendix G: Vaccine supplies, packaging and accountabilityAppendix H: Example of Temperature log sheetAppendix I: Amendments and Modifications to the Protocol


14

List of AbbreviationsAE(s) Adverse Event(s)ATP According-to-protocolCCID50 Median Cell Culture Infective DosesCI Confidence IntervalCPMS Clinical Programs Monitoring SystemCSF Cerebrospinal fluideCRF Electronic Case Report FormGMT Geometric mean titreGSK Bio GlaxoSmithKline BiologicalsHIV Human immunodeficiency virusIEC Independent Ethics CommitteeIFA Immunofluorescence assayIU International unitIU/ml International unit per millilitreMedDRA Medical Dictionary for Regulatory ActivitiesMMR Measles-Mumps-Rubellamg MilligrammIU/ml Milli-international units per millilitremm MillimetrePCR Polymerase Chain Reactionpfu Plaque forming unitsPID Patient identification number® Registered trademark of a companyRDE Remote Data EntrySAE(s) Serious Adverse Event(s)SBIR GlaxoSmithKline RandomisationSC SubcutaneousSOP Standard Operating ProcedureSST Serum separator tubesU UnitU/ml Unit per millilitreVZV Varicella-Zoster VirusWHO World Health Organisation


15

Glossary of TermsAdverse event: Any untoward medical occurrence in a patient or clinical

investigation subject administered a pharmaceuticalproduct and which does not necessarily have a causalrelationship with the pharmaceutical product (as definedby ICH Guideline for Good Clinical Practice).

Blinding: A procedure in which one or more parties to the trial arekept unaware of the treatment assignment in order toreduce the risk of biased study outcomes. In a single-blindtrial, the investigator and/or his staff are aware of thetreatment assignment but the subject is not. When theinvestigator and sponsor staff who are involved in thetreatment or clinical evaluation of the subjects andreview/analysis of data are also unaware of the treatmentassignments, the study is double blind. This level ofblinding is maintained throughout the conduct of the trial,and only when the data are cleaned to an acceptable levelof quality will appropriate personnel be unblinded or whenrequired in case of a serious adverse event.

Central Study Coordinator: An individual assigned by and centrally located at GSKBiologicals at Rixensart who is responsible for assuringproper conduct of a clinical study.

Eligible: Qualified for enrolment into the study based upon strictadherence to inclusion/exclusion criteria.

Evaluable: Meeting all eligibility criteria, complying with theprocedures defined in the protocol, and, therefore, includedin the according-to-protocol (ATP) analysis (see Sections4.4 and 9.4 for details on criteria for evaluability).

Investigational product: A pharmaceutical form of an active ingredient or placebobeing tested or used as a reference in a clinical trial,including a product with a marketing authorization whenused in a way different from the approved form, or whenused for an unapproved indication, or when used to gainfurther information about an approved use.

Medical Monitor: An individual medically qualified to assume theresponsibilities of the sponsor (GSK Biologicals)especially in regards to the ethics, clinical safety of a studyand the assessment of adverse events.

Protocol amendment: Any change in a clinical protocol which affects the safetyof subjects, the scope, design, assessments or scientificvalidity of the clinical investigation, e.g., dose change,duration of treatment, number of subjects, controlgroup(s), the assessments.


16

Protocol modification: Strictly, any change to a clinical protocol that is notconsidered to be a protocol amendment. In essence,changes to clarify (but not alter) existing design features ofa clinical investigation or to encourage greater compliancewith the intent of the clinical protocol may be issued asmodifications rather than amendments. A protocolmodification addresses logistical or administrative aspectsof the study (e.g., change of monitor(s), telephonenumber(s).

Site Monitor: An individual assigned by the sponsor who is responsiblefor assuring proper conduct of clinical studies at one ormore investigational sites.

Solicited adverse event: Adverse events (AEs) to be recorded as endpoints in theclinical study. The presence/occurrence/intensity of theseevents is actively solicited from the subject or an observerduring a specified post-vaccination follow-up period.

Study Monitor: An individual assigned by the sponsor who is responsiblefor assuring proper conduct of a clinical study.

Subject(s): Term used throughout the protocol to denote the enrolledindividual(s), who participate in the clinical study, eitheras a recipient of the investigational product(s) or as acontrol).

Unsolicited adverse event: Any adverse event (AE) reported in addition to thosesolicited during the clinical study. Also any “solicited”symptom with onset outside the specified period of follow-up for solicited symptoms will be reported as anunsolicited adverse event.

MeMuRu-OKA GSK Biologicals’ combined measles-mumps-rubella-varicella candidate vaccine.

Priorix GSK Biologicals’ licensed vaccine against measles,mumps and rubella.

Varilrix GSK Biologicals’ licensed vaccine against varicella.


17

1 Introduction

1.1 Background

Measles (M)-mumps (M)-rubella (R) and varicella vaccines are both indicated in childrenduring the second year of life, and can be given concomitantly but at separate injectionsites. The possibility to give both vaccines in a single injection as a tetravalent measles-mumps-rubella-varicella vaccine would be of convenience for medical practitioners andwould lead to better compliance to vaccination.

MMR vaccine is routinely used worldwide for immunisation against measles, mumps andrubella diseases. Vaccines against varicella are licensed in many countries and universalvaricella vaccination has been implemented in the USA and Uruguay. GlaxoSmithKline(GSK) Biologicals' measles-mumps-rubella vaccine (Priorix ) and varicella vaccine(Varilrix ) are registered in many countries worldwide. GSK Biologicals has alsodeveloped a combined tetravalent measles-mumps-rubella-varicella vaccine (referred toas “MeMuRu-OKA”). Such a combination offers convenience for medical practitionersand parents by combining the benefits of MMR and varicella vaccination in a singleinjection.

1.2 Rationale for the study

Many countries worldwide recommend two doses of MMR vaccine, the first dosegenerally in the second year of life and the second dose either at 4-6 years or 11-12 yearsof age, depending on local recommendations. Because the vaccination coverage for thesecond dose is not always optimal, some countries like Germany now recommend to giveboth doses of MMR vaccine in the second year of life1.

On the other hand, recent studies 2, 3 have reported that the current vaccination strategyfor varicella may not be appropriate because of the occurrence of varicella breakthroughcases and outbreaks after routine vaccination. The need for a second dose of varicellavaccine to children has been proposed as a strategy to enhance protection against anyvaricella disease. Because of the observation that the occurrence of breakthrough cases ofvaricella increases with the time since vaccination, the second dose of varicella shouldideally be given in a reasonable time frame after the first one.

Based on these considerations, the availability of a combined measles-mumps-rubella-varicella vaccine that could be given on a two-dose schedule in the second year of lifemay adequately address vaccination needs against measles, mumps, rubella (increasedvaccination coverage for the second dose of MMR) and varicella (increased protection


18

against any varicella disease, and decreased number of breakthrough cases of varicellaafter vaccination) as well as offering the convenience of less injections.

GSK Biologicals' MeMuRu-OKA candidate vaccine administered on a two-doseschedule has been tested in a previous trial (study MeMuRu-OKA-018). In this study, thefirst dose was given at 9 months of age and the second dose was given at 12 months ofage. After two doses, the candidate vaccine was shown to be immunogenic (100%seroconversion to measles, mumps, rubella and varicella), safe and well tolerated.

The present study is proposed to evaluate the consistency of three production lots ofMeMuRu-OKA vaccine, as well as the immunogenicity and safety of MeMuRu-OKAvaccine administered on a two-dose schedule to healthy children in their second year oflife, in comparison to GSK Biologicals' MMR vaccine (Priorix) given on a two-doseschedule and one dose of GSK Biologicals' Varicella vaccine (Varilrix). The study willalso evaluate the antibody persistence for measles, mumps, rubella and varicella and willassess the occurrence of varicella breakthrough cases for a three-year period aftervaccination in a subset of subjects.

2 Objective(s)

2.1 Active phase of the study

2.1.1 Co-primary objectives (sequential)

• To demonstrate the consistency of three production lots of MeMuRu-OKA candidatevaccine in terms of measles, mumps, rubella and varicella seroconversion, 42-56 daysafter the second dose.

• To demonstrate the non-inferiority of MeMuRu-OKA candidate vaccine to separateadministration of Priorix and Varilrix vaccines in terms of measles, mumps, rubellaand varicella seroconversion, 42-56 days after the second dose.

Refer to Section 9.1.1 for definition of the co-primary endpoint.

2.1.2 Secondary objectives

• To assess the immunogenicity of the study vaccines in terms of antibody titres to eachvaccine component, 42-56 days after the second dose.


19

• To assess the immunogenicity of the study vaccines in terms of seroconversion andantibody titres to each vaccine component, 42-56 days after the first dose.

• To assess the safety of the study vaccines after the first and the second dose.

Refer to Section 9.1.2 for definitions of secondary endpoints.

2.2 Long-term objectives

• To evaluate the persistence of measles, mumps, rubella and varicella antibodies on ayearly basis for a period of three years after vaccination.

• To assess the occurrence of breakthrough cases (confirmed by a physician) ofmeasles, mumps, rubella and/or varicella for a period of three years after vaccination.

• To assess the occurrence of contacts with measles, mumps, rubella and/orvaricella/herpes zoster for a period of three years after vaccination.

The long-term objectives will be reported as 208136/039 (MeMuRu-OKA-039) studyreport for Year 1, 208136/040 (MeMuRu-OKA-040) study report for Year 2 and208136/041 (MeMuRu-OKA-041) study report for Year 3.

3 Study Design Overview

Visit 1, Day 0 Visit 2, Week 6 Visit 3, Week 12 Visit 4/ Visit 5/ Visit 6/Vaccination 1 Vaccination 2 Year 1 Year 2 Year 3

Randomisation (1:1:1:1)

Group MeMuRu-OKA lot A (N=120)

Group MeMuRu-OKA lot C (N=120)

Group MeMuRu-OKA lot B (N=120)

Group Priorix + Varilrix (N=120)

Follow-up visits


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• Phase III, randomised (1:1:1:1), controlled study with four parallel groups:

Subjects in Group MeMuRu-OKA lot A will receive two doses of GSKBiologicals’ MeMuRu-OKA vaccine lot A administered at Visit 1/Day 0 andVisit 2/Week 6

Subjects in Group MeMuRu-OKA lot B will receive two doses of GSKBiologicals’ MeMuRu-OKA vaccine lot B administered at Visit 1/Day 0 andVisit 2/Week 6

Subjects in Group MeMuRu-OKA lot C will receive two doses of GSKBiologicals’ MeMuRu-OKA vaccine lot C administered at Visit 1/Day 0 andVisit 2/Week 6

Subjects in Group Priorix + Varilrix will receive one dose of GSK Biologicals’licensed measles-mumps-rubella (Priorix) vaccine administered concomitantlywith one dose of varicella (Varilrix) vaccine at Visit 1/Day 0 and a second dose ofPriorix administered at Visit 2/Week 6.

• All vaccines will be administered subcutaneously to healthy infants in their secondyear of life (6-week apart).

• Blinding: The study will be conducted double-blind for Groups MeMuRu-OKA lotsA-B-C and open for Groups MeMuRu-OKA lots A-B-C versus Group Priorix +Varilrix. Refer to Section 6.5 for details.

• Four millilitres (4 ml) of blood will be collected for all subjects at each time point asfollows: Pre-vaccination (Visit1/Day 0), post-dose 1 (Visit 2/ Week 6) and post-dose2 (Visit 3/Week 12). Three additional blood samples will also be collected during the3-year follow-up period (4 ml of blood per year) in a subset of subjects for theassessment of antibody persistence at Visit 4/Year 1, Visit 5/Year 2 and Visit 6/Year3.

• The study duration for each subject will be approximately 12 weeks for the activephase of the study and 3 years for the whole study, including the long-term follow-up.The long-term follow-up will be identified by CPMS protocol numbers 208136/039(MeMuRu-OKA-039) for Year 1, 208136/040 (MeMuRu-OKA-040) for Year 2 and208136/041 (MeMuRu-OKA-041) for Year 3.

• All subjects should be enrolled within a period of 8 weeks (see Appendix C).

• Data Collection: Electronic Case Report Forms (eCRF) or Remote Data Entry (RDE).



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4 Study Cohort

4.1 Number of subjects / centres

A total of 480 eligible children will be enrolled in the study to achieve the target samplesize of 400 evaluable subjects (100 subjects per group) at the time of analysis for theaccording to protocol (ATP) immunogenicity cohort at Week 12.

Refer to Section 9.3 for a detailed description of the criteria used in the estimation ofsample size).

4.2 Inclusion criteria

4.2.1 Inclusion criteria for the active phase of the study

All subjects must satisfy the following criteria at study entry:

• Subjects who the investigator believes that their parents/guardians can and willcomply with the requirements of the protocol (e.g., completion of the diary cards,return for follow-up visits) should be enrolled in the study.

• A male or female child between 12 to 18 months of age at the time of the firstvaccination. Subjects older than 18 months may be enrolled in the study if theinvestigator can ensure these subjects receive the second vaccination planned in thestudy before the subject is 24 months old (i.e., before the subject's second year'sbirthday).

• Written informed consent obtained from the parent or guardian of the subjects.

• Free of obvious health problems as established by medical history and clinicalexamination before entering into the study.

4.2.2 Inclusion criteria for the long-term follow-up

• Written informed consent has to be obtained from the parents/guardians of the childbefore their participation in the long-term follow-up. If parents/guardians of thesubjects do not wish their child to participate in the long-term follow-up, reasons ofwithdrawal should be recorded in the subject log.


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• Subjects eligible for participation in the long-term follow-up must have received theircomplete vaccination course according to the group allocation (i.e. subjects must havereceived either two doses of MeMuRu-OKA vaccine (either lot A, B or C), or twodoses of Priorix (during Visit 1 and Visit 2) vaccine and one dose of Varilrix vaccine(during Visit 1) as separate injections.

4.3 Exclusion criteria for enrolment

4.3.1 Exclusion criteria for the active phase of the study

The following criteria should be checked at the time of study entry. If any apply, thesubject must not be included in the study:

• Use of any investigational or non-registered product (drug or vaccine) other than thestudy vaccines within 30 days preceding the first dose of study vaccine, or planneduse during the study period.

• Chronic administration (defined as more than 14 days) of immunosuppressants orother immune-modifying drugs within six months prior to the first vaccine dose. (Forcorticosteroids, this will mean prednisone, or equivalent, ≥ 0.5 mg/kg/day. Inhaledand topical steroids are allowed.)

• Planned administration/ administration of a vaccine not foreseen by the studyprotocol from 30 days prior to study start until study conclusion at Week 12.

• Previous vaccination against measles, mumps, rubella and/or varicella.

• History of measles, mumps, rubella and/or varicella/ zoster diseases.

• Known exposure to measles, mumps, rubella and/or varicella/ zoster within within 30days prior to the start of the present trial

• Any confirmed or suspected immunosuppressive or immunodeficient condition,including human immunodeficiency virus (HIV) infection.

• A family history of congenital or hereditary immunodeficiency.

• History of allergic disease or reactions likely to be exacerbated by any component ofthe vaccines, including obvious allergic reactions to streptomycin, neomycin, eggproteins, and/or gelatin.

• Major congenital defects or serious chronic illness.


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• History of any neurologic disorders or seizures.

• Residence in the same household as the following persons:

- New-born infants (0-4 weeks of age)

- Pregnant mother/ women with a negative history of chickenpox disease andwithout recorded vaccination against chickenpox

- Persons with known immunodeficiency.

• Acute disease at the time of enrolment. (Acute disease is defined as the presence of amoderate or severe illness with or without fever. All vaccines can be administered topersons with a minor illness such as diarrhoea, mild upper respiratory infection withor without low-grade febrile illness, i.e., oral temperature <37.5°C/ axillarytemperature <37.5°C / rectal temperature <38.0°C / tympanic temperature on oralsetting <37.5°C / tympanic temperature on rectal setting <38.0°C).

• Rectal temperature ≥ 38.0°C or axillary temperature ≥ 37.5°C at the time ofvaccination

• Administration of immunoglobulins and/or any blood products since birth or plannedadministration during the study period.

4.3.2 Exclusion criteria for the long-term follow-up

• Subjects must not have received an additional dose of measles, mumps, rubella orvaricella vaccine (e.g. subjects re-vaccinated for sub-optimal response, see Section5.4.4).

4.4 Elimination criteria

4.4.1 Elimination criteria for the active phase

The following criteria should be checked at Visit 2 and Visit 3. If any become applicable,it will not require withdrawal of the subject from the study but does determine a subject’sevaluability in the ATP analysis. See Section 9.4 for definition of study cohorts to beevaluated.

• Chronic administration (defined as more than 14 days) of immunosuppressants orother immune-modifying drugs during the study period up to Week 12 visit. (Forcorticosteroids, this will mean prednisone, or equivalent, ≥ 0.5 mg/kg/day. Inhaledand topical steroids are allowed.)


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• Administration of a vaccine not foreseen by the study protocol during the studyperiod up to Week 12 visit.

• Administration of immunoglobulins and/or any blood products during the studyperiod up to Week 12 visit.

• Use of any investigational or non-registered product (drug or vaccine) other than thestudy vaccines during the study period, up to Week 12 visit.

4.4.2 Elimination criteria for the long-term follow-up

• Subjects must not have received an additional dose of measles, mumps, rubella orvaricella vaccine since the last study visit (e.g. subjects re-vaccinated for sub-optimalresponse, see Section 5.4.4).

4.5 Precautions to vaccination

It is recommended that members of the investigation team be immune to the vaccinecomponents under investigation.

Residence in a household in which a susceptible high-risk person (e.g., newbornsbetween 0-4 weeks old, pregnant women with negative history of chickenpox andwithout recorded vaccination against chickenpox, immunocompromised personsincluding those with HIV) resides is considered an exclusion criterion. It is howeverrecommended that this information should be given to the parents/guardians. Such that inthe advent of a household member becoming high risk during the study period, vaccinerecipients and especially those that develop a vaccine-associated rash, should know toavoid close association with these susceptible high risk individuals. In suchcircumstances, the potential risk of transmission of the attenuated virus present in thevaccine should be weighed against the risk of infection and subsequent transmission ofnatural varicella by individuals who have not benefited from vaccination.

Additionally, vaccine recipients should be instructed to avoid the use of salicylates duringthe study period (12 weeks) as Reye’s Syndrome has been reported following the use ofsalicylates during natural varicella infection.


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5 Conduct of Study

5.1 Ethics and regulatory considerations

The study will be conducted according to Good Clinical Practice (GCP), the Declarationof Helsinki (Protocol Appendix A) and local rules and regulations of the country.

5.1.1 Institutional Review Board/Independent Ethics Committee (IRB/IEC)

The IRB/IEC must be constituted according to the local laws/customs of eachparticipating country. The ICH Harmonised Tripartite Guideline for Good ClinicalPractice recommends that the IRB/IEC should include:

1. At least five members.

2. At least one member whose primary area of interest is in a non-scientific area.

3. At least one member who is independent of the institution/ study site.

Only those IRB/IEC members who are independent of the investigator and the sponsor ofthe study should vote/ provide opinion on a study-related matter.

A list of IRB/IEC members and their qualifications should be obtained by theinvestigator.

This protocol and any other documents that the IRB/IEC may need to fulfil itsresponsibilities, including subject recruitment procedures and information aboutpayments and compensation available to subjects, will be submitted to the IRB/IEC byinvestigator. Written unconditional approval of the IRB/IEC must be in the possession ofthe investigator and GSK Biologicals before commencement of the study. This approvalmust refer to the study by exact protocol title and number, and should identify thedocuments reviewed and state the date of review. Relevant GSK Biologicals’ data will besupplied by investigator to the hospital/ university/ independent IRB/IEC for review andapproval of the protocol. Verification of IRB/IEC unconditional approval of the protocoland the written informed consent statement will be transmitted by investigator to GSKBiologicals’ (Central Study Coordinator [CSC]/ local CRA) using the standardnotification form, prior to shipment of vaccine supplies and CRFs to the site.

No deviations from, or changes to, the protocol should be initiated without prior writtensponsor and IRB/IEC approval/ favourable opinion of an appropriate amendment, exceptwhen necessary to eliminate immediate hazards to the subjects or when the change(s)involves only logistical or administrative aspects of the study (e.g., change of monitor[s],telephone number[s].).Modifications are submitted to the IRB/IEC for information only.However, written verification that the modification was submitted should be obtained.


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Approvals/ verifications must be transmitted in writing to GSK Biologicals’ (CentralStudy Coordinator [CSC]/ local CRA) by the investigator.

The IRB/IEC must be informed by the investigator of:

• all subsequent protocol amendments, informed consent changes or revisions of otherdocuments originally submitted for review,

• serious and/or unexpected adverse events occurring during the study, where required,

• all subsequent protocol modifications (for information)

• new information that may affect adversely the safety of the subjects or the conduct ofthe study,

• an annual update and/or request for re-approval, where required,

• when the study has been completed, where required.

5.1.2 Informed consent

In obtaining and documenting informed consent, the investigator should comply with theapplicable regulatory requirement(s), and should adhere to GCP and to the ethicalprinciples that have their origin in the 1996 version of the Declaration of Helsinki. Priorto the beginning of the trial, the investigator should have the IRB/IEC’s writtenapproval/favourable opinion of the written informed consent form and any other writteninformation to be provided to the subjects’ parents/guardians.

Information should be given in both oral and written form whenever possible and asdeemed appropriate by the IRB/IEC.

An investigator or designate will describe the protocol to potential subjects’parents/guardians face to face. The Subject Information and Consent Form may be readto the subjects’ parents/guardians, but in any event, the investigator or designate shallgive the subjects’ parents/guardians ample opportunity to inquire about details of thestudy and ask any questions before dating and signing the Consent Form.

Subject information and consent forms must be in a language fully comprehensible to theprospective subjects’ parents/guardians. Informed consent shall be documented by theuse of a written consent form approved by the IRB/IEC and signed and dated by theparents/guardians and by the person who conducted the informed consent discussion. Thesignature confirms the consent is based on information that has been understood. Allilliterate individuals will have the study, the Subject Information and Consent Formexplained to them point by point by the interviewer in the presence of an impartial


27

witness. The witness will personally sign and date the consent form. Oral witnessedconsent will replace written consent only in countries where the local custom is contraryor if the subject’s parents’/guardians’ incapacity precludes this and provided that the locallegal obligations are fulfilled.

Each subject’s signed informed consent form must be kept on file by the investigator forpossible inspection by Regulatory Authorities and/or GSK Biologicals’ professional andRegulatory Compliance persons. The subjects parents/guardians should receive a copy ofthe signed and dated written informed consent form and any other written informationprovided to the subjects’ parents/guardians, and should receive copies of any signed anddated consent form updates. Any amendments to the written information will be providedto subjects’ parents/guardians.

Both the informed consent discussion and the written informed consent form and anyother written information to be provided to the subjects’ parents/guardians should includeexplanations of the following:

(a) That the trial involves research.

(b) The purpose of the trial.

(c) The trial treatment(s) and the probability for random assignment to each treatment.

(d) The trial procedures to be followed, including all invasive procedures.

(e) The subject’s parents’/guardians’ responsibilities.

(f) Those aspects of the trial that are experimental.

(g) The reasonably foreseeable risks or inconveniences to the subjects and, whenapplicable, to an embryo, fetus or nursing infant.

(h) The reasonable expected benefits. When there is no intended clinical benefit tosubjects, the subjects’ parents/guardians should be made aware of this.

(i) The alternative procedure(s) or course(s) of treatment/ methods of prevention thatmay be available to subjects, and their important potential benefits and risks.

(j) The compensation and/or treatment available to subjects in the event of trial-relatedinjury.

(k) The anticipated prorated payment, if any, to subjects’ parents/guardians forparticipating in the trial.


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(l) The anticipated expenses, if any, to subjects’ parents/guardians for participating in thetrial.

(m)That the subjects’ participation in the trial is voluntary and subjects’parents/guardians may refuse to participate or withdraw from the trial, at any time,without penalty or loss of benefits to which subjects are otherwise entitled.

(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) willbe granted direct access to the subject’s original medical records for verification ofclinical trial procedures and/or data, without violating the confidentiality of subjects,to the extent permitted by the applicable laws and regulations and that, by signing awritten informed consent, the subject’s parents/guardians is authorising such access.

(o) That records identifying subjects will be kept confidential and, to the extent permittedby the applicable laws and/or regulations, will not be made publicly available. If theresults of the trial are published, subjects’ identity will remain confidential.

(p) That the subjects’ parents/guardians will be informed in a timely manner ifinformation becomes available that may be relevant to the subjects’ parents/guardianswillingness for continued participation in the trial.

(q) The person(s) to contact for further information regarding the trial and the rights oftrial subjects, and who to contact in the event of trial-related injury.

(r) The foreseeable circumstances and/or reasons under which a subject’s participation inthe trial may be terminated.

(s) The expected duration of a subject’s participation in the trial.

(t) The approximate number of subjects involved in the trial.

GSK Biologicals will prepare a representative subject information sheet/informedconsent document which will embody all the elements described above. While it isstrongly recommended that this representative document be followed as closely aspossible, the informed consent requirements given in this document are not intended topre-empt any local regulations which require additional information to be disclosed forinformed consent to be legally effective. Clinical judgement, local regulations andrequirements should guide the final structure and content of the document.

The investigator has the final responsibility for the final presentation of the subjectinformation sheet/ informed consent document, respecting the mandatory requirements oflocal regulations. The consent form generated by the investigator with the assistance of


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the local sponsor’s representative, must be approved (along with the protocol, and anyother necessary documentation) by the IRB/IEC and be acceptable to GSK Biologicals.

5.2 General study aspects

The investigator will be asked to record any main epidemics (e.g. flu) that occurredduring or just before the study period and comment on symptoms (e.g. fever) that mayhave a relationship with concomitant infections.


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5.2.1 Outline of study procedures

Table 1: List of study procedures during the active phase

Age 12-24 monthsVaccination DOSE 1 DOSE 2

Visit VISIT 1 42-56 day VISIT 2 42-56 day VISIT 3Timing Day 0 interval Week 6 interval Week 12

Sampling timepoint Pre Vacc Post Vacc 1 Post Vacc2


Check of inclusion/ exclusion criteria ●


Medical history and prior (30 days pre-vaccination) concomitant medication/vaccination

●

Physical examination ● ● ● #Pre-vaccination body temperature ● ●

Randomisation ●

Blood sampling (4 ml) ●●●● ●●●●(before dose 2)

●


Recording of solicited local symptoms onthe diary cards by the parents/guardians ofthe subject

●(Day 0)

●(Days 1-3)

●(Day 0)

●(Days 1-3)

Recording of solicited general symptoms &unsolicited adverse events on the diary cardsby the parents/guardians of the subject

●(Day 0)

●(Days 1-42)

●(Day 0)

●(Days 1-42)

Recording of concomitant medication on thediary cards by the parents/guardians of thesubject

●(Day 0)

●(Days 1-42)

●(Day 0)

●(Days 1-42)

Reporting of all serious adverse events(SAEs) by the parents/guardians of thesubject to the investigator.


Return of diary cards by the parents/guardians

● ●

Diary card verification & transcription bythe investigator

● ●

Reporting of all SAEs to GSK Biologicalsby the investigator




Distribution of postcards to parents/guardians of the vaccinees -Parents/guardians of the vaccinees are instructed to fill one of the postcards and mail it to thestudy personnel in case his/her child experiences a breakthrough case (confirmed by aphysician) of measles, mumps, rubella and/or varicella or contact with measles, mumps,rubella and/or varicella/herpes zoster diseases after Visit 3/Week 12

●

� is used to indicate a study procedure that requires documentation in the individual eCRF/ diary cards.# if deemed necessary based on interim medical history


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Table 2: List of study procedures for subjects who participate in the long-term follow-up

Visit VISIT 4 VISIT 5 VISIT 6

TIMING YEAR 1

1-year ±±±± 1month

intervalYEAR 2

1-year ±±±± 1month

intervalYEAR 3

Sampling timepoint Post Vacc 2Year 1

Post Vacc 2Year 2

Post Vacc 2Year 3

Check of elimination criteria ● ● ●

Blood sampling to evaluate antibodypersistence

● ● ●

Distribution of postcards toparents/guardians of the vaccinees.

● ●

Parents/guardians of the vaccinees areinstructed to fill a postcard and mail it tothe study personnel in case the subjectexperiences:• a breakthrough case (confirmed by a

physician) of measles, mumps, rubellaand/or varicella, or

• a contact with measles, mumps,rubella and/or varicella/herpes zosterdiseases.

● ●

Query occurrence of breakthrough case(confirmed by a physician) of measles,mumps, rubella and/or varicella, oroccurrence of contact with measles,mumps, rubella and/or varicella/herpeszoster diseases since the last visit.

● ● ●

Long-term follow-up study conclusion ● ● ●� is used to indicate a study procedure that requires documentation in the individual eCRF/ diary cards.The above-mentioned intervals between visits are indicative and should be followed as close as possible. However,if circumstances dictate other intervals, this may not necessarily lead to the exclusion of the subject(s) from theanalysis.

It is the investigator’s responsibility to ensure that the intervals between visits/contactsare strictly followed. These intervals determine each subject’s evaluability in the ATPanalyses (see Sections 4.4 and 9.4 for details of criteria for evaluability and cohorts to beanalyzed).


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5.3 Detailed description of study stages/visits

The following procedures will be followed for all groups:

Visit 1

Day 012-18 months of age

• Written informed consent to be obtained from parents/guardian.

• Review of inclusion/ exclusion criteria.

• Recording of general medical history and prior/ concomitantmedication/ vaccination.

• Physical examination, including palpation of the parotid andother salivary glands and body temperature recording(axillary/ rectal temperature)*.

• Randomisation using a central internet randomisation system(SBIR).

• Collection of a pre-vaccination blood sample (4 ml) forbaseline antibody determination.

• Administration of vaccination 1 (see Section 6.2).

• The vaccinee will be observed closely for at least 30 minuteswith appropriate medical treatment readily available in case ofa rare anaphylactic reaction following the administration ofvaccines.

• Parents/ guardians of the subject are given diary cards torecord any AEs that may occur in the subject during thefollow-up period (see Section 7.5.1).

* Vaccination should not be performed when the body temperature prior to vaccination iseither ≥38.0°C (rectal route) or ≥ 37.5°C (axillary route).


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Interval between Visit 1 and Visit 2

During the period between study visits, the parents/ guardians of thesubject will inspect their child daily at bedtime and record all adverseevents & any concomitant medication on the diary cards as follows (SeeSection 7.5.1 for details of symptoms):

Local Reactions Days Measuring MethodRedness 0 – 3 Diameter in mm

Swelling 0 – 3 Diameter in mmPain 0 – 3 Reaction to touch

Concomitant Medication0 – 42

General Symptoms

Temperature/ fever 0 – 14Direct measurement of axillarytemperature everyday

15 - 42

Screening of fever with atemperature sensitive pad or athermometer (recording on eCRFonly in case of fever)

Rash * 0 – 42 Physical inspectionParotid/ salivary gland swelling * 0 – 42 Physical inspection

Any suspected sign of meningism *(including febrile convulsions)

0 – 42 General observation

Unsolicited Adverse EventsAny other symptoms 0 – 42 General observation

Serious Adverse Events

Any serious symptoms*Day 0 to Week 12

(Visit 3)General observation

* Should any of these signs be observed, the child must be examined by the investigator(or a designated member of his/ her staff) as soon as possible. On such an occasion,biological samples (vesicular fluid, saliva or CSF samples) may be taken from the childboth to aid diagnosis and for use in the clinical study.

Visit 2

Week 642-56 days after Visit 1

• Query the parents/guardians of the subject on occurrence ofsolicited, unsolicited and serious adverse events since the lastvisit.

• Return of diary cards (for dose 1) to the investigator by theparents/ guardians of the subjects.

• Transfer of all data (for dose 1) from the diary cards onto theindividual electronic case report form (eCRF or RDE).

• Check of elimination criteria.

• Physical examination, including palpation of the parotid andother salivary glands and body temperature recording (axillary orrectal temperature)*.


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• Collection of a blood sample (4 ml) for antibody determination(before administration of dose 2).

• Administration of vaccination 2 (see Section 6.2).

• The vaccinee will be observed closely for at least 30 minuteswith appropriate medical treatment readily available in case of arare anaphylactic reaction following the administration ofvaccines.

• Parents/ guardians of the subject are given diary cards to recordany AEs that may occur in the subject during the follow-upperiod (see Section 7.5.1).

* Vaccination should not be performed when the body temperature prior tovaccination is either ≥38.0°C (rectal route) or ≥ 37.5°C (axillary route).

Interval between Visit 2 and Visit 3

During the period between study visits, the parents/ guardians of the subject willinspect their child daily at bedtime and record all adverse events & anyconcomitant medication on the diary cards as follows (See Section 7.5.1 fordetails of symptoms):Local Reactions Days Measuring Method

Redness 0 – 3 Diameter in mmSwelling 0 – 3 Diameter in mm

Pain 0 – 3 Reaction to touchConcomitant Medication

0 – 42General Symptoms

Temperature/ fever 0 – 14Direct measurement of axillarytemperature everyday

15 - 42

Screening of fever with atemperature sensitive pad or athermometer (recording on eCRFonly in case of fever)

Rash * 0 – 42 Physical inspectionParotid/ salivary gland swelling * 0 – 42 Physical inspection

Any suspected sign of meningism *(including febrile convulsions)

0 – 42 General observation

Unsolicited Adverse EventsAny other symptoms 0 – 42 General observation

Serious Adverse Events

Any serious symptoms*Day 0 to Week 12

(Visit 3)General observation

* Should any of these signs be observed, the child must be examined by the investigator(or a designated member of his/ her staff) as soon as possible. On such an occasion,biological samples (vesicular fluid, saliva or CSF samples) may be taken from the childboth to aid diagnosis and for use in the clinical study.


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Visit 3

Week 1242-56 days after Visit 2

• Query the parents/guardians of the subject on occurrence ofsolicited, unsolicited and serious adverse events since the last visit.

• Return of diary cards (for dose 2) to the investigator by theparents/ guardians of the subjects.

• Transfer of all data from the diary cards onto the individualelectronic case report form (eCRF or RDE).


• Collection of a blood sample (4 ml) for antibody determination.

• Physical examination if deemed necessary based on interimmedical history.

• Study conclusion for the active phase of the study.

Parents/guardians of subjects will be proposed to have their child participate in the long-term follow-up extension. If they agree, the following procedures will be followed:

• Written Informed consent for long-term follow-up to be obtainedfrom parents/guardians of the subjects.

• Check of inclusion/ exclusion criteria.

• Parents/guardians of the subjects will be provided with postcardsfor the long-term follow-up and will be instructed to fill onepostcard and mail it to the study personnel in case their childexperiences any:

- breakthrough case (confirmed by a physician) of measles,mumps, rubella and/or varicella, or

- contact with measles, mumps, rubella and/or varicella/herpeszoster diseases since the last visit.

Visit 4

Year 11 year ±±±± 1 month after Visit 2 (i.e., after dose 2)


• Postcards review and verification with parents/guardians of thesubject and transcription by the investigator on the eCRF (whenapplicable).

• Query the subject's parents/guardians on the occurrence ofbreakthrough cases of measles, mumps, rubella and/or varicellasince the last visit.


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• Query the subject's parents/guardians on the occurrence of contactwith measles, mumps, rubella and/or varicella/zoster diseasessince the last visit.


• Conclusion of Year 1 long-term follow-up of the study.

• Parents/guardians of the subjects will be provided with postcardsand will be instructed to fill one postcard and mail it to the studypersonnel in case their child experiences any:



Visit 5

Year 21 year ±±±± 1 month after Visit 4





• Collection of a blood sample (4 ml) for the antibodydetermination.


• Parents/guardians of the subjects will be provided with postcardsfor the long-term follow-up and will be instructed to fill onepostcard and mail it to the study personnel in case their childexperience any:




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Visit 6

Year 31 year ±±±± 1 month after Visit 5







When materials are provided by GSK Biologicals, it is MANDATORY that all clinicalsamples (including serum samples) will be collected and stored using exclusively thosematerials in the appropriate manner. The use of other materials could result in theexclusion of the subject from the ATP analysis (See Section 9.4 for definition of studycohorts to be evaluated). The investigator must ensure that his/her personnel and thelaboratory(ies) under his/her supervision comply with this requirement. However, whenGSK Biologicals does not provide material for collecting and storing clinical samples,then appropriate materials from the investigator’s site are to be used. Refer to AppendixD and Appendix E.

The subjects’ parents/guardians will be instructed to contact the investigatorimmediately should the subject manifest any signs or symptoms they perceive asserious.

5.4 Sample handling and analysis

5.4.1 Treatment and storage of biological samples

See Appendix D of the protocol for details of treatment and storage of biologicalsamples.

See Appendix E for instructions for shipment of biological samples.


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5.4.2 Laboratory assays

Table 3 summarises the laboratory assays to be performed with the biological samplescollected from the subjects. All serum samples will be tested in a blinded fashion for thepresence of antibodies to measles, mumps, rubella, and varicella.

Table 3 Laboratory assays

Biologicalsample

Timepoint Identification Assay

MethodTest Kit/

ManufacturerAssayunit

Assaycut-off

Performedby

Anti-measlesvirus/IgG ELISA

Enzygnost/Behring mIU/ml 150

GSKBiologicals

Anti-mumpsvirus/IgG

ELISAEnzygnost/

BehringU/ml 231

GSKBiologicals

Anti-rubellavirus/IgG

ELISAEnzygnost/

BehringIU/ml 4

GSKBiologicalsserum

(1) Pre Vacc 1Day 0(2) Post Vacc1Week 6(3) Post Vacc 2Week 12(4) Post Vacc 2Year 1(5) Post Vacc 2Year 2(6) Post Vacc 2Year 3

Anti-varicellavirus/IgG

IFAVirgo/ Hemagen

DiagnosticsDilution-1 4

GSKBiologicals

Vesicular fluidNo pre-specified

time pointVaricella virus PCR - - -

GSKBiologicals

SalivaNo pre-specified

time point Mumps virus PCR - - -GSK

Biologicals,Belgium

Cerebrospinalfluid

No pre-specifiedtime point

Mumps virus PCR - - -GSK

Biologicals,Belgium

See Appendix F for more details on viral identification and characterization by PCRmethod.

5.4.3 Serology plan

In case of insufficient blood sample volume to perform assays for all antibodies, they willbe analyzed according to the following priority ranking: mumps, measles, rubella andvaricella.

Any additional serology on antigens contained in the study vaccines will be performed ifdeemed necessary by GlaxoSmithKline Biologicals if any findings in the present study orin other studies necessitate investigation of the immunogenicity of the vaccine. In thiscase, the ranking above may also be changed.

5.4.4 Endpoints for sub-optimal response

When the results of serology assay become available, subjects who demonstrate a sub-optimal response to any of the four antigens will be offered an additional dose of GSK


39

Biological’s measles-mumps-rubella vaccine (Priorix) and/or GSK Biological’s varicellavaccine (Varilrix).

Antibodies Definition ofSub-optimal Response

Boost with

Anti-measles < 150 mIU/ml PriorixAnti-mumps < 231 U/ml PriorixAnti-rubella < 4 IU/ml PriorixAny combination of the above PriorixAnti-varicella < 4 dilution -1 Varilrix

6 Investigational Products and Administration

6.1 Study vaccines

The Quality Control Standards and Requirements for the candidate vaccine are describedin separate release protocols and the required approvals have been obtained.

Commercial vaccines are assumed to comply with the specifications given in themanufacturer's Summary of Product Characteristics.

The candidate MeMuRu-OKA vaccine and the licensed Priorix and Varilrix vaccines aredeveloped and manufactured by GlaxoSmithKline Biologicals.

One dose of 0.5 ml of vaccine contains the following viral titres after reconstitution:

Virus strain MeMuRu-OKA Priorix Varilrix

Schwarz measles ≥103.0

CCID50 ≥103.0

CCID50

RIT 4385 (Jeryl Lynn-derived) mumps ≥10

4.0CCID50 ≥10

3.7CCID50

RA 27/3 rubella ≥103.0

CCID50 ≥103.0

CCID50

Oka varicella ≥103.3 pfu ≥10

3.3 pfuCCID50 = median cell culture infective dosepfu = plaque forming unit

The measles and mumps virus strains are produced on chicken embryo fibroblasts, andthe rubella and varicella virus strains are produced on MRC-5 human diploid cells.

The measles and mumps virus strains are propagated on chicken embryo fibroblasts whilethe rubella virus is propagated in WI-38 human diploid lung fibroblasts. Varicella virus ispropagated in human diploid cell cultures (MRC-5).

Commercial lots of Priorix and Varilrix vaccines will be used in this study.


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6.2 Dosage and administration

PresentationGroups Vaccines

Vaccine DiluentInstructions for reconstitution and administration

MeM

uRu-

OK

A

MeMuRu-OKA

Lyophilizedin a vial

Pre-filledsyringe

The MeMuRu-OKA vaccine should be reconstituted byinjecting the entire volume of diluent in the pre-filledsyringe into the vial of lyophilized vaccine. The vialmust be shaken well until the pellet is completelydissolved. Withdraw the entire contents of thereconstituted vaccine into the syringe, change theneedle, and inject the total volume subcutaneously intothe LEFT upper arm (deltoid region).

PriorixLyophilized

in a vialPre-filledsyringe

Priorix should be reconstituted by injecting the entirevolume of diluent in the pre-filled syringe into the vialof lyophilized vaccine. The vial must be shaken welluntil the pellet is completely dissolved. Withdraw theentire contents of the reconstituted vaccine into thesyringe, change the needle, and administersubcutaneously into the LEFT upper arm (deltoidregion).

Pri

orix

+V

arilr

ix

VarilrixLyophilized

in a vialPre-filledsyringe

Varilrix should be reconstituted by injecting the entirevolume of diluent in the pre-filled syringe into the vialof lyophilized vaccine. The vial must be shaken welluntil the pellet is completely dissolved. Withdraw theentire contents of the reconstituted vaccine into thesyringe, change the needle, and administersubcutaneously into the RIGHT upper arm (deltoidregion).

After reconstitution, the vaccines should be injected promptly. For the purpose of thestudy, the reconstituted vaccine should be injected within 30 minutes.

Subcutaneous injections should be given in the upper arm by inserting the needle in apinched-up fold of skin and subcutaneous tissue. A 23 or 25-gauge needle, 5/8-3/4 inchlong is recommended. The needle should be changed between withdrawing the vaccineinto the syringe and injecting it into the child.

The vaccinees will be observed closely for at least 30 minutes with appropriate medicaltreatment readily available in case of a rare anaphylactic reaction following theadministration of vaccines.

Attenuated viruses in these vaccines are rapidly inactivated by ether, alcohol anddetergents. Care should be taken to avoid contact between the reconstituted vaccine andthese substances (e.g. disinfection of the skin prior to vaccination).


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6.3 Storage

The vaccines must be stored in a dark, safe and locked place with no access forunauthorized personnel.

GSK Biologicals’ MeMuRu-OKA, Priorix and Varilrix vaccines must be kept in therefrigerator (+2°C to +8°C). The diluents supplied for reconstitution of these vaccinesmay be stored at room temperature or in the refrigerator.

The storage temperature should be monitored and recorded daily on the temperature logsheet provided by the sponsor (See Appendix H for example). It is advisable to have aback-up refrigerator in case of power failure/ breakdown. The study monitor must becontacted if the cold chain is broken (e.g. refrigeration fails).

Storage conditions for transport of vaccines from country medical department or dispatchcentre to study sites or between sites are described in Appendix E.

6.4 Treatment allocation and randomisation

6.4.1 Randomization of supplies

A randomisation list will be generated at GSK Biologicals, Rixensart, using a standardSAS (Statistical Analysis System) program and will be used to number the vaccines. Arandomisation blocking scheme (1:1:1:1 ratio) will be used to ensure that balancebetween treatment is maintained: a randomisation number will identify uniquely thevaccine dose to be administered to the subject.

To allow GSK Biologicals to take advantage of greater rates of recruitment thananticipated at individual centres, and to thus reduce the overall study recruitment period,a 20% over-randomisation of supplies will be prepared. However, the enrolment will beterminated when 480 subjects have been enrolled. The vaccine doses will be distributedto the study centres while respecting the randomisation block.

6.4.2 Randomisation of subjects

The treatment allocation at the investigator site will be performed using a centralrandomisation call-in system on Internet (SBIR). The randomisation algorithm uses aminimization procedure stratified by centre 4.

After having checked that a subject is eligible, the person in charge of the vaccinationwill access the randomisation system on Internet. Upon providing a screeningidentification number (screening ID) for the subject, the randomisation system will use


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the minimization algorithm to determine the vaccine number to be used for the subject.This vaccine number will also be used as patient identification number (PID) for all datacollected on the subject during the study.

6.5 Method of blinding and breaking the study blind

The study will be carried out in a double-blind manner with respect to Groups MeMuRu-OKA lots A, B and C, i.e. the investigator(s)/ study personnel and the subjects’parents/guardians are not aware of the MeMuRu-OKA vaccine lot to be administered tothe subject. However, the study will be performed open with respect to GroupsMeMuRu-OKA lots A-B-C versus Group Priorix + Varilrix, i.e. the investigators orstudy personnel and subject’s parents/guardians will be aware which vaccine (either thesingle injection of MeMuRu-OKA or the separate injection of Priorix and Varilrix) isadministered to the subject.

No set of individual codes will be held at the local GSK Biologicals’ Safety Office orGSK Biologicals’ Central Safety Office. The Clinical Safety physician will be able toaccess the individual randomisation code from the central randomisation system on theInternet. The code will be broken by the Clinical Safety physician only in the case ofmedical events that the investigator/physician in charge of the subject feels cannot betreated without knowing the identity of the study vaccine.

GSK Biologicals’ policy (incorporating ICH E2A guidance, EU Clinical Trial Directiveand Federal Regulations) is to unblind any serious adverse event (SAE) report associatedwith the use of the investigational product, which is unexpected andattributable/suspected, prior to regulatory reporting. The Clinical Safety physician isresponsible for unblinding the treatment assignment in accordance with specified timeframes for expedited reporting of SAEs (Refer to Section 7.9).

6.6 Replacement of unusable vaccine doses

Additional vaccine doses will be provided to replace those that are unusable (seeAppendix G).

In addition to the vaccine doses provided for the planned number of subjects, adequateamount of additional doses will be supplied. In case a vaccine dose is broken or unusable,the investigator should replace it with a replacement vaccine dose. Although the sponsorneed not be notified immediately in these cases, documentation of the use of thereplacement vaccine must be recorded by the investigator on the vaccine administrationpage of the CRF and on the vaccine accountability form.


43

The investigator will use the central randomisation system (SBIR) to obtain thereplacement vial number. The system will ensure, in a blinded manner, that thereplacement vial is of the same formulation as the randomised vaccine.

6.7 Packaging

See Appendix G.

6.8 Vaccine accountability

See Appendix G.

6.9 Concomitant medication/treatment

At each study visit/contact, the investigator should question the subject’sparents/guardian about any medication(s) taken.

All concomitant medication, with the exception of vitamins and/or dietary supplements,administered at ANY time during the period starting with administration of each dose andending 42 days after each dose are to be recorded with generic name of the medication(trade names are allowed for combination drugs, i.e., multi-component drugs), medicalindication, total daily dose, route of administration, start and end dates of treatment.

Any treatments and/or medications specifically contraindicated, e.g., anyimmunoglobulins, other blood products and any immune modifying drugs administeredsince birth or at any time until Visit 3 are to be recorded with generic name of themedication (trade names are allowed for combination drugs only), medical indication,total daily dose, route of administration, start and end dates of treatment. Refer toSections 4.3 and 4.4.

Any vaccine not foreseen in the study protocol administered in the period beginning 30days preceding each dose and ending 42 days after each dose is to be recorded with tradename, route of administration and date(s) of administration. Refer to Sections 4.3 and 4.4.

Any concomitant medication administered prophylactically in anticipation of reaction tothe vaccination must be recorded in the CRF with generic name of the medication (tradenames are allowed for combination drugs only), total daily dose, route of administration,start and end dates of treatment and coded as ‘Prophylactic’.

Concomitant medication administered for the treatment of an AE or SAE must berecorded in the CRF with generic name of the medication (trade names are allowed for


44

combination drugs only), medical indication (including which AE/SAE), total daily dose,route of administration, start and end dates of treatment. Refer to Section 7.2 fordefinition of SAE.

7 Adverse Events and Serious Adverse Events

The investigator is responsible for the detection and documentation of events meeting thecriteria and definition of an adverse event (AE) or serious adverse event (SAE) asprovided in this protocol. During the study, when there is a safety evaluation, theinvestigator or site staff will be responsible for detecting AEs and SAEs, as detailed inthis section of the protocol.

Each subject’s parents/guardians will be instructed to contact the investigatorimmediately should the subject manifest any signs or symptoms they perceive as serious.

7.1 Definition of an adverse event

An AE is any untoward medical occurrence in a clinical investigation subject, temporallyassociated with the use of a medicinal product, whether or not considered related to themedicinal product.

An AE can therefore be any unfavourable and unintended sign (including an abnormallaboratory finding), symptom, or disease (new or exacerbated) temporally associated withthe use of a medicinal product. For marketed medicinal products, this also includesfailure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.

Examples of an AE include:

• Significant or unexpected worsening or exacerbation of the condition/ indicationunder study. See Section 7.3‘Lack of Efficacy’ for additional information.

• Exacerbation of a chronic or intermittent pre-existing condition including either anincrease in frequency and/or intensity of the condition.

• New conditions detected or diagnosed after investigational product administrationeven though it may have been present prior to the start of the study.

• Signs, symptoms, or the clinical sequelae of a suspected interaction.

• Signs, symptoms, or the clinical sequelae of a suspected overdose of eitherinvestigational product or a concurrent medication (overdose per se should not bereported as an AE/SAE).


45

• Signs, symptoms temporally associated with vaccine administration.

Examples of an AE DO NOT include:

• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition thatleads to the procedure is an AE.

• Situations where an untoward medical occurrence did not occur (social and/orconvenience admission to a hospital).

• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) presentor detected at the start of the study that do not worsen.

• The disease/disorder being studied, or expected progression, signs, or symptoms ofthe disease/disorder being studied, unless more severe than expected for the subject’scondition.

AEs may include pre- or post-treatment events that occur as a result of protocol-mandated procedures (i.e., invasive procedures, modification of subject’s previoustherapeutic regimen).

N.B. AEs to be recorded as endpoints (solicited events) are described in Section 7.5.1.All other AEs will be recorded as UNSOLICITED AES.

Example of events to be recorded in the medical history section of the CRF:

• Pre-existing conditions or signs and/or symptoms present in a subject prior to the startof the study (i.e. prior to the first study procedure) should be recorded in the medicalhistory section of the subject’s CRF.

7.2 Definition of a serious adverse event

A serious adverse event (SAE) is any untoward medical occurrence that:

a) results in death,

b) is life-threatening,

NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in whichthe subject was at risk of death at the time of the event. It does not refer to an event,which hypothetically might have caused death, if it were more severe.

c) requires hospitalization or prolongation of existing hospitalization,


46

NOTE: In general, hospitalization signifies that the subject has been detained (usuallyinvolving at least an overnight stay) at the hospital or emergency ward for observationand/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization are AEs. If acomplication prolongs hospitalization or fulfils any other serious criteria, the event isserious. When in doubt as to whether “hospitalization” occurred or was necessary, theAE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen frombaseline is not considered an AE.

d) results in disability/incapacity,

NOTE: The term disability means a substantial disruption of a person’s ability to conductnormal life functions. This definition is not intended to include experiences of relativelyminor medical significance such as uncomplicated headache, nausea, vomiting,diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere orprevent everyday life functions but do not constitute a substantial disruption.

e) is a congenital anomaly/birth defect in the offspring of a study subject,

f) medical or scientific judgement should be exercised in deciding whether reportingis appropriate in other situations, such as important medical events that may notbe immediately life-threatening or result in death or hospitalization but mayjeopardize the subject or may require medical or surgical intervention to preventone of the other outcomes listed in the above definition. These should also beconsidered serious. Examples of such events are invasive or malignant cancers,intensive treatment in an emergency room or at home for allergic bronchospasm,blood dyscrasias or convulsions that do not result in hospitalization.

7.3 Lack of efficacy

“Lack of efficacy” per se will not be reported as an AE. The signs and symptoms orclinical sequelae resulting from lack of efficacy will be reported if they fulfil the AE orSAE definition (including clarifications).

7.4 Clinical laboratory parameters and other abnormal assessmentsqualifying as adverse events and serious adverse events

Abnormal laboratory findings (e.g., clinical chemistry, haematology, urinalysis) or otherabnormal assessments that are judged by the investigator to be clinically significant willbe recorded as AEs or SAEs if they meet the definition of an AE, as defined in Section


47

7.1 or SAE, as defined in Section 7.2. Clinically significant abnormal laboratory findingsor other abnormal assessments that are detected during the study or are present at baselineand significantly worsen following the start of the study will be reported as AEs or SAEs.However, clinically significant abnormal laboratory findings or other abnormalassessments that are associated with the disease being studied, unless judged by theinvestigator as more severe than expected for the subject’s condition, or that are presentor detected at the start of the study and do not worsen, will not be reported as AEs orSAEs.

The investigator will exercise his or her medical and scientific judgement in decidingwhether an abnormal laboratory finding or other abnormal assessment is clinicallysignificant.

7.5 Time period, frequency, and method of detecting adverse eventsand serious adverse events

All AEs occurring within 43 days (Day 0-42) following administration of each dose ofvaccine/ comparator must be recorded on the Adverse Event form in the subject's CRF,irrespective of severity or whether or not they are considered vaccination-related.

The standard time period for collecting and recording SAEs will begin at randomisationor the first receipt of vaccine/ comparator and will end 42 days following administrationof the last dose of study vaccine/ comparator for each subject. See Section 7.8 forinstructions for reporting and recording SAEs.

Additionally, in order to fulfil international reporting obligations, SAEs that are related tostudy participation (e.g. procedures, invasive tests, a change from existing therapy) or arerelated to a concurrent medication will be collected and recorded from the time thesubject consents to participate in the study until she/he is discharged.

The investigator will inquire about the occurrence of AEs/SAEs at every visit/contactduring the study.

All AEs either observed by the investigator or one of his clinical collaborators or reportedby the subject’s parent/guardian spontaneously or in response to a direct question will beevaluated by the investigator. AEs not previously documented in the study will berecorded in the Adverse Event form within the subject's CRF. The nature of each event,date and time (where appropriate) of onset, outcome, intensity and relationship tovaccination should be established. Details of any corrective treatment should be recordedon the appropriate page of the CRF. Refer to Section 6.9.


48

As a consistent method of soliciting AEs, the subject’s parent/guardian should be asked anon-leading question such as:

"Has your child acted differently or felt different in any way since receiving the vaccineor since the last visit?"

N.B. The investigator should record only those AEs having occurred within the timeframe defined above.

AEs already documented in the CRF, i.e. at a previous assessment, and designated as‘ongoing’ should be reviewed at subsequent visits, as necessary. If these have resolved,the documentation in the CRF should be completed.

N.B. If an AE changes in frequency or intensity during the specified reporting period, anew record of the event will be entered.

When an AE/SAE occurs, it is the responsibility of the investigator to review alldocumentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relativeto the event. The investigator will then record all relevant information regarding anAE/SAE on the CRF or SAE Report Form as applicable. It is not acceptable for theinvestigator to send photocopies of the subject’s medical records to GSK Biologicals inlieu of the appropriate completed AE/SAE pages. However, there may be instances whencopies of medical records for certain cases are requested by GSK Biologicals. In thisinstance, all subject identifiers will be blinded on the copies of the medical records priorto submission to GSK Biologicals.

The investigator will attempt to establish a diagnosis of the event based on signs,symptoms, and/or other clinical information. In such cases, the diagnosis should bedocumented as the AE/SAE and not the individual signs/symptoms.

7.5.1 Solicited adverse events

Parents/guardians will be provided with diary cards and instruct them on how to recordsymptoms as well as any other reactions (see Section 5.3 Detailed description of studystages).

7.5.1.1 Local (injection site) adverse events

The following local signs and symptoms will be recorded from Day 0 to Day 3 followingeach vaccination:

• Redness at injection site is to be measured in millimetres.


49

• Swelling at injection site is to be measured in millimetres.

• Pain at injection site on digital pressure, will be recorded as:

0 = Absent

1 = Minor reaction to touch

2 = Cries/protests on touch

3 = Cries when limb is moved/spontaneously painful.

7.5.1.2 General adverse events

The following general signs and symptoms will be recorded from Day 0 to Day 42following each vaccination:

• Temperature/ fever: From Day 0 to Day 14, parents are requested to record child’sbody temperature measured by axillary route each evening at bedtime.

From Day 15 to Day 42, the child’s temperature will be screened each evening atbedtime for signs of fever by means of either a thermometer or a temperaturesensitive pad. The temperature sensitive pad will be placed on the child’s forehead toscreen fever. If the sensitive pad indicates fever (i.e. internal temperature ≥ 38.0°C)or if the parents/guardians suspect any possible fever, then an accurate temperaturemeasurement is to be performed using the thermometer supplied (axillary route) andthe measurement should be recorded on the diary card.

N.B. Should additional temperature measurements be performed at another time of day,the highest temperature will be recorded.

• Rash/ exanthem: Subjects who develop any kind of skin eruption - even mild - haveto be examined as soon as possible by the investigator and record the followingassessments:

- Exanthem: describe and classify as

(1) Measles/ rubella rashes (macular or maculo-papular rashes): presenceof macules, discolored small patches or spots of the skin, neither elevatednor depressed below the skin's surface

(2) varicella rash (maculo-papulo-vesicular): simultaneous presence ofmacules, papules and vesicles raised above the skin's surface

(3) Or other types of rash (heat rash, diaper rash etc…)


50

- causality;

- date of onset and end of eruption will be indicated, as well as the locality ofthe rash (injection site or non-injection site), and

- intensity as follows: 0: no lesion

1: 1-50 lesions

2: 51-150 lesions

3: > 150 lesions.

- outcome

On this occasion, parents/guardians of the subject are encouraged to contact the study siteand come for a visit if vesicles are present, an attempt will be made to collect vesicularfluid for varicella virus identification (see Appendix F). See Appendix D for fluidsampling and Appendix E for the shipment instructions.

• Parotid/salivary gland swelling: Should parotitis be clinically suspected (swelling /tenderness in the mandibular / submandibular region), the child will have to bebrought back to the investigator as soon as possible for an additional visit. At thatvisit the investigator will assess the symptom as follows:

- swelling without difficulty moving the jaw- swelling with difficulty moving the jaw- swelling with accompanying general symptoms

A saliva sample will be collected for mumps virus detection and strain identification byPCR (see Appendix F). See Appendix F for instructions on sample collection andAppendix E for shipment instructions.

• Any suspected signs of meningism, including febrile convulsions: Should the childexperience febrile convulsions or present any other neurological signs or symptomsindicative of meningism during the study period, the parents/guardians should contactthe investigator immediately who in turn will contact the local monitor. The child willundergo a neurological test at the discretion of the testing physician (see AppendixD). The local monitor - in collaboration with the investigator - will make sure that allrelevant and supportive information (clinical, biological, etc) is made available tofully document the case. The investigator is requested to write a descriptiveassessment of the case and evaluate the relationship to the study vaccination.


51

IMPORTANT: Should any of these symptoms be suspected, the child must be returnedto the investigator’s centre for an examination.

7.5.1.3 Recording of signs and symptoms during the long-term follow-up period

The following information will be recorded on each yearly follow-up visit, onto a specificCRF sheet:

• Occurrence of breakthrough case (confirmed by a physician) of measles, mumps,rubella and/or varicella

(1) date of onset

(2) duration

(3) description of skin eruption if applicable (refer to rashdescription stated above).

(4) outcome

On this occasion and if vesicles are present an attempt will bemade to collect vesicular fluid for varicella virus identification(see Appendix F). See Appendix D for fluid sampling andAppendix E for the shipment instructions.

• Occurrence of any contact with measles, mumps, rubella and/or varicella/zosterdiseases (and date of contact if applicable)

Parents will be given post-cards at Visit 3, 4 and 5, on which they will be asked to reportall information relative to breakthrough cases of measles, mumps, rubella and varicella,and information relative to contacts with measles, mumps, rubella and/or varicella/zostercases. In case of the occurrence of such events, parents/guardians will be asked to mailthe filled in postcard to the investigator.

7.6 Evaluating adverse events and serious adverse events

7.6.1 Assessment of intensity

Intensity of the following adverse events will be assessed as described:


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Table 4: Intensity scales for solicited symptoms

Adverse Events Grade ParameterLocal symptoms

Pain at injection site 0 Absent1 Minor reaction to touch2 Cries/protests on touch3 Cries when limb is moved/spontaneously painful

Redness at injection site Record greatest surface diameter in mm1 ≤52 >5 - ≤203 > 20

Swelling at injection site Record greatest surface diameter in mm1 ≤52 >5 - ≤203 > 20

General symptomsFever* (°C) Axillary temperature Rectal temperature

1 ≥37.5 - ≤38.0 ≥38.0 - ≤38.52 >38.0 - ≤39.0 >38.5 - ≤39.03 > 39.0 > 39.5

*Fever is defined as rectal temperature ≥38°C / axillary temperature ≥37.5°C / oral temperature≥37.5°C.

For fever symptom, the subjects’ parents/guardians will be asked to record on the diarycard if they sought medical advice for this symptom. The causality will be assessed bythe investigator(s).

The investigator will make an assessment of intensity for all other AEs, i.e. unsolicitedsymptoms, including SAEs reported during the study. The assessment will be based onthe investigator’s clinical judgement. The intensity of each AE and SAE recorded in theCRF or SAE Report Form, as applicable, should be assigned to one of the followingcategories:


53

1 (mild) = An AE which is easily tolerated by the subject, causingminimal discomfort and not interfering with everydayactivities.

2 (moderate) = An AE which is sufficiently discomforting to interfere withnormal everyday activities.

3 (severe) = An AE which prevents normal, everyday activities. (In ayoung child, such an AE would, for example, preventattendance at school/ kindergarten/ a day-care centre andwould cause the parents/ guardians to seek medical advice.In adults/ adolescents, such an AE would, for example,prevent attendance at work/ school and would necessitatethe administration of corrective therapy.)

An AE that is assessed as Grade 3 (severe) should not be confused with a SAE.Grade 3 is a category utilised for rating the intensity of an event; and both AEsand SAEs can be assessed as Grade 3. An event is defined as ‘serious’ when itmeets one of the pre-defined outcomes as described in Section 7.2.

7.6.2 Assessment of causality

The investigator is obligated to assess the relationship between investigational productand the occurrence of each AE/SAE. The investigator will use clinical judgement todetermine the relationship. Alternative causes, such as natural history of the underlyingdiseases, concomitant therapy, other risk factors and the temporal relationship of theevent to the investigational product will be considered and investigated. The investigatorwill also consult the Investigator Brochure and/or Product Information, for marketedproducts, in the determination of his/her assessment.

There may be situations when a SAE has occurred and the investigator has minimalinformation to include in the initial report to GSK Biologicals. However, it is veryimportant that the investigator always makes an assessment of causality for every eventprior to transmission of the SAE Report Form to GSK Biologicals. The investigator maychange his/her opinion of causality in light of follow-up information, amending the SAEReport Form accordingly. The causality assessment is one of the criteria used whendetermining regulatory reporting requirements.

In case of concomitant administration of multiple vaccines, it may not be possible todetermine the causal relationship of general AEs to the individual vaccines administered.The investigator should, therefore, assess whether the AE could be causally related tovaccination rather than to the individual vaccines.

All solicited local (injection site) reactions will be considered causally related tovaccination. Causality of all other AEs should be assessed by the investigator using thefollowing question:


54

In your opinion, did the vaccine(s) possibly contribute to the adverse event?

NO : The AE is not causally related to administration of the studyvaccine(s). There are other, more likely causes and administrationof the study vaccine(s) is not suspected to have contributed to theAE.

YES : There is a reasonable possibility that the vaccine contributed to theAE.

Non-serious and serious AEs will be evaluated as two distinct events. If an event meetsthe criteria to be determined “serious” (see Section 7.2 for definition of serious adverseevent), it will be examined by the investigator to the extent to be able to determine ALLcontributing factors applicable to each serious adverse event.

Other possible contributors include:

• Medical history

• Other medication

• Protocol required procedure

• Other procedure not required by the protocol

• Lack of efficacy of the vaccine, if applicable

• Erroneous administration

• Other cause (specify)

7.7 Follow-up of adverse events and serious adverse events andassessment of outcome

After the initial AE/SAE report, the investigator is required to proactively follow eachsubject and provide further information to GSK Biologicals on the subject’s condition.

All AEs and SAEs documented at a previous visit/contact and designated as notrecovered/not resolved or recovering/resolving will be reviewed at subsequentvisits/contacts.

Investigators will follow-up subjects:


55

• with SAEs or subjects withdrawn from the study as a result of an AE, until the eventhas resolved, subsided, stabilized, disappeared, the event is otherwise explained, or thesubject is lost to follow-up;

• or, in the case of other non-serious AEs, until they complete the study or they are lostto follow-up.

Clinically significant laboratory abnormalities will be followed up until they havereturned to normal, or a satisfactory explanation has been provided. Reports relative tothe subsequent course of an AE noted for any subject must be submitted to the StudyMonitor.

GSK Biologicals may request that the investigator perform or arrange for the conduct ofsupplemental measurements and/or evaluations to elucidate as fully as possible the natureand/or causality of the AE or SAE. The investigator is obliged to assist. If a subject diesduring participation in the study or during a recognized follow-up period, GSKBiologicals will be provided with a copy of any available post-mortem findings,including histopathology.

New or updated information will be recorded on the originally completed SAE ReportForm, with all changes signed and dated by the investigator. The updated SAE reportform should be resent to GSK Biologicals within 24 hours of receipt of the follow-upinformation as outlined in Section 7.8.1.

Outcome of any non-serious AE occurring within 30 days post-vaccination (i.e.unsolicited AE) or any SAE reported during the entire study will be assessed as:

• Recovered/resolved

• Not recovered/not resolved

• Recovering/resolving

• Recovered with sequelae/resolved with sequelae

7.8 Prompt reporting of serious adverse events to GSK Biologicals

7.8.1 Time frames for submitting serious adverse event reports to GSK Biologicals

SAEs will be reported promptly to GSK Biologicals once the investigator determines thatthe event meets the protocol definition of an SAE. The investigator or designate will faxthe SAE reports to GSK Biologicals’ Study Contact for Serious Adverse Event ReportingWITHIN 24 HOURS OF HIS/HER BECOMING AWARE OF THESE EVENTS. Additional or


56

follow-up information relating to the initial SAE report is also to be reported to the GSKBiologicals’ Study Contact for Serious Adverse Event Reporting within 24 hours ofreceipt of such information.

7.8.2 Completion and transmission of serious adverse event reports to GSKBiologicals

Once an investigator becomes aware that a SAE has occurred in a study subject, she/hewill report the information to GSK Biologicals within 24 hours as outlined in Section7.8.1. The SAE Report Form will always be completed as thoroughly as possible with allavailable details of the event, signed by the investigator (or designee), and forwarded toGSK Biologicals within the designated time frames. If the investigator does not have allinformation regarding an SAE, he/she will not wait to receive additional informationbefore notifying GSK Biologicals of the event and completing the form. The form will beupdated when additional information is received and forwarded to GSK BiologicalsWITHIN 24 HOURS as outlined in Section 7.8.1.

The investigator will always provide an assessment of causality at the time of the initialreport as described in Section 7.6.2.

Facsimile (Fax) transmission of the SAE Report Form is the preferred method to transmitthis information to the Study Contact for Reporting SAEs. In rare circumstances and inthe absence of facsimile equipment, notification by telephone is acceptable, with a copyof the SAE Report Form sent by overnight mail. Initial notification via the telephone doesnot replace the need for the investigator to complete and sign the SAE Report Formwithin 24 hours as outlined in Section 7.8.1.

In the event of a death determined by the investigator to be related to vaccination,sending of the fax must be accompanied by telephone call to the Study Contact forReporting SAEs.


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Study Contact for Reporting SAEsGermany

Dr.GlaxoSmithKline GmbH & Co. KG,

Theresienhoehe 11 /11 a,80339 München

Tel:Fax:

AustriaDr.

Albert Schweitzer-Gasse 6A-1140 Vienna

Tel.Fax:

Back-up Study Contact for Reporting SAEsManager Clinical Safety Vaccines

M.DGlaxoSmithKline Biologicals,

Rixensart, BelgiumTel:Fax:

Mobile phone for 7/7 day availability:24/24 hour and 7/7 day availability

7.9 Regulatory reporting requirements for serious adverse events

The investigator will promptly report all SAEs to GSK Biologicals in accordance withthe procedures detailed in Section 7.8. GSK Biologicals has a legal responsibility topromptly notify, as appropriate, both the local regulatory authority and other regulatoryagencies about the safety of a product under clinical investigation. Prompt notification ofSAEs by the investigator to the Study Contact for Reporting SAEs is essential so thatlegal obligations and ethical responsibilities towards the safety of other subjects are met.

The investigator, or responsible person according to local requirements, will comply withthe applicable local regulatory requirements related to the reporting of SAEs to regulatoryauthorities and the IRB/IEC.

Expedited Investigator Safety Reports (EISR) are prepared according to GSK Biologicalspolicy and are forwarded to investigators as necessary. An EISR is prepared for a SAEthat is both attributable to the investigational product and unexpected. The purpose of theEISR is to fulfil specific regulatory and Good Clinical Practice (GCP) requirements,regarding the product under investigation.


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An investigator who receives an EISR describing a SAE or other specific safetyinformation from GSK Biologicals will file it with the Investigator Brochure and willnotify the IRB/IEC, if appropriate according to local requirements.

7.10 Post study adverse events and serious adverse events

A post-study AE/SAE is defined as any event that occurs outside of the AE/SAEdetection period defined in Section 7.5. Investigators are not obligated to actively seekAEs or SAEs in former study participants.

However, if the investigator learns of any SAE, including a death, at any time after asubject has been discharged from the study, and he/she considers the event reasonablyrelated to the investigational product, the investigator will promptly notify the StudyContact for Reporting SAEs.

7.11 Pregnancy

Not applicable

7.12 Treatment of adverse events

Treatment of any adverse event is at the sole discretion of the investigator and accordingto current good medical practice. Any medication administered for the treatment of anAE should be recorded in the subject’s CRF. Refer to Section 6.9.

8 Subject Completion and Withdrawal

8.1 Subject completion

A subject who returns for the concluding visit of the active phase of the study foreseen inthe protocol (i.e., Visit 3/Week 12) is considered to have completed the active phase ofthe study.

8.2 Subject withdrawal

Subjects who are withdrawn for AEs must be clearly distinguished from subjects who arewithdrawn for other reasons. Investigators will follow subjects who are withdrawn asresult of a SAE/AE until resolution of the event (see Section 7.7).


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8.2.1 Subject withdrawal from the study

From an analysis perspective, a ‘withdrawal’ from the study is any subject who did notcome back for the concluding visit/was not available for the concluding contact foreseenin the protocol.

A subject qualifies as a ‘withdrawal’ from the study when no study procedure hasoccurred, no follow-up has been performed and no further information has been collectedfor this subject from the date of withdrawal/last contact.

Investigators will make an attempt to contact those subjects who do not return forscheduled visits or follow-up.

Information relative to the withdrawal will be documented on the Study Conclusion pageof the CRF. The investigator will document whether the decision to withdraw from thestudy was made by the subject’s parent or guardian or the investigator and which of thefollowing possible reasons was responsible for withdrawal:

• serious adverse event

• non-serious adverse event

• protocol violation (specify)

• consent withdrawal, not due to an adverse event

• moved from the study area

• lost to follow-up

• other (specify)

8.2.2 Subject withdrawal from investigational product

A ‘withdrawal’ from the investigational product is any subject who does not receive thecomplete treatment, i.e. when no further planned dose is administered from the date ofwithdrawal. A subject withdrawn from the investigational product may not necessarily bewithdrawn from the study as further study procedures or follow-up may be performed(safety or immunogenicity) if planned in the study protocol.

Information relative to premature discontinuation of the investigational product will bedocumented on the Vaccine Administration page of the CRF. The investigator willdocument whether the decision to discontinue further vaccination was made by the


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subject’s parent or guardian or the investigator and which of the following possiblereasons was responsible for withdrawal:

• serious adverse event,

• non-serious adverse event,

• other (specify).

9 Data Evaluation: Criteria for Evaluation of Objectives

9.1 Active phase of the study

9.1.1 Co-primary endpoints

• Measles, mumps, rubella and varicella seroconversion, 42-56 days after the seconddose.

9.1.2 Secondary endpoints

Immunogenicity

• Measles, mumps, rubella and varicella antibody titres, 42-56 days after the first doseand 42-56 days after the second dose.

• Measles, mumps, rubella and varicella seroconversion and antibody titres, 42-56 daysafter the first dose.

Safety

• Occurrence of any fever and grade 3 fever (defined as axillary temperature >39.0°C)within 15 days after each vaccination (Day 0-14).

• Occurrence of any and grade 3 solicited local symptoms within 4 days after eachvaccination (Day 0-3).

• Occurrence of any and grade 3 solicited general symptoms (fever, rash, any sign ofmeningitis including febrile convulsion, parotitis gland swelling) within 43 days aftereach vaccination (Day 0-42).

• Occurrence, intensity and relationship to vaccination of unsolicited symptoms within43 days after each vaccination (Day 0-42).


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• Occurrence of SAEs throughout the entire study up to and including 42 days aftervaccination.

9.2 Long-term endpoints

• Seroconversion/seropositivity and antibody titres to measles, mumps, rubella andvaricella at 1, 2 and 3 years after vaccination.

• Occurence of breakthrough cases (confirmed by a physician) of measles, mumps,rubella and/or varicella during the 3-year follow-up period after vaccination.

• Contacts with measles, mumps, rubella and/or varicella/herpes zoster diseases duringthe 3-year follow-up period after vaccination.

9.3 Estimated sample size

The target sample size is 400 evaluable subjects for the analysis of immunogenicity (100subjects equally distributed in each study group). Considering that 20% of the enrolledsubjects might be excluded for the ATP immunogenicity cohort at Week 12, a total of480 subjects will be enrolled.

To control the impact of multiple primary objectives on the Type I and Type II error rate,the primary objectives of the study will be evaluated sequentially: the subsequentobjective will only be evaluated in a confirmatory manner if the previous objective hasbeen reached. The objectives will be evaluated as follows:

(1) Demonstrate the consistency of three production lots of MeMuRu-OKAcandidate vaccine in terms of seroconversion to measles, mumps, rubella andvaricella 42-56 days after the second dose;

(2) Demonstrate the non-inferiority of the MeMuRu-OKA candidate vaccine toseparate administration of Priorix and Varilrix vaccines in terms of seroconversionto measles, mumps, rubella and varicella 42-56 days after the second dose.

The criterion to conclude that the lots are consistent after the second dose is that, for allpairs of lots and all antigens, the 90% confidence interval (CI) for the difference inseroconversion rates are within [-10%; 10%].

The criterion to conclude non-inferiority of the MeMuRu-OKA vaccine to Priorix andVarilrix after the second dose is that the lower limit of the 95% CI around the differencein seroconversion rates between groups (MeMuRu-OKA pooled lots minusPriorix+Varilrix) is [–10%] or higher.


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Assuming that the expected seroconversion rate would be 99% for each of the vaccinecomponents after the second dose, the overall power to demonstrate both the consistencyand the non-inferiority objectives will be above 90% (Pass®-2000: Equivalence -Proportions).

9.4 Study cohorts to be evaluated

The following subject cohorts will be evaluated:

Total cohort

The Total cohort will include all subjects for whom data are available. For the totalanalysis of safety, this will include all vaccinated subjects for whom safety data areavailable. For the total cohort analysis of immunogenicity, this will include vaccinatedsubjects for whom data concerning immunogenicity are available.

Protocol defined or According To Protocol (ATP) cohort for analysis of safety

The protocol-defined cohort for analysis of safety will include subjects:

• who have received complete dosing of study vaccine according to the randomisationlist,

• with sufficient data to perform an analysis of safety,

• who only received vaccine specified or allowed in the protocol,

• for whom the administration site, side and route of study vaccine(s) is/are known.

Protocol defined or According To Protocol (ATP) cohort for analysis ofimmunogenicity

The protocol-defined cohort for analysis of immunogenicity will include eligible subjectsin the protocol-defined cohort for safety:

• with blood samples available,

• who complied with all protocol procedures,

• who are seronegative for all four antigens (i.e., measles, mumps, rubella andvaricella) at baseline, and

• whose post-vaccination serology data are available for at least one of the vaccineantigens.


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Long-term follow-up cohort

The long-term follow-up analyses will be based on all subjects:

- who have received their complete vaccination course according to the groupallocation,

- who have not received an additional dose of measles, mumps, rubella orvaricella vaccine,

- who have available immunogenicity results at each time point, for at least oneantigen.

9.5 Derived and transformed data

For a given subject and the analysis of a given measurement, missing or unevaluablemeasurements will not be replaced. Therefore, an analysis will exclude subjects withmissing or with unevaluable measurements (e.g. total analysis of mumps antibody titrewill include all vaccinated subjects with mumps antibody titre results after vaccination;total analysis of solicited symptoms will include all vaccinated subjects with documentedsolicited symptom sheets).

For the analysis of immunogenicity, the following definition will be applied:

• A seronegative subject is a subject whose titre is below the cut-off value. The cut-offvalue is defined by the laboratory before the analysis and is described inSection 5.4.2.

• A seropositive subject is a subject whose titre is greater than or equal to the cut-offvalue.

• Seroconversion is defined as the appearance of antibodies (i.e. titre greater than orequal to the cut-off value) in the serum of subjects seronegative before vaccination.

• The Geometric Mean Titres (GMTs) calculations are performed by taking the anti-logof the mean of the log titre transformations. Antibody titre below the cut-off of theassay will be given an arbitrary value of half the cut-off for the purpose of GMTcalculation.


64

9.6 Final analyses

The final analysis will be performed with all data until study conclusion of the activephase period (i.e., until Visit 3 as described in the Outline of study procedures in Section5.2.1).The data of the 3-year long-term follow-up period will be analyzed on a yearly basis andwill be reported as annexes to the main study (i.e. active phase period).

The primary analysis will be based on the ATP cohort for analysis of immunogenicity. Ifthe percentage of enrolled subjects excluded from this ATP cohort is more than 5%, asecond analysis based on the Total cohort will be performed to complement the ATPanalysis.

All descriptive analyses will be performed by study groups (each MeMuRu-OKA lotsand Group Priorix+Varilrix individually) and by vaccine groups (pooled MeMuRu-OKAlots compared to Group Priorix+Varilrix).

9.6.1 Analysis of demographics/baseline characteristics

Demographic characteristics (age, race and gender) and distribution of subjects enrolledin all study centres will be tabulated by group and overall.

9.6.2 Analysis of immunogenicity

Active phase period

The primary objectives will be demonstrated sequentially (i.e., the subsequent objectivewill be evaluated in a confirmatory manner only if the previous objective has beenreached).

To demonstrate the consistency primary objective, the pair wise standardized asymptotic90% CIs for seroconversion rates difference between MeMuRu-OKA lots will becomputed for each antigen (measles, mumps, rubella and varicella) after the second dose.The three MeMuRu-OKA lots will be considered consistent if, for each antigen and eachpair wise comparison, the 90% CI is included between [-10%, +10%].

To demonstrate the non-inferiority of Group MeMuRu-OKA as compared to GroupPriorix+Varilrix, the standardized asymptotic 95% CIs for seroconversion ratesdifference between vaccine groups (pooled Groups MeMuRu-OKA minus GroupPriorix+Varilrix) will be computed for each antigen (measles, mumps, rubella andvaricella) after the second dose. The objective will be achieved if the lower limit of thestandardized asymptotic 95% CI is [-10%] or higher.


65

To support these analyses, the following descriptive analyses will be performed for eachgroup and each antigen (measles, mumps, rubella and varicella):

• seroconversion/seropositivity rates and their exact 95% CIs will be tabulated aftereach dose;

• antibody titres distribution will be displayed as reverse cumulative curves for eachantigen and each treatment group after each dose;

• antibody titres will also be summarized by GMTs with their 95% CIs after each dose.

Finally, the 90% CI for GMT ratio between MeMuRu-OKA vaccine lots and the 95% CIfor GMT ratio between vaccine groups (pooled Groups MeMuRu-OKA over GroupPriorix+Varilrix) will also be computed after each dose. This will be performed using aone-way ANOVA model on the logarithm10 transformation of the concentrations.

Long-term follow-up period

On a yearly basis, for each treatment group and each antigen, theseroconversion/seropositivity rate and its 95% CIs will be tabulated whereas the antibodytitres for subjects seronegative before vaccination will be summarized in terms of GMTswith the 95% CI and displayed as Reverse Cumulative Curves (RCCs).

All breakthrough cases will be fully described (time of onset, duration, description ofskin eruption, presence of contact, number of days since the last contact, titre at Week 12,last titre measured). The number of contacts with the disease(s) and the subject-yearbreakthrough rate will be calculated for each vaccine group (pooled MeMuRu-OKAgroups vs Group Priorix+Varilrix).

9.6.3 Analysis of safety

For each group, the following results will be tabulated, after each vaccine doses:

• the number and percentage of subjects (with exact 95% CIs) with at least one local,general, and any adverse event (solicited and/ or unsolicited) after vaccination andduring the 43-day follow-up period;

• the number and percentage of subjects (with exact 95% CIs) reporting each localsolicited symptom, during the 4-day follow-up period (Day 0-3);

• the number and percentage of subjects (with exact 95% CIs) reporting grade 3 feverand any fever during the first 15 days after vaccination (Day 0-14);


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• the number and percentage of subjects (with exact 95% CIs) reporting each generalsolicited symptom during the follow-up period (Day 0-42). Similar tabulations will beperformed for grade 3 general solicited adverse events and for general solicitedadverse events with causal relationship to vaccination. In addition, the prevalence offever will also be presented graphically by intensity over time;

• the number and percentage of subjects with exact 95% CIs for whom unsolicitedadverse events are reported within 42 days after vaccination (Day 0-42). Theverbatim reports of unsolicited symptoms will be reviewed by a physician and thesigns and symptoms will be coded according to MedDRA, the Medical Dictionary forRegulatory Activities. Every verbatim term will be matched with the appropriatePreferred Term. Similar tabulations will be done for grade 3 unsolicited adverseevents and for unsolicited adverse events with a possibility of having a relationship tovaccination;

• the number and percentage of subjects who received at least one concomitantmedication after vaccination will be calculated by group. Additionally, the numberand percentage of subjects receiving antipyretic drugs (assumed due to fever) willalso be calculated by group.

Finally, subjects who experienced at least one serious adverse event during the entirestudy period will be reported with their associated Clinical Narratives.

9.7 Planned interim analysis

No interim analysis is planned during the course of the active phase of the study.

10 Administrative Matters

To comply with Good Clinical Practice important administrative obligations relating toinvestigator responsibilities, monitoring, archiving data, audits, confidentiality andpublications must be fulfilled. See Appendix B for details.


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References

[1] Recommendation of the Standing Committee on Immunization (STIKO) atRobert Koch Institute. Epidemiologisches Bulletin 2002, 28: 227-242.

[2] Gershon A. A. Varicella vaccine-Are two doses better than one? (Editorials).The New England Journal of Medicine 2002, 347 (24): 1962-1963.

[3] Galil K. et. al. Outbreak of varicella at a day-care center despite vaccination. TheNew England Journal of Medicine 2002, 347 (24): 1909-1915.

[4] White S.J., Freedman L.S. Allocation of patients to treatment groups in acontrolled clinical study. Br. J. Cancer 1978, 37: 849-857

[5] Meurice F., De Bouver J-L., Vandervoorde D., Woods S. and Bogaerts H.Immunogenicity and safety of a live attenuated varicella vaccine (OKA/SB Bio)in healthy children. The J. of Infectious Disease. 1996,174 (3): 324-329.

[6] Usonis V., Bakasenas V, Kaufhold A., Chitour K. and Clemens R.Reactogenicity and immunogenicity of a new live attenuated combined measles,mumps and rubella vaccine in healthy children.Pediatr. Infect. Dis. J. 1999, 18: 42-48

[7] Combined Measles, Mumps and Rubella vaccine (Priorix®): ProductMonograph. 2002. GlaxoSmithKline Biologicals.

[8] Varicella Vaccine (Varilrix®): Product Monograph. 2002. GlaxoSmithKlineBiologicals.


Appendix A 1

Appendix A: World Medical Association Declaration of Helsinki

Recommendations guiding physiciansin biomedical research involving human subjects

Adopted by the 18th World Medical AssemblyHelsinki, Finland, June 1964

and amended by the29th World Medical AssemblyTokyo, Japan, October 1975

35th World Medical AssemblyVenice, Italy, October 1983

41st World Medical AssemblyHong Kong, September 1989

and the48th General Assembly

Somerset West, Republic of South Africa, October 1996

INTRODUCTION

It is the mission of the physician to safeguard the health of the people. His or herknowledge and conscience are dedicated to the fulfilment of this mission.

The Declaration of Geneva of the World Medical Association binds the physician withthe words, "The health of my patient will be my first consideration," and the InternationalCode of Medical Ethics declares that, "A physician shall act only in the patient's interestwhen providing medical care which might have the effect of weakening the physical andmental condition of the patient."

The purpose of biomedical research involving human subjects must be to improvediagnostic, therapeutic and prophylactic procedures and the understanding of the etiologyand pathogenesis of disease.

In current medical practice most diagnostic, therapeutic or prophylactic proceduresinvolve hazards. This applies especially to biomedical research.

Medical progress is based on research which ultimately must rest in part onexperimentation involving human subjects.


Appendix A 2

In the field of biomedical research a fundamental distinction must be recognized betweenmedical research in which the aim is essentially diagnostic or therapeutic for a patient,and medical research, the essential object of which is purely scientific and withoutimplying direct diagnostic or therapeutic value to the person subjected to the research.

Special caution must be exercised in the conduct of research which may affect theenvironment, and the welfare of animals used for research must be respected.

Because it is essential that the results of laboratory experiments be applied to humanbeings to further scientific knowledge and to help suffering humanity, the World MedicalAssociation has prepared the following recommendations as a guide to every physician inbiomedical research involving human subjects. They should be kept under review in thefuture. It must be stressed that the standards as drafted are only a guide to physicians allover the world. Physicians are not relieved from criminal, civil and ethicalresponsibilities under the laws of their own countries.

I. BASIC PRINCIPLES

1. Biomedical research involving human subjects must conform to generally acceptedscientific principles and should be based on adequately performed laboratory andanimal experimentation and on a thorough knowledge of the scientific literature.

2. The design and performance of each experimental procedure involving humansubjects should be clearly formulated in an experimental protocol which should betransmitted for consideration, comment and guidance to a specially appointedcommittee independent of the investigator and the sponsor provided that thisindependent committee is in conformity with the laws and regulations of the countryin which the research experiment is performed.

3. Biomedical research involving human subjects should be conducted only byscientifically qualified persons and under the supervision of a clinically competentmedical person. The responsibility for the human subject must always rest with amedically qualified person and never rest on the subject of research, even though thesubject has given his or her consent.

4. Biomedical research involving human subjects cannot legitimately be carried outunless the importance of the objective is in proportion to the inherent risk to thesubject.

5. Every biomedical research project involving human subjects should be preceded bycareful assessment of predictable risks in comparison with foreseeable benefits to the


Appendix A 3

subject or to others. Concern for the interests of the subject must always prevail overthe interests of science and society.

6. The right of the research subject to safeguard his or her integrity must always berespected. Every precaution should be taken to respect the privacy of the subject andto minimize the impact of the study on the subject's physical and mental integrity andon the personality of the subject.

7. Physicians should abstain from engaging in research projects involving humansubjects unless they are satisfied that the hazards involved are believed to bepredictable. Physicians should cease any investigation if the hazards are found tooutweigh the potential benefits.

8. In publication of the results of his or her research, the physician is obliged to preservethe accuracy of the results. Reports of experimentation not in accordance with theprinciples laid down in this Declaration should not be accepted for publication.

9. In any research on human beings, each potential subject must be adequately informedof the aims, methods, anticipated benefits and potential hazards of the study and thediscomfort it may entail. He or she should be informed that he or she is at liberty toabstain from participation in the study and that he or she is free to withdraw his or herconsent to participation at any time. The physician should then obtain the subject'sfreely-given informed consent, preferably in writing.

10. When obtaining informed consent for the research project the physician should beparticularly cautious if the subject is in a dependent relationship to him or her or mayconsent under duress. In that case the informed consent should be obtained by aphysician who is not engaged in the investigation and who is completely independentof this official relationship.

11. In case of legal incompetence, informed consent should be obtained from the legalguardian in accordance with national legislation. Where physical or mental incapacitymakes it impossible to obtain informed consent, or when the subject is a minor,permission from the responsible relative replaces that of the subject in accordancewith national legislation.

Whenever the minor child is in fact able to give a consent, the minor's consent mustbe obtained in addition to the consent of the minor's legal guardian.

12. The research protocol should always contain a statement of the ethical considerationsinvolved and should indicate that the principles enunciated in the present Declarationare complied with.


Appendix A 4

II. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE(Clinical research)

1. In the treatment of the sick person, the physician must be free to use a new diagnosticand therapeutic measure, if in his or her judgement it offers hope of saving life, re-establishing health or alleviating suffering.

2. The potential benefits, hazards and discomfort of a new method should be weighedagainst the advantages of the best current diagnostic and therapeutic methods.

3. In any medical study, every patient - including those of a control group, if any -should be assured of the best proven diagnostic and therapeutic method. This does notexclude the use of inert placebo in studies where no proven diagnostic or therapeuticmethod exists.

4. The refusal of the patient to participate in a study must never interfere with thephysician–patient relationship.

5. If the physician considers it essential not to obtain informed consent, the specificreasons for this proposal should be stated in the experimental protocol fortransmission to the independent committee (I, 2).

6. The Physician can combine medical research with professional care, the objectivebeing the acquisition of new medical knowledge, only to the extent that medicalresearch is justified by its potential diagnostic or therapeutic value for the patient.

III. NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMANSUBJECTS(Non-clinical biomedical research)

1. In the purely scientific application of medical research carried out on a human being,it is the duty of the physician to remain the protector of the life and health of thatperson on whom biomedical research is being carried out.

2. The subjects should be volunteers - either healthy persons or patients for whom theexperimental design is not related to the patient's illness.

3. The investigator or the investigating team should discontinue the research if in his/heror their judgement it may, if continued, be harmful to the individual.

4. In research on man, the interest of science and society should never take precedenceover considerations related to the well being of the subject.


Appendix B 1

Appendix B: Administrative Matters

I. Responsibilities of the Investigator• To ensure that he/she has sufficient time to conduct and complete the study and has

adequate staff and appropriate facilities and equipment which are available for theduration of the study and to ensure that other studies do not divert essential subjects orfacilities away from the study at hand.

• To submit an up-to-date curriculum vitae and other credentials (e.g., medical licensenumber in the United States) to GSK Biologicals and—where required—to relevantauthorities.

• To acquire the normal ranges for laboratory tests performed locally and, if requiredby local regulations, obtain the Laboratory License or Certification.

• To ensure that no clinical samples (including serum samples) are retained on site orelsewhere without the approval of GSK Biologicals and the express written informedconsent of the subject and/or the subject’s legally authorized representative.

• To perform no other biological assays at the investigator site except those describedin the protocol or its amendment(s).

• To prepare and maintain adequate case histories designed to record observations andother data pertinent to the study.

• To conduct the study in compliance with the protocol and appendices.

• To co-operate with a representative of GSK Biologicals in the monitoring process ofthe study and in resolution of queries about the data.

II. Protocol Amendments and Modifications• No changes to the study protocol will be allowed unless discussed in detail with the

GSK Biologicals' Clinical Development Manager/Medical Monitor and filed as anamendment/modification to this protocol.

• Any amendment/modification to the protocol will be adhered to by the participatingcentre(s) and will apply to all subjects. Written IRB/IEC approval of protocolamendments is required prior to implementation; modifications are submitted toIRBs/IECs for information only.


Appendix B 2

III. Sponsor’s Termination of StudyGSK Biologicals reserves the right to discontinue the clinical study at any time formedical or administrative reasons. When feasible, a 30-day written notification will betendered.

IV. Remote Data Entry InstructionsRemote Data Entry (RDE) will be used as the method for data collection, which meansthat subject information will be entered into a computer at the investigational site. Thesite will be capable of modifying the data to assure accuracy with source documentation.All new/updated information will be reviewed and verified by a GSK Biologicals'representative. This information will finally be stored in a central database maintained byGSK Biologicals. At the conclusion of the study, GSK Biologicals will archive the studydata in accordance with internal procedures. In addition, the investigator will be providedwith a CD-ROM of the final version of the data generated at the investigational site.

Specific instructions for use of RDE will be included in the training material provided tothe investigational site.

V. Monitoring by GSK BiologicalsMonitoring visits by a professional representative of the sponsor will be scheduled to takeplace as close as possible to entry of the first subject, during the study at appropriateintervals and after the last subject has completed the study. It is anticipated thatmonitoring visits will occur at a frequency defined before study start.

These visits are for the purpose of confirming that GSK Biologicals’ sponsored studiesare being conducted in compliance with the relevant Good Clinical Practice regulations/guidelines, verifying adherence to the protocol and the completeness and accuracy of dataentered on the RDE screens and Vaccine Inventory Forms. The monitor will verify RDEentries by comparing them with the source data/documents that will be made available bythe investigator for this purpose. Data to be recorded directly into the RDE screens willbe specified in writing preferably in the source documentation agreement form that iscontained in both the monitor’s and investigator’s study file. For RDE, the monitor willmark completed and approved screens at each visit. The investigator must ensureprovision of reasonable time, space and adequate qualified personnel for monitoringvisits.

VI. Archiving of DataFollowing closure of the study, the investigator must maintain all site study records in asafe and secure location. The records must be maintained to allow easy and timelyretrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow anysubsequent review of data in conjunction with assessment of the facility, supporting


Appendix B 3

systems, and staff. Where permitted by applicable laws/regulations or institutional policy,some or all of these records can be maintained in a validated format other than hard copy(e.g., microfiche, scanned, electronic for studies with an eCRF, for example); however,caution needs to be exercised before such action is taken. The investigator must assurethat all reproductions are legible and are a true and accurate copy of the original, andmeet accessibility and retrieval standards, including re-generating a hard copy, ifrequired. Furthermore, the investigator must ensure there is an acceptable back-up ofthese reproductions and that an acceptable quality control process exists for making thesereproductions.

GSK will inform the investigator of the time period for retaining these records to complywith all applicable regulatory requirements. However, the investigator should seek thewritten approval of the sponsor before proceeding with the disposal of these records. Theminimum retention time will meet the strictest standard applicable to that site for thestudy, as dictated by ICH GCP E6 Section 4.9, any institutional requirements orapplicable laws or regulations, or GSK standards/procedures; otherwise, the minimumretention period will default to 15 years.

The investigator must notify GSK of any changes in the archival arrangements, including,but not limited to, the following: archival at an off-site facility, transfer of ownership ofthe records in the event the investigator leaves the site.

VII. AuditsFor the purpose of compliance with Good Clinical Practice and Regulatory AgencyGuidelines it may be necessary for GSK Biologicals or a Drug Regulatory Agency toconduct a site audit. This may occur at any time from start to after conclusion of thestudy.

When an investigator signs the protocol, he agrees to permit drug regulatory agencies andGSK Biologicals audits, providing direct access to source data/ documents. Furthermore,if an investigator refuses an inspection, his data will not be accepted in support of a NewDrug Registration and/or Application, Biologics Licensing Application.

GSK Biologicals has a substantial investment in clinical studies. Having the highestquality data and studies are essential aspects of vaccine development. GSK Biologicalshas a Regulatory Compliance staff who audit investigational sites. RegulatoryCompliance assesses the quality of data with regard to accuracy, adequacy andconsistency. In addition, Regulatory Compliance assures that GSK Biologicals sponsoredstudies are in accordance with GCP and that relevant regulations/guidelines are beingfollowed.


Appendix B 4

To accomplish these functions, Regulatory Compliance selects investigational sites toaudit. These audits usually take 1 to 2 days. The GSK Biologicals’ audits entail review ofsource documents supporting the adequacy and accuracy of eCRFs, review ofdocumentation required to be maintained, and checks on vaccine accountability. TheGSK Biologicals’ audit therefore helps prepare an investigator for a possible regulatoryagency inspection as well as assuring GSK Biologicals of the validity of the databaseacross investigational sites.

The Inspector will be especially interested in the following items:• Log of visits from the sponsor’s representatives• IRB/IEC approval• Vaccine accountability• Approved study protocol and amendments• Informed consent of the subjects (written consent [or witnessed oral if applicable] )• Medical records and other source documents supportive of CRF data• Reports to the IRB/IEC and the sponsor• Record retention

GSK Biologicals will gladly help investigators prepare for an inspection.

VIII. Ownership, Confidentiality and PublicationOwnership:All information provided by GSK and all data and information generated by the site aspart of the study (other than a subject’s medical records) are the sole property of GSK.

All rights, title, and interests in any inventions, know-how or other intellectual orindustrial property rights which are conceived or reduced to practice by site staff duringthe course of or as a result of the study are the sole property of GSK, and are herebyassigned to GSK.

If a written contract for the conduct of the study which includes ownership provisionsinconsistent with this statement is executed between GSK and the study site, thatcontract’s ownership provisions shall apply rather than this statement.

Confidentiality:All information provided by GSK and all data and information generated by the site aspart of the study (other than a subject’s medical records) will be kept confidential by theinvestigator and other site staff. This information and data will not be used by theinvestigator or other site personnel for any purpose other than conducting the study.These restrictions do not apply to: (1) information which becomes publicly availablethrough no fault of the investigator or site staff; (2) information which it is necessary to


Appendix B 5

disclose in confidence to an IEC or IRB solely for the evaluation of the study; (3)information which it is necessary to disclose in order to provide appropriate medical careto a study subject; or (4) study results which may be published as described in the nextparagraph. If a written contract for the conduct of the study which includesconfidentiality provisions inconsistent with this statement is executed, that contract’sconfidentiality provisions shall apply rather than this statement.

Publication:For multicentre studies, the first publication or disclosure of study results shall be acomplete, joint multicentre publication or disclosure coordinated by GSK. Thereafter,any secondary publications will reference the original publication(s).

Prior to submitting for publication, presentation, use for instructional purposes, orotherwise disclosing the study results generated by the site (collectively, a “Publication”),the investigator shall provide GSK with a copy of the proposed Publication and allowGSK a period of at least thirty (30) days [or, for abstracts, at least five (5) working days]to review the proposed Publication. Proposed Publications shall not include either GSKconfidential information other than the study results or personal data on any subject, suchas name or initials.

At GSK’s request, the submission or other disclosure of a proposed Publication will bedelayed a sufficient time to allow GSK to seek patent or similar protection of anyinventions, know-how or other intellectual or industrial property rights disclosed in theproposed Publication.

If a written contract for the conduct of the study, which includes publication provisionsinconsistent with this statement is executed, that contract’s publication provisions shallapply rather than this statement.


Appendix C 1

Appendix C: Overview of the Recruitment Plan

• Target enrolment is 480 subjects to be recruited from multiple study centres inGermany and Austria.

• It is anticipated that all subjects will be enrolled within the period of eight weeks.

• Monitoring of actual enrolment against target will be performed by the CentralMonitor on a weekly basis and by using SBIR.


Appendix D 1

Appendix D: Handling of Biological Samples Collected by the Investigator

Instructions for Handling of Serum Samples

When materials are provided by GSK Biologicals, it is mandatory that all clinicalsamples (including serum samples) be collected and stored using exclusively thosematerials in the appropriate manner. The use of other materials could result in theexclusion of the subject from analysis. The investigator must ensure that his/herpersonnel and the laboratory(ies) under his/her supervision comply with this requirement.

1. CollectionThe whole blood (by capillary or venous route) should be collected observing appropriateaseptic conditions. It is recommended that Vacutainer tubes WITH integrated serumseparator (e.g. Becton-Dickinson Vacutainer SST or Corvac Sherwood Medical) beused to minimize the risk of haemolysis and to avoid blood cell contamination of theserum when transferring to standard serum tubes.

2. Serum separationThese guidelines aim to ensure high quality serum by minimizing the risk of haemolysis,blood cell contamination of the serum or serum adverse cell toxicity at testing.

• For separation of serum using Vacutainer® tubes, the instructions provided by themanufacturer should be followed. Siliconized tubes should never be used (celltoxicity). Often the manufacturer’s instruction states that the relative centrifugalacceleration known also as “G” must be “between 1000 and 1300 G” with tubesspinning for ten minutes. Error in calculation of centrifuge speed can occur whenlaboratory personnel confuse “G” acceleration with “RPM” (revolutions per minute).The speed of centrifugation must be calculated using the “G” rate provided in themanufacturer’s instructions and the radius of the centrifuge head. After measuring theradius of the centrifuge machine, a speed/acceleration nomograph must be employedto determine the centrifuge speed in “RPM”.

• Following separation, the serum should be aseptically transferred to the appropriatestandard tubes using a sterile disposable pipette. The serum should be transferred asgently as possible to avoid blood cell contamination.

• The tube should not be overfilled (max. 3/4 of the total volume) to allow room forexpansion upon freezing.

• The tube should be identified by the appropriate label provided by GSK Biologicals(see point 3).


Appendix D 2

3. Labelling• The standard labels provided by GSK Biologicals should be used to label each serum

sample.

• If necessary, any hand-written additions to the labels should be made using indelibleink.

• The label should be attached to the tube as follows (see diagram):− first attach the paper part of the label to the tube− then wrap the label around the tube so that the transparent, plastic part of the label

overlaps with the label text and bar code and shields them.This will ensure optimal label attachment.

Plastic, transparent part

Paper, text part

Bar code

Study N°.........

Subject N° ......

POST VACC. ISTUDY MTH 1

For GlaxoSmithKlineBiologicals

• Labels should not be attached to caps.

4. Sorting and storage• Tubes should be placed in the GSK Biologicals’ carton in numerical order from left to

right, starting from the lower left hand corner, beginning with the pre-vaccinationsamples series, then with the post-vaccination sample series.

• The tubes of serum should be stored in a vertical position at -20°C (alternatively at -70°/80°C is also acceptable) until shipment to GSK Biologicals. Wherever possible, abackup facility for storage of serum samples should be available.


Appendix D 3

• A standard Serum Listing Form, specifying the samples being shipped for individualsubjects at each timepoint, should be prepared for each shipment. A copy of this listshould be retained at the study site, while the original should be sealed in a plasticenvelope and shipped with the serum samples.

• Once flight details are known, a standard Specimen Transfer Form must be completedand faxed to GSK Biologicals to the number provided below. A copy of the SpecimenTransfer Form must be in the parcel.1

GLAXOSMITHKLINE BIOLOGICALSAttention

Clinical ImmunologyR & D Department/Building 44

Rue de l'Institut, 89B-1330 Rixensart – Belgium

Telephone:Fax:

Instructions for Collection & Handling of Vesicular Fluid Samples

For subjects with varicella-like rash (papulo-vesicular or vesicular rash), samples of fluidin the vesicles/blisters should be collected for varicella PCR testing (as described inAppendix F) according to the following instruction:

1. Fresh vesicles/blisters (not crusted) should be chosen.

2. Insert needle (23G x 1”, i.e. 0.6 x 25 mm or 21G x 2”, i.e. 0.8 x 50 mm) parallel tothe skin in a full vesicle without connecting the needle to a syringe so that the fluidgoes up the needle by capillary action. Only if very little vesicular fluid is available, aswab of the lesion can be used with a small cotton/ dacron swab. The sample shouldnot contain any blood.

3. Repeat the procedure for 2-3 vesicles per subject.

4. The material after sampling must not be diluted into any liquid but the needle or swabshould be placed as it is in the dry tube provided by GSK.

5. Close the tube and label it with labels provided by GSK.

1 The Serum Listing Form and the Specimen Transfer Form are standard documents used in GSKBiologicals’ clinical trials. These documents are provided by GSK Biologicals’ Clinical Trials’ monitor atstudy initiation.


Appendix D 4

6. Store the tube at −20°C.

7. Samples should be shipped as soon as possible to GSK.

Labels for vesicular fluid samples will be provided by GSK Biologicals. The investigatorwill identify the sample with the subject’s identification number and the date thevesicular fluid sample was taken.

Varicella strain identification and characterization will be based on the Polymerase ChainReaction (PCR) method (described in Appendix F).

Instructions for Collection and Handling of Saliva samples

Subjects who develop parotid/salivary gland(s) enlargement have to be examined as soonas possible by the investigator or other designee.

On that occasion, a saliva sample will be collected as follows: The enlarged salivaryglands should be palpated first, then a saliva sample will be collected by swabbing thebuccal area (swab should be saturated) if the parotid/salivary glands are swollen (ifunilateral, then the buccal area on the side that is affected is swabbed) or the base of thetongue swabbed if only the submandibular or sublingual glands are affected. No foodmay be taken 30 minutes before. The swab must be stored in transport media in the viralculturette provided by the sponsor per package instructions and placed if possible at -70°C or at least -20°C until shipment as described in Appendix E.

Labels for saliva samples will be provided by GSK Biologicals. The investigator willidentify the sample with the subject’s identification number and the date the salivasample was taken

Mumps strain identification and characterization will be based on the Polymerase ChainReaction (PCR) method (described in Appendix F).

Collection and Handling of cerebrospinal fluid (CSF)

During the study period, should the child experience febrile convulsions or present anyother neurological signs or symptoms indicative of meningism (e.g. vomiting, neckstiffness, photophobia), the child will undergo a neurological examination according tothe current local medical practice. Lumbar puncture should be performed at the discretionof the testing physician.

In the event of lumbar puncture, the CSF will be tested for cell count, proteins, glucose,and other microbiological assays. It is advised to do this at the centre’s laboratory.


Appendix D 5

It is requested that a sample of CSF be saved and send to GlaxoSmithKline Biologicalsfor further analysis (see Appendix F). The CSF specimen must be stored frozen andlabelled with the subject’s identification number and the date that the sample wasobtained.

Mumps strain identification and characterisation will be based on the polymerase chainreaction (PCR) method (described in Appendix F).


Appendix E 1

Appendix E: Shipment of Biological Samples

Instructions for shipment of serum, vesicular fluid, saliva, and CSF samples

When materials are provided by GlaxoSmithKline Biologicals, it is mandatory that allbiological samples be collected using exclusively those materials in the appropriatemanner. The use of other materials could result in the exclusion of the subject fromanalysis. The investigator must ensure that his/her personnel and the laboratory(ies) underhis/her supervision comply with this requirement.

Biological samples should be sent to GSK Biologicals at regular intervals. The frequencyof shipment of samples should be decided upon by the Site Monitor, Central StudyCoordinator and the investigator prior to the study start.

The samples should always be sent by air, preferably on a Monday, Tuesday orWednesday, unless otherwise requested by the sponsor.

The samples must be placed with dry ice (maximum -20°C) in a container complyingwith International Air Transport Association (IATA) requirements. The completedstandard listing (e.g. serum listing) form should always accompany the shipment.

The container must be clearly identified with the labels provided by GSK Biologicalsspecifying the shipment address and the storage temperature (-20°C).

The airway bill should contain the instruction for storage of samples at maximum -20°C.

A "proforma" invoice, stating a value for customs purposes only, should be prepared andattached to the container. This document should contain the instruction for storage ofsamples at maximum -20°C.

Details of the shipment, including:* number of samples (serum, vesicular fluid, CSF or saliva)* airway bill* flight number* flight departure and arrival times

should be sent by fax, two days before shipment, to:


Appendix E 2

GLAXOSMITHKLINE BIOLOGICALSAttention

Clinical ImmunologyR & D Department/Building 44

Rue de l'Institut, 89B-1330 Rixensart – Belgium

Telephone:Fax:


Appendix F 1

Appendix F: Laboratory Assays

Detection of mumps virus in CSF and saliva samples

Any CSF or saliva samples collected from subjects with suspected parotitis or meningismare to be sent to GlaxoSmithKline Biologicals in Rixensart. These samples are to betested for the presence of mumps virus by Polymerase Chain Reaction (PCR).

The PCR technique used employs a reverse transcriptase to amplify the regionoverlapping part of the Hemagglutinin-Neuramidase (HN) and of the small hydrophobicprotein (SH) genes.

Positive and negative controls are added to verify specificity; the positive controls consistof serial dilutions of mumps virus (vaccine strain) which undergo the same treatment asthe CSF/ saliva samples to be analyzed. Controls and CSF/ saliva samples are also”spiked” with a known quantity of virus to ensure that the clinical specimens contain noreaction inhibitors.

If the clinical sample displays a signal, a second PCR will be performed to confirm theresult. The PCR fragment will be subsequently sequenced to identify the strain typepresent (vaccine or wild type).

Detection of varicella virus in vesicular fluid samples

Any samples of vesicular fluid collected from subjects with suspected varicella case areto be sent to GSK Biologicals in Rixensart. These samples are to be tested for thepresence of varicella virus by PCR.

La Russa et al. (J. Virology, 1992, 66, 1016-1020) identified nucleotide changes thatresult in two restriction endonuclease polymorphisms that differentiate the wild-typevaricella virus from the vaccine strain OKA.

The following RFLP method was developed: PCR amplification using two sets of primerpairs generates 2 DNA fragments, one 350 base pairs (bp) in length and the other one 222bp. According to the cited reference, for the OKA strain, digestion with Bgl I cuts the 222bp fragment into a 137 bp and a 85 bp fragment. In case of wild-type virus, Bgl I does notcut either of the fragments, whereas Pst I leaves the 222 bp fragment intact and cuts the350 bp fragment into a 250 bp and a 100 bp fragment. This means that the presence ofBgl I site in the 222 bp fragment and the absence of Pst I site in the 350 bp fragment arespecific to OKA. An overview is presented in Table 5.


Appendix F 2

Table 5: Overview of the presence of Pst I and Bgl I restriction sites in the DNAfragments of varicella genome

strain Pst I Bgl IOKA 350 bp DNA fragment / (2)

310 & 40 bp fragments

222 bp DNA fragment / (1)137 & 85 bp fragments

Wild-type 350 bp DNA fragment (1)250 & 100 bp fragments

(2)310 & 40 bp fragments

222 bp DNA fragment / /(1): presence according to P. La Russa et al., J. Virology, 1992, 66, 1016-1020(2): presence according to A.J. Davison et al., J. Gen. Virol., 1986, 67(9), 1759-1816/: restriction site not present

Cleavage by the corresponding restriction endonucleases differentiates between wild-type(PstI+ and BglI- or BglI+ for Western or Asian varicella strains, respectively) andvaccine-strain (PstI-/BglI+) viruses.

Positive and negative controls are added to verify specificity; the positive controls usedare the Webster (wild-type) and the OKA (vaccine) strain.


Appendix G 1

Appendix G: Vaccine supplies, packaging and accountability

It is NOT permitted to use any of the supplies provided by GSK Biologicals for purposesother than those specified in the protocol. Unused supplies will be collected by GSKBiologicals on completion of the study. Used vaccine vials/pre-filled syringes/containerscan be disposed on site according to local biosafety standard for disposal of biologicalwaste material.

1. Vaccine suppliesGSK Biologicals will supply adequate amounts of numbered doses of study vaccines,sufficient to administer to all subjects as described in the present protocol.

The number of doses in this study will include 20% over-randomisation. An additionalamount of the study vaccines will be supplied for replacement in case of breakage, badstorage conditions or any other reason that would make the vaccine unusable (i.e., givento another subject by mistake).

Another additional 5% of doses will be provided as a control. They are to be stored atstudy centres and will be shipped back to GSK Biologicals for re-titration when the studyended. These doses must not be used.

All monodose vials/pre-filled syringes/containers must be accounted for on the formprovided.

2. Vaccine packagingThe vaccines will be packed in labelled boxes. The box label will contain, as a minimum,the following information: study number, subject number, lot number (or numbers, whendouble-blind), instructions for vaccine administration.

3. Vaccine accountabilityThe investigator or pharmacist must sign a statement that he/she has received the clinicalsupplies for the study. At all times the figures on supplied, used and remaining vaccinedoses should match. At the end of the study, it must be possible to reconcile deliveryrecords with those of used and unused stocks. An explanation must be given of anydiscrepancies.

After approval from GSK Biologicals, used vaccine vials/syringes/containers should bedestroyed at the study site using locally approved biosafety procedures anddocumentation unless otherwise described in the protocol. If no adequate biosafetyprocedures are available at the study site, the used vaccine vials/syringes/containers are tobe returned to an appropriate GSK Biologicals site for destruction in accordance with


Appendix G 2

current GSK SOP NPD-112. Unused vaccine vials/syringes/containers will be disposed atthe local GSK Biologicals site in accordance with GSK SOP NPD-112. If no processesfor destruction of unused vaccines are in place in the local GSK Biologicals site; theunused vials/syringes/containers must be returned to GSK Biologicals in Rixensart,Belgium.

4. Transfers of clinical vaccines or products from country medical department ordispatch centre to study sites or between sites:Storage temperatures must be maintained during transport and deviations must bereported to Logistics and Packaging for guidance. All transfers of clinical vaccines orproducts must be documented using the Clinical Supply Transfer Form. If the duration ofthe transfer is less than four hours, a transportable fridge or any suitable container (e.g.styrofoam container) with a maximum of eight refrigerated cold packs (cooling elements)must be used in order to maintain the vaccines at 2°-8°C during transport. If the durationis more than four hours, a transportable fridge or any suitable container (e.g. styrofoamcontainer) with a minimum of eight cold packs (cooling elements) must be used as wellas a temperature monitoring system that must be placed as close as possible to the dosesand checked upon reception at the final destination. Never place frozen cold packs or dryice inside vaccine boxes for vaccine that must be kept at +4°C in order to avoid cold-chain deviation (e.g. frozen vaccines). Exceptions to these instructions are detailed inproduct-specific transport guidelines.

5. Labels for sample identificationThe investigator will receive labels from GSK Biologicals to identify samples taken fromeach subject at each timepoint. Each label will contain the following information:

• serum samples: the study number, subject number, sampling timepoint (pre-vacc dose1/Day 0, post-vacc dose 1/Week 6, post-vacc dose 2/Week 12).

• Vesicular fluid, CSF and saliva samples: the subject’s identificationnumber/randomisation number, the subject’s initials, the protocol number, centrenumber, type of specimen and the date the specimen is/are collected.

6. Other supplies provided by GSK BiologicalsIn addition to the vaccines, the study documentation and the sample labels, theinvestigator will receive the following supplies:• tubes with screw caps for serum samples• racks for the tubes of serum• viral culturettes for saliva sample collection• vesicular fluid kits• temperature sensitive pads


Appendix G 3

• thermometers


Appendix H 1

Appendix H: Example of Temperature log sheet

Investigator Name: ________________________ Refrigerator:

CPMS Protocol No: ________________________ Freezer:

Date Temperature(°C)

Minimum

Temperature(°C)

Maximum

Name of PersonReading

Temperature

Signature

25 March 2003 GlaxoSmithKline Biologicals Appendix I 1Confidential and Proprietary InformationFinal Protocol 208136/038 (MeMuRu-OKA-038)

Appendix I: Amendments and Modifications to the Protocol

25 March 2003 GlaxoSmithKline BiologicalsConfidential and Proprietary Information

Final Protocol 208136/038 (MeMuRu-OKA-038) Active phase period208136/039 (MeMuRu-OKA-039) Year 1 Follow-up208136/040 (MeMuRu-OKA-040) Year 2 Follow-up208136/041 (MeMuRu-OKA-041) Year 3 Follow-up

Sponsor Information

CPMS Study Number 208136/038 (MeMuRu-OKA-038) Active phase period208136/039 (MeMuRu-OKA-039) Year 1 Follow-up208136/040 (MeMuRu-OKA-040) Year 2 Follow-up208136/041 (MeMuRu-OKA-041) Year 3 Follow-up

1. Principal investigatorGermany:

Prof. Dr.

phone fax:

Austria:Dr.

Tel. Fax

Dr.

Tel. Fax.

Dr.

Tel. Fax

Dr.

Tel. Fax

2. Medical MonitorGermany:

Dr. GlaxoSmithKline GmbH & Co.KG,Theresienhoehe 11 /11 a,80339 München, Germany.Phone: Fax: +

Austria:Dr. GlaxoSmithKline Pharma GmbHAlbert Schweitzer-Gasse 6A-1140 ViennaTel. Fax:

25 March 2003 GlaxoSmithKline BiologicalsConfidential and Proprietary Information

Final Protocol 208136/038 (MeMuRu-OKA-038) Active phase period208136/039 (MeMuRu-OKA-039) Year 1 Follow-up208136/040 (MeMuRu-OKA-040) Year 2 Follow-up208136/041 (MeMuRu-OKA-041) Year 3 Follow-up

3. Study MonitorGermany:

Projectmanager, Clinical ResearchGlaxoSmithKline GmbH & Co.KG,Theresienhoehe 11 /11 a,80339 München, Germany.Tel: Fax:

Austria:Study monitoring to be performed byCRO:

Dipl.Ing. Hoernesgasse 16/19A-1030 ViennaTel. mobile: email:

4. Study Contact for Reporting of a Serious Adverse EventGermany:

Dr. GlaxoSmithKline GmbH & Co.KG,Theresienhoehe 11 /11 a,80339 München, Germany.Tel: Fax:

Austria:Dr. Albert Schweitzer-Gasse 6A-1140 ViennaTel. Fax:

5. Study Contact for Emergency Code Break M.D

GlaxoSmithKline BiologicalsRixensart, BelgiumTel: Fax: Mobile phone for 7/7 day availability:

Protocol InvestigatorAgreement


2

Investigator Agreement (Germany)













4

Investigator Agreement (Austria)












RepresentativeSIS/IC

GLAXOSMITHKLINE BIOLOGICALS

SUBJECT/PATIENT INFORMATION SHEET AND INFORMED CONSENT

Study title: A phase III, randomised, controlled study to evaluate theimmunogenicity and safety of three production lots ofGlaxoSmithKline Biologicals� combined measles-mumps-rubella-varicella (MeMuRu-OKA) candidate vaccine given on atwo-dose schedule to healthy children in their second year of life,as compared to separate administration of GlaxoSmithKlineBiologicals� measles-mumps-rubella vaccine (Priorix®) andvaricella vaccine (Varilrix®).

Investigators:

Investigator signatoryapproval:

Sponsor: GlaxoSmithKline Biologicals

Sponsor signatoryapproval:

MDAssociate Director, Clinical Research &DevelopmentGlaxoSmithKline Biologicals

CPMS Protocol number: 208136/038 (MeMuRu-OKA-038)

Date of approval: Version 1.0 25 March 2003

Prepared by: Scientific Writer

CLINICAL RESEARCH AND DEVELOPMENT

GlaxoSmithKline Biologicals

This document should be presented to the subject or patient in full; no page(s) orsection(s) should be omitted. The document contents should be explained verballyto the parents/guardians of the participant.

Subject Information Sheet & Informed Consent Date: Version 1.0 25 March 2003CPMS Protocol No 208136/038 (MeMuRu-OKA-038)

Subject No.__________

Version No 1.0 Page 2 of 11

Introduction

The main objective of this document is to provide the parents/guardians of apotential study participant with the information necessary to help in deciding tohave their child participate in the study with GlaxoSmithKline Biologicals�combined measles-mumps-rubella-varicella vaccine (referred to as�MeMuRu-OKA�). The document provides a full but simple understanding of thescientific reasons for investigation of the vaccine, the characteristics,effectiveness and safety of the vaccine, the likely effects and benefits of the studyvaccine in the subjects. This document also informs parents/guardians of thesubjects about their rights and responsibilities in participating in the trial.

Background of the study

Measles (M)-mumps (M)-rubella (R) and varicella vaccines are both indicated inchildren during the second year of life, and can be given concomitantly though atseparate injection sites. GSK Biologicals has developed a combined measles-mumps-rubella-varicella vaccine (referred to as �MeMuRu-OKA�). Such acombination offers children, parents and medical practitioners the convenience ofcombining the benefits of MMR and varicella vaccination with no additionalinjection. The development of this combined measles-mumps-rubella-varicellavaccine is based on GlaxoSmithKline Biologicals' measles-mumps-rubellavaccine, Priorix (licensed in Germany since 1997) and GlaxoSmithKlineBiologicals' varicella vaccine, Varilrix (licensed in Germany since 1994).

Two doses of MMR vaccine are recommended in many countries worldwide. InGermany, since July 2002, it is recommended to administer the two doses ofMMR vaccine in the second year of life (by the age of 24 months).

Typically, one dose of varicella vaccine is indicated to be given in the second yearof life. After varicella vaccination, it is possible that some children experience anattenuated form of varicella disease (generally it is a mild skin eruption, with veryfew lesions as compared to the natural infection). The possibility of administeringa second dose of varicella vaccine to children to enhance protection against thesemoderate infections is curently under debate. The second dose could convenientlybe given as a combined measles-mumps-rubella-varicella vaccine.

Based on these considerations, GlaxoSmithKline Biologicals is exploring thepossibility of administering the combined measles-mumps-rubella-varicellavaccine on a two-dose schedule to children in their second year of life, which mayadequately address vaccination needs to:

• increase the vaccination coverage for the second dose of MMR




• increase the protection against varicella disease without increasing the numberof injections.

Measles, Mumps, Rubella and Varicella Diseases

Measles, mumps and rubella are common viral diseases of childhood. Thesehighly infectious diseases and their complications are responsible for considerablemorbidity and mortality throughout the world. Varicella (or chickenpox) is also ahighly contagious disease; children otherwise healthy may die from varicella andits complications.

Measles is characterized by respiratory disease and a rash. The disease is causedby a virus transmitted via airborne droplets from the respiratory tract of infectedindividuals during the first 3-4 days following the appearance of the rash.Following exposure, measles is characterized by fever, malaise, conjunctivitis(eye infection), cold, cough, and the appearance of small bright red spots in themouth. Measles rash appears 14-18 days after exposure and usually lasts forseveral days. The rash often starts behind the ears and on the face and spread tothe trunk and arms. Fever is usually observed 2-3 days after the appearance of therash.

Mumps is characterized by the painful swelling of one or both parotid glands(parotitis). The disease is also caused by a virus transmitted via airborne dropletsfrom the respiratory tract of infected individuals or by direct contact with infectedsaliva. The swelling may last until 10 days and is usually accompanied with feverthat lasts for 1-6 days. Other symptoms such as headache, malaise, muscle pain,loss of appetite may be displayed.

Rubella (or German measles) is also caused by a virus. The disease can bedifficult to diagnose because of mild, variable symptoms. In some children, theonly symptoms may be a temporary rash or a sore throat with low-grade fever.The rash starts on the face and neck, during 1-3 days the rash spreads to the trunkand then disappears. The infected individual is contagious from about 1 weekbefore until 5 days after the rash appears. If a pregnant woman is infected with thevirus, it can cause serious complications to the fetus.

Varicella (or chickenpox) is also a disease caused by a virus. In children, thevirus can be transmitted by inhalation of airborne droplets and contact withvaricella lesions. The disease is highly contagious: approximately 90% ofsusceptible individuals will develop the disease after contact with an infectedperson. The characteristic feature of varicella is the severe itching of the skin(pruritic) with a characteristic rash (a rash with vesicles filled with fluid)sometimes with fever.




Purpose of the study

The present study is proposed to evaluate whether the production process of theMeMuRu-OKA vaccine is consistent (i.e., the study will aim demonstrating thatthree different lots of MeMuRu-OKA vaccine are similar with respect to theimmune response they induce in children) and to evaluate whether two doses ofMeMuRu-OKA vaccine administered to children in their second year of life aresimilar in terms of production of antibodies (a substance produced by the bodythat protects against a disease) and safety when compared to GSK Biologicals'MMR vaccine (Priorix) given on a two-dose schedule and one dose of GSKBiologicals' Varicella vaccine (Varilrix).

Approval

This study protocol has been reviewed and accepted by an Independent EthicsReview Committee/ Institutional Review Board of the country.

Study Participation

The study will involve a total of three visits: at Day 0 (Visit 1), at Week 6 (Visit2) and Week 12 (Visit 3). A total of 480 children are foreseen to participate in thisclinical study.

The vaccines that will be administered to your child will depend on the studygroup your child will be assigned to. The assignment to a study group will bedone at random (e.g., like flipping a coin). According to group allocation, yourchild may receive either 1 or 2 injections at the first visit, as follows:

Visit Visit 1 (Day 0) Visit 2 (Week 6)Vaccine Dose 1 Dose 2MeMuRu-OKA √ √PriorixVarilrix

√√

√

Children who will be assigned to the MeMuRu-OKA group will receive oneinjection of MeMuRu-OKA vaccine at Visit 1 and one injection ofMeMuRu-OKA vaccine at Visit 2. Three different lots of the MeMuRu-OKAvaccine will be used so your child will receive one of the three lots, but neitheryou nor the study doctor will be aware of which lot of MeMuRu-OKA vaccineyour child has received.

Children who will be assigned to the Priorix+Varilrix group will receive oneinjection of Priorix and one injection of Varilrix at Visit 1 and one injection ofPriorix at Visit 2.




All children in this study, regardless of their study group, will have a total of threeblood samples collected (about 4 millilitres each from an arm vein):

• A sample at the first visit (Day 0) before administration of the first dose.

• A sample at the second visit (Week 6) before administration of the seconddose.

• A sample at the third visit (Week 12).

These blood samples will be tested to show how the vaccines work in terms of theimmune response they induce in the vaccinee (i. e. production of antibodies). Anyside effects seen after vaccination will also be documented.

Details of study visits and procedures:

At Visit 1 (Day 0), after you have given your written consent, your child will beexamined by the doctor who will look particularly at the size of the glands next tothe jaw (these are the glands which usually become swollen when a child hasmumps), your child�s temperature will be taken, a blood sample will be collectedand one dose of vaccine(s) is to be administered. Your child will be observed for30 minutes after the injection; any symptoms seen during this period is to berecorded by the doctor. You will receive a set of diary cards.

Between Day 0 and Day 42 after vaccination 1 (from Day 0/Visit 1 to Week6/Visit 2): you will be asked to record on the diary cards any signs/symptoms orillnesses you have seen in your child on the day of vaccination and/or during thefollowing 42 days as follows:

� any reactions at the injection site (Day 0-3).

� any medication taken between Visit 1 and Visit 2

� any fever occurring on the day of vaccination (Day 0) and for the next 42days. On Days 0-14, your child's temperature must be measured axillary witha thermometer. After Day 14 (from Day 15 to Day 42, you will be requestedeither to continue taking your child's temperature with a thermometer (axillaryroute) or to screen for the presence of fever with a temperature sensitive pad.The sensitive pad should be applied to your child�s forehead at bedtime eachday or at any time that you suspect that they may have a fever. If the paddetects fever (i.e. a temperature equal to or greater than 38.0°C), then anaccurate temperature should be taken by the axillary route using thethermometer supplied. If fever is present, the temperature should be recordedon the diary card.




� If your child experiences any symptoms listed below, you are asked to contactthe doctor immediately so that he can arrange a visit to examine your child.

- any skin rash or eruption (Day 0-42)

- any swelling or tenderness around the jaw (Day 0-42)

- any suspected sign of meningism (e.g. vomiting, neck stiffness,photophobia) or febrile convulsions (Day 0-42).

If necessary, the investigator or his/her study staff will take asample of saliva or a sample of fluid from any skin vesicles.The samples would be examined to see if they contain the virusthat causes mumps (saliva sample) or the virus that causesvaricella (fluid sample from the vesicles).

� any other signs or symptoms seen in your child on the day of vaccination orduring the next 43 days.

At Visit 2 (Day 42), you will be requested to return the diary cards of your child tothe study doctor, your child will undergo physical examination and a bloodsample will be collected. Your child�s temperature will be taken and the seconddose of vaccine(s) is to be administered depending on group allocation. Yourchild will be observed for 30 minutes after the injection; any symptoms seenduring this period is to be recorded by the doctor. You will receive a set of diarycards.

Between Day 0 and Day 42 after vaccination 2 (from Day 42/Visit 2 to Week12/Visit 3): you will be asked to perform exactly the same procedures as you didbetween Visit 1 and Visit 2.

During the study period (i.e. Day 0 to Week 12), you should contact theinvestigator and/or his/her study staff immediately should your childmanifest any signs or symptoms you perceive as serious.

At Visit 3 (Week 12), you will be requested to return the diary cards of your childto the study doctor, your child will undergo physical examination (if deemednecessary) and a blood sample will be collected.

The investigator or his/her study staff will propose that your child participates inan extension to this study. If you agree, you will be requested to sign a separateInformed consent for long-term follow-up. The objective of the extension to theprotocol is to monitor your child's antibody level for a period of three years after




vaccination. The extension will include another three visits with a blood samplecollected at each visit.

Please discuss with your study doctor the long-term extension.

Risks associated with the study

More than 3000 children were immunized with the candidate MeMuRu-OKAvaccine in clinical trials. In general, the safety profile of MeMuRu-OKA wascomparable to separate injections of Priorix and Varilrix vaccines. Fever wasfrequently reported during the first 14 days after vaccination with eitherMeMuRu-OKA vaccine or when children received separate injections of Priorixand Varilrix vaccines.

During the routine use of measles-mumps-rubella vaccine some undesirableeffects have been reported. The most common of these was a mild and temporarydiscomfort at the injection site (occasionally with swelling and redness). Othersymptoms seen were extremely mild versions of the symptoms usually seen whena child has measles, mumps or rubella (also referred to as German measles) suchas fever, malaise, headache and skin rashes. Very rare mild versions of thecomplications that can follow measles, mumps or rubella (e.g. swollen glands,joint reactions or nervous symptoms) have been reported.

As seen in other studies, chickenpox (varicella) vaccine can cause a mild andtemporary rash and occasionally a mild fever in some people. After naturalchickenpox, the virus which causes the disease (chickenpox virus) remains quietlyin the body without causing problems; however under certain conditions, oftenlater in life, it can cause shingles which appears as a localized chickenpox typerash with pain. A weakened version of the chickenpox virus is used in thisvaccine and observations to date suggest that the risk of shingles after vaccinationis no greater, and may eventually be lower, than after natural chickenpoxinfection.

If ever your child develops vaccine-related rash, you are requested to avoid yourchild in close association with susceptible high-risk individuals (e.g., newborns or0-4 weeks old, pregnant women, immunocompromised persons including thosewith HIV) who have never have varicella disease or have not been vaccinatedagainst varicella. In addition, you are also requested not to give any salicylates toyour child for 6 weeks after study vaccination.

Blood sampling may cause momentary discomfort. The amount of blood to betaken will not cause any symptoms or anaemia. As with any experimentalvaccine, unexpected serious adverse experiences, including allergic reactions to




the candidate vaccine, may occur. If your child is ill on the day of vaccination, itwill be rescheduled. You will be informed of any new findings developed duringthe course of this research study.

Additional Information

The doctor may withdraw your child from the study at any time that he/she feels itis in your child�s best interest. If you withdraw your child voluntarily from thestudy, the doctor would still like to ask questions about any experiences that yourchild had with the study vaccine and would ask you to cooperate in any otherprocedures that are considered necessary.

Voluntary participation

Your child's participation is voluntary. Refusal that your child take part orcontinue with the study will involve no penalty or loss of benefits or attention towhich your child are otherwise entitled to receive from his/her healthcareprovider. You are entitled to receive a signed copy of this form.

Alternative measures of prevention

Vaccines against measles, mumps, rubella and the vaccine against varicella arecommercially available in many countries and can be purchased in a pharmacy.

Confidentiality and source document review

You understand and consent to the following:

It will be necessary for representatives of GlaxoSmithKline or possibly healthauthorities / drug regulatory agencies to access your child�s medical records. Yourchild�s participation in the study will be treated as confidential, that is, anypersonally identifiable information will be held and processed under secureconditions at GlaxoSmithKline (or an agent of GlaxoSmithKline) with accesslimited to appropriate GlaxoSmithKline staff or other authorized agents having arequirement to maintain the confidentiality of the information. Your child will notbe referred to by name in any report of the study. Your child�s identity will not bedisclosed to any person, except for the purposes described above and in the eventof a medical emergency or if required by law.

Your child�s data will be processed electronically to determine the outcome ofthis study, and to provide it to health authorities / drug regulatory agencies. Yourchild�s data may be transferred to other countries (such as USA�) for thesepurposes GlaxoSmithKline complies with internal procedures to protect personal




information even in countries whose data privacy laws are less strict than those ofthis country. The data may also be used for other medical or scientific researchpurposes. If your child�s data is used for any other purpose it will first be de-identified, that is all personally identifiable information will be removed, and willbe processed in a de-identifiable form.

You may be entitled under law to access your child�s personal data and to haveany justifiable corrections made. If you wish to do so, you should request thisfrom the doctor conducting the study.

Right to ask questions and/or withdraw from the study

You may ask questions about the study. Although your continuous support isappreciated, you have the right to withdraw your child from the study at any timeand he/she will be under no further obligation for blood samplings orvaccinations.

If you have any questions, please contact the investigator(s).

Benefits of the study:

The principal benefit of this study is the opportunity to ensure protection againstmeasles, mumps, rubella and varicella. Thus your child (and you as parents) willavoid the usual inconveniences associated with these diseases (fever, skin rashand irritation, eye infection, painful glands, poor appetite, isolation at home) aswell as the risk of serious complications that can follow. If the outcome of thisstudy is successful it should allow other children to benefit from this vaccine inthe future.

Your child will be under the care of an experienced physician during participationin the study.

There is also the benefit of a detailed assessment of your child�s response to thevaccination through analysis of blood samples, a procedure not usually performedoutside a study situation. If your child�s response to vaccination is not optimal, anadditional dose of vaccine will be offered to your child free of charge.

Compensation:

If your child becomes ill or injured as a result of taking part in this clinical study,medical treatment will be provided according to good clinical practice and costsof such treatment will be paid for by GlaxoSmithKline Biologicals. Allparticipants in the study are covered by global insurance policy contracted by




GlaxoSmithKline Biologicals. If you have any questions concerning theavailability of medical care or if you think your child has experienced a research-related illness or injury, please contact the investigators(s).


Informed ConsentThe vaccine study has been clearly explained to me and I have read andunderstood the information provided. I agree that my son/daughter be enrolled inthe study. I understand that my son/daughter has the right to decline to enter thestudy and to withdraw from it at any time for any reasons, without consequence tohis/her present or future health care and attention which my child/ward receivesfrom his/her healthcare provider. I have been made aware of my right to accessand request correction of my child�s/ward�s personal data. I acknowledge that Ihave received a copy of this form for future reference.

I, ,

(subject�s parent or legal guardian�s first name and family name)

hereby freely give my consent for my child/ward to take part in thisvaccine study.

Participant�s Name:

(First Name, Family Name)

Parent/Guardian�s name:

(First Name, Family Name)

Parent/Guardian�s signature:

Relationship to participant:

Participant�s main address:

Participant�s phone number:

Date: Time:

(DD-MM-YY)

Witness:Statement by Doctor, Nurse or Project Assistant who conducted the informedconsent discussion:

I have carefully explained the nature, demands and foreseeable risks and benefitsof the vaccination study to the person named above and witnessed the completionof the written consent form.

Name:

Signature:

Designation:

Date: Time:

(DD-MM-YY)

Sample CRF

GlaxoSmithKline Biologicals Version 12Date : April 17, 2003

Rue de l�Institut 89, B � 1330 Rixensart, BelgiumTel: Fax:

Center Subject number

|__|__|__| |__|__|__|__|__|

Protocol 208136/038

A phase III, randomised, controlled study to evaluate theimmunogenicity and safety of three production lots ofGlaxoSmithKline Biologicals� combined measles-mumps-rubella-varicella (MeMuRu-OKA) candidate vaccine givenon a two-dose schedule to healthy children in their secondyear of life, as compared to separate administration ofGlaxoSmithKline Biologicals� measles-mumps-rubellavaccine (Priorix®) and varicella vaccine (Varilrix®).

WORKBOOK

GENERAL INSTRUCTIONS FOR RDE

ABBREVIATIONS: Abbreviations for medical conditions, clinical events or drug names should not be used.Units and route of administration of medication may be abbreviated. NA: not applicable.

DATE

Use the following three-letter abbreviations for each month:

January = JANFebruary = FEBMarch = MARApril = APRMay = MAYJune = JUNJuly = JULAugust = AUGSeptember = SEPOctober = OCTNovember = NOVDecember = DEC

Example : |__|__| |__|__|__| |__|__|__|__|= 1st January 2002day month year

TIMEUnless specified otherwise, use the 24 hour clock :Example: |__|__| : |__|__|

hours min

The Medication section, the Concomitant Vaccination section, the Non-Serious Adverse Eventssection and the Serious Adverse Event (SAE) form must be checked for final assessment at the end ofthe study.

For all subjects enrolled, please complete the Study Conclusion form.

0 1 J A N 2 0 0 2

1 5 3 0 = 3.30 p.m.

ADVERSE EVENT DEFINITIONSINTENSITY FOR SOLICITED SYMPTOMSPain at injection site0 : Absent1 : Minor reaction to touch2 : Cries/protests on touch3 : Cries when limb is moved/spontaneously painful

INTENSITY FOR NON-SOLICITED SYMPTOMS1 : Mild : An adverse event which is easily tolerated by the subject, causing minimal discomfort and not

interfering with everyday activities.2 : Moderate : An adverse event which is sufficiently discomforting to interfere with normal everyday

activities.3 : Severe : An adverse event which prevents normal, everyday activities

(In a young child, such an adverse event would, for example, prevent attendance at school/kindergarten/a day-care center and would cause the parents/guardians to seek medical advice).

CAUSALITY / RELATIONSHIP TO INVESTIGATIONAL PRODUCTSIs there a reasonable possibility that the AE may have been caused by the investigational product ?

NO : The adverse event is not causally related to administration of the study vaccine(s). There areother, more likely causes and administration of the study vaccine(s) is not suspected to havecontributed to the adverse event.

YES: There is a reasonable possibility that the vaccine contributed to the adverse event.

OUTCOME1: Recovered / Resolved2 :Recovering / Resolving : If the subject is recovering at the time the subject completes the study or at

the time the subject dropped out3: Not recovered / Not resolved : This means an AE ongoing at the time the subject completes the study

or becomes lost to follow-up; if AE/SAE was ongoing at the time of death, but was not the cause ofdeath.

4: Recovered with sequelae/ Resolved with sequelae

SERIOUS ADVERSE EVENTA serious adverse event is any untoward medical occurrence that:

• results in death• is life threatening• results in persistent or significant disability / incapacity• requires in-patient hospitalization• prolongation of existing hospitalization• is a congenital anomaly / birth defect in the offspring of a study subject• In addition, important medical events that may jeopardize the subject or may require intervention to

prevent one of the other outcomes listed above should be considered serious. (Examples of suchevents are invasive or malignant cancers, intensive treatment in an emergency room or at home forallergic bronchospasm; blood dyscrasias or convulsions that do not results in hospitalization; ordevelopment of drug dependency or drug abuse).

For each serious adverse event, please fill in the Serious Adverse Event (SAE) form and contactGlaxoSmithKline within 24 hours.Although not considered as �serious adverse events�, cancers must be reported in the same way asserious adverse events.


208136/038 (MeMuRu-OKA-038)

FLOW SHEET

Age 12-24 monthsVaccination DOSE 1 DOSE 2

Visit VISIT 1 42-56 day VISIT 2 42-56 day VISIT 3Timing Day 0 interval Week 6 interval Week 12

Sampling timepoint Pre Vacc Post Vacc 1 Post Vacc2


Check of inclusion/ exclusion criteria ●


Medical history and prior (30 days pre-vaccination) concomitant medication/ vaccination ●

Physical examination ● ● ● #Pre-vaccination body temperature ● ●

Randomisation ●

Blood sampling (4 ml) ●●●●●●●●

(before dose2)

●


Recording of solicited local symptoms on thediary cards by the parents/guardians of thesubject

● (Day 0)

●(Days 1-3)

●(Day 0)

●(Days 1-3)

Recording of solicited general symptoms &unsolicited adverse events on the diary cards bythe parents/guardians of the subject

●(Day 0)

●(Days 1-

42)●

(Day 0)●

(Days 1-42)

Recording of concomitant medication on thediary cards by the parents/guardians of thesubject

● (Day 0)

●(Days 1-

42)●

(Day 0)●

(Days 1-42)

Reporting of all serious adverse events (SAEs)by the parents/guardians of the subject to theinvestigator.


Return of diary cards by the parents/ guardians ● ●

Diary card verification & transcription by theinvestigator ● ●

Reporting of all SAEs to GSK Biologicals by theinvestigator Day 0 to Week 12 (Visit 3)



Distribution of postcards to parents/guardians of the vaccinees -Parents/guardians of the vaccinees are instructed to fill one of the postcards and mail it to the studypersonnel in case his/her child experiences a breakthrough case (confirmed by a physician) ofmeasles, mumps, rubella and/or varicella or contact with measles, mumps, rubella and/orvaricella/herpes zoster diseases after Visit 3/Week 12

●

� is used to indicate a study procedure that requires documentation in the individual eCRF/ diary cards.# if deemed necessary based on interim medical history

VISIT 1

DAY 0

DOSE 1

Informed Consent has to be obtainedprior to any study procedure

GlaxoSmithKline BiologicalsProtocol

208136/038 (MeMuRu-OKA-038)

ELIMINATION CRITERIA DURING THE STUDY

The following criteria should be checked at Visit 2 and Visit 3. If any become applicable, it will not requirewithdrawal of the subject from the study but does determine a subject’s evaluability in the ATP analysis.

• Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs during the study period up to Week 12 visit. (For corticosteroids, this will mean prednisone, or equivalent, ≥ 0.5 mg/kg/day. Inhaled and topical steroids are allowed.)

• Administration of a vaccine not foreseen by the study protocol during the study period up to Week 12 visit.

• Administration of immunoglobulins and/or any blood products during the study period up to Week 12 visit.

• Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines during the study period, up to Week 12 visit.

Precautions to vaccination

It is recommended that members of the investigation team be immune to the vaccine components underinvestigation.

Residence in a household in which a susceptible high-risk person (e.g., newborns between 0-4 weeks old,pregnant women with negative history of chickenpox and without recorded vaccination against chickenpox,immunocompromised persons including those with HIV) resides is considered an exclusion criterion. It ishowever recommended that this information should be given to the parents/guardians. Such that in theadvent of a household member becoming high risk during the study period, vaccine recipients andespecially those that develop a vaccine-associated rash, should know to avoid close association with thesesusceptible high risk individuals. In such circumstances, the potential risk of transmission of the attenuatedvirus present in the vaccine should be weighed against the risk of infection and subsequent transmission ofnatural varicella by individuals who have not benefited from vaccination.

Additionally, vaccine recipients should be instructed to avoid the use of salicylates during the study period(12 weeks) as Reye�s Syndrome has been reported following the use of salicylates during natural varicellainfection.

208136/038 (MeMuRu-OKA-038)Protocol CRF Center Visit Date of visit Subject Number

208136/038 |___| |__|__|__| VISIT 1 |__|__| |__|__|__| |__|__|__|__|day month year |__|__|__|__|__|

INFORMED CONSENTI certify that Informed Consent has been obtained prior to any study procedure.

Informed Consent Date : |__|__| |__|__|__| |__|__|__|__|day month year

DEMOGRAPHICS

Date of birth : |__|__| |__|__|__| |__|__|__|__|day month year

Gender : Male

Female

Race : [ 1 ] Black[ 4 ] Arabic/North African[ 2 ] White/Caucasian[ 5 ] East & South East Asian[ 6 ] South Asian[ 9 ] Other, please specify: _________________________________

1.

Screening ID : |__|__|__|__|__|Center Code

208136/038 (MeMuRu-OKA-038)Protocol CRF Visit Subject Number

208136/038 |___| VISIT 1 |__|__|__|__|__|

ELIGIBILITY QUESTIONDid the subject meet all the entry criteria ?

Yes No

If No, please complete below.

INCLUSION CRITERIATick (�) the box next to any of the inclusion criteria the subject failed

[ 1 ] � Subjects who the investigator believes that their parents/guardians can and will comply withthe requirements of the protocol (e.g., completion of the diary cards, return for follow-upvisits) should be enrolled in the study.

[ 2 ] � A male or female child between 12 to 18 months of age at the time of the first vaccination.Subjects older than 18 months may be enrolled in the study if the investigator can ensurethese subjects receive the second vaccination planned in the study before the subject is 24months old (i.e., before the subject's second year's birthday).

[ 3 ] � Written informed consent obtained from the parent or guardian of the subjects.

[ 4 ] � Free of obvious health problems as established by medical history and clinical examinationbefore entering into the study.

EXCLUSION CRITERIATick (�) the box next to any of the exclusion criteria the subject met

[ 5 ] � Use of any investigational or non-registered product (drug or vaccine) other than the studyvaccines within 30 days preceding the first dose of study vaccine, or planned use during thestudy period.

[ 6 ] � Chronic administration (defined as more than 14 days) of immunosuppressants or otherimmune-modifying drugs within six months prior to the first vaccine dose. (Forcorticosteroids, this will mean prednisone, or equivalent, ≥ 0.5 mg/kg/day. Inhaled and topicalsteroids are allowed.)

[ 7 ] � Planned administration/ administration of a vaccine not foreseen by the study protocol from30 days prior to study start until study conclusion at Week 12.

[ 8 ] � Previous vaccination against measles, mumps, rubella and/or varicella.

[ 9 ] � History of measles, mumps, rubella and/or varicella/ zoster diseases.

[ 10 ] � Known exposure to measles, mumps, rubella and/or varicella/ zoster within within 30 daysprior to the start of the present trial

[ 11 ] � Any confirmed or suspected immunosuppressive or immunodeficient condition, includinghuman immunodeficiency virus (HIV) infection.

[ 12 ] � A family history of congenital or hereditary immunodeficiency.

2.


208136/038 |___| VISIT 1 |__|__|__|__|__|

EXCLUSION CRITERIA (continued)Tick (�) the box next to any of the exclusion criteria the subject met

[ 13 ] � History of allergic disease or reactions likely to be exacerbated by any component of thevaccines, including obvious allergic reactions to streptomycin, neomycin, egg proteins,and/or gelatin.

[ 14 ] � Major congenital defects or serious chronic illness.

[ 15 ] � History of any neurologic disorders or seizures.

[ 16 ] � Residence in the same household as the following persons:- New-born infants (0-4 weeks of age)- Pregnant mother/ women with a negative history of chickenpox disease and without

recorded vaccination against chickenpox- Persons with known immunodeficiency.

[ 17 ] � Acute disease at the time of enrolment. (Acute disease is defined as the presence of amoderate or severe illness with or without fever. All vaccines can be administered to personswith a minor illness such as diarrhoea, mild upper respiratory infection with or without low-grade febrile illness, i.e., oral temperature <37.5°C/ axillary temperature <37.5°C / rectaltemperature <38.0°C / tympanic temperature on oral setting <37.5°C / tympanic temperatureon rectal setting <38.0°C).

[ 18 ] � Rectal temperature ≥ 38.0°C or axillary temperature ≥ 37.5°C at the time of vaccination

[ 19 ] � Administration of immunoglobulins and/or any blood products since birth or plannedadministration during the study period.

3.


208136/038 |___| VISIT 1 |__|__|__|__|__|

GENERAL MEDICAL HISTORY / PHYSICAL EXAMINATIONAre you aware of any pre-existing conditions or signs and/or symptoms present in the subject prior to the startof the study ?

NoYes, please tick appropriate box(es) and give diagnosis

DIAGNOSIS PAST CURRENT

�� [10] Cutaneous 1 ---------------------------------------------------

2 ---------------------------------------------------

�� [ 5] Eyes 1 ---------------------------------------------------

2 ---------------------------------------------------

�� [ 6] Ears-nose-throat 1 ---------------------------------------------------

2 ---------------------------------------------------

�� [ 2] Cardiovascular 1 ---------------------------------------------------

2 ---------------------------------------------------

�� [ 3] Respiratory 1 ---------------------------------------------------

2 ---------------------------------------------------

�� [ 1] Gastrointestinal 1 ---------------------------------------------------

2 ---------------------------------------------------

�� [ 7] Muskuloskeletal 1 ---------------------------------------------------

2 ---------------------------------------------------

�� [ 8] Neurological 1 ---------------------------------------------------

2 ---------------------------------------------------

�� [12] Genitourinary 1 ---------------------------------------------------

2 ---------------------------------------------------

�� [11] Haematology 1 ---------------------------------------------------

2 ---------------------------------------------------

�� [ 4] Allergies 1 ---------------------------------------------------

2 ---------------------------------------------------

�� [ 9] Endocrine 1 ---------------------------------------------------

2 ---------------------------------------------------

�� [99] Other (specify) 1 ---------------------------------------------------

2 ---------------------------------------------------Please report medication(s) as specified in the protocol and fill in the Medication section.

4.


208136/038 |___| VISIT 1 |__|__|__|__|__|

PRE-VACCINATION ASSESSMENT

Temperature : |__|__| . |__| °C � Route : [ A ] Axillary[ R ] Rectal

LABORATORY TESTS

BLOOD SAMPLE

Has a blood sample been taken ?

Yes → Please complete only if different from visit date: |__|__| |__|__|__| |__|__|__|__|day month year

No

5.


208136/038 |___| VISIT 1 |__|__|__|__|__|

VACCINE ADMINISTRATION

Please complete only if different from visit date : |__|__| |__|__|__| |__|__|__|__|day month year

VACCINE ADMINISTRATION(only one box must be ticked by vaccine)

Side / siteroute

Has the study vaccine been administeredaccording to the Protocol ?

MeMuRu-OKA VaccineReplacement vial (*)Wrong vial number (*)Not administered (**)

Left

Upper arm

Deltoid region

S.C.

YesNo � please tick all items that apply

Side : Site : Route : Upper left Deltoid I.M. Lower left Thigh S.C. Upper right Buttock Lower right

OR

Priorix VaccineReplacement vial (*)Wrong vial number (*)Not administered (**)

Left

Upper arm

Deltoid region

S.C.



ANDVarilrix VaccineReplacement vial (*)Wrong vial number (*)Not administered (**)

Right

Upper arm

Deltoid region

S.C.



(*) : Comments : -------------------------------------------------------------------------------------------------------------------

(**) : Please complete next page

6.


208136/038 |___| VISIT 1 |__|__|__|__|__|

VACCINE ADMINISTRATION (continued)

(**) Why not administered ?

Please tick the ONE most appropriate category for non administration :

(SAE) Serious adverse event (complete the Serious Adverse Event form)

Please specify SAE N° : |__|__|

(AEX) Non-Serious adverse event (complete the Non-serious Adverse Event page)

Please specify AE N° (Unsol.) : |__|__| or code (Solicited) : |__|__|

(OTH) Other, please specify : ___________________________________________________

(e.g. : consent withdrawal, Protocol violation, �)

Please tick who took the decision : Investigator Parents/Guardians

IMMEDIATE POST-VACCINATION OBSERVATION

If any adverse events occurred during the immediate post-vaccination time (at least 30min) please fill in theSolicited Adverse Events section, the Non-Serious Adverse Events section or a Serious Adverse Eventform.

If any prophylactic medication has been administered in anticipation of study vaccine reaction,please complete the Medication section.Any other vaccines administered during the study period must be recorded in the Concomitant Vaccinationsection.

7.


208136/038 |___| VISIT 1 |__|__|__|__|__|

ADVERSE EVENTS – POST–VACCINATION OBSERVATION

Has the subject experienced any serious or non-serious unsolicited adverse events within minimum 42 dayspost-vaccination ?

[ U ] Information not retrievable

[ N A ] No Vaccine administered

[ N ] No

[ Y ] Yes, fill in the Non-Serious Adverse Event pages or Serious Adverse Event form.

8.

208136/038 (MeMuRu-OKA-038)Protocol CRF Subject Number

208136/038 |___| DOSE 1 |__|__|__|__|__|

SOLICITED ADVERSE EVENTS – LOCAL SYMPTOMSFor each vaccine, has the subject experienced any of the following signs/symptoms at the administration site during thesolicited period?

LOCAL SYMPTOMS Day 0 Day 1 Day 2 Day 3 Ongoingafter day 3?

Date of last day of symptomsday month year

MeMuRu-OKA vaccine[ N ] No [ U ] Information not retrievable [ N A ] No vaccine administered[ Y ] Yes, please tick No/Yes for each symptom. If Yes is ticked, please complete all items.

Redness (RE)

� No� Yes � size (mm) :

_____ _____ _____ _____ � No � Yes � |__|__| |__|__|__| |__|__|__|__|

Swelling (SW)

� No� Yes � size (mm) : _____ _____ _____ _____

� No � Yes � |__|__| |__|__|__| |__|__|__|__|

Pain (PA)

� No� Yes � intensity : |___| |___| |___| |___|

� No � Yes � |__|__| |__|__|__| |__|__|__|__|

ORPriorix vaccine[ N ] No [ U ] Information not retrievable [ N A ] No vaccine administered[ Y ] Yes, please tick No/Yes for each symptom. If Yes is ticked, please complete all items.

Redness (RE)


_____ _____ _____ _____ � No � Yes � |__|__| |__|__|__| |__|__|__|__|

Swelling (SW)

� No� Yes � size (mm) : _____ _____ _____ _____

� No � Yes � |__|__| |__|__|__| |__|__|__|__|

Pain (PA)

� No� Yes � intensity : |___| |___| |___| |___|

� No � Yes � |__|__| |__|__|__| |__|__|__|__|

ANDVarilrix vaccine[ N ] No [ U ] Information not retrievable [ N A ] No vaccine administered[ Y ] Yes, please tick No/Yes for each symptom. If Yes is ticked, please complete all items.

Redness (RE)


_____ _____ _____ _____ � No � Yes � |__|__| |__|__|__| |__|__|__|__|

Swelling (SW)

� No� Yes � size (mm) : _____ _____ _____ _____

� No � Yes � |__|__| |__|__|__| |__|__|__|__|

Pain (PA)

� No� Yes � intensity : |___| |___| |___| |___|

� No � Yes � |__|__| |__|__|__| |__|__|__|__|

Intensity: 0 : None1 : Mild2 : Moderate3 : Severe

If any of these adverse events are serious according to Protocol definition, please report event to GSK monitor by telephone or fax within 24 hours (see Protocol) and complete the Serious Adverse Event form.

9.


208136/038 |___| DOSE 1 |__|__|__|__|__|

SOLICITED ADVERSE EVENTS – GENERAL SYMPTOMS

Has the subject experienced any of the following signs/symptoms during the solicited period?

[ U ] � Information not retrievable[ N A ] � No vaccine administered[ N ] � No[ Y ] � Yes, please tick No/Yes for each symptom. If Yes is ticked, please complete all items.

Fever� No �� Yes �

Please complete the Temperature section

General rash/ exanthema � No� Yes �

Please complete the Rash / Exanthema section

Parotid / salivary gland swelling � No� Yes �

Please complete the Parotid / Salivary GlandSwelling section

Febrile convulsions �suspected signs of meningism

� No� Yes �

Please complete the Febrile Convulsions –Suspected Signs of Meningism section

If any of these adverse events are serious according to Protocol definition, please report event to GSKmonitor by telephone or fax within 24 hours (see Protocol) and complete the Serious Adverse Event form.

10.

TEMPERATUREVISIT 2

Post Dose 1

208136/038 (MeMuRu-OKA-038) Protocol CRF Subject Number

208136/038 |___|VISIT 2

(Post Dose 1) |__|__|__|__|__|

TEMPERATURE

Please record below all temperatures within 15 days post-vaccination

Fever:Axillary > 37.5°C

Episode No Temperature not taken Causality Medical advice

Day 0 ___.__ °C � if fever �� No� Yes

� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes

If any antipyretics or antibiotics has been taken, please complete the Medication section.If fever occurs after the solicited period, please complete the Non-Serious Adverse Event pages.

11.


208136/038 |___|VISIT 2

(Post Dose 1) |__|__|__|__|__|

TEMPERATUREScreen fever and record temperature in case of suspected fever.

Fever : Axillary > 37.5° C

DAY Fever Temperature Causality Medicaladvice

15� No� Yes �� Unknown ___.__

� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes

If any antipyretics or antibiotics has been taken, please complete the Medication section.

12.


208136/038 |___|VISIT 2

(Post Dose 1) |__|__|__|__|__|





� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


13.

VISIT 2WEEK 6

42 – 56 days after Visit 1

Dose 2

REMINDERS

ELIMINATION CRITERIA

Please check all appropriate criteria before continuing the visit.

ADVERSE EVENTS

Please report adverse events as specified in the Protocol and fill in the Non-Serious Adverse Eventspages or the Serious Event (SAE) form, as appropriate. This SAE form must be faxed toGlaxoSmithKline within 24 hours of you becoming aware of these events.

MEDICATION

Please report medication as specified in the Protocol and fill in the Medication section.

Please report concomitant vaccination in the Concomitant Vaccination section.

CONTRAINDICATIONS

Before any vaccine administration, please review the Contraindications as specified in the Protocol.


208136/038 |___| VISIT 2 |__|__|__|__|__|

CHECK FOR STUDY CONTINUATION

Did the subject come at visit 2 ?

Yes, please complete the next pages. No

please tick the ONE most appropriate reason and skip the following pages of this visit.

(SAE) Serious adverse event(complete the Serious Adverse Event form)


(AEX) Non-Serious adverse event

(complete the Non-serious Adverse Event page)


(OTH) Other, please specify : ______________________________________


Investigator�s decision Parents/Guardian�s decision

14.

208136/038 (MeMuRu-OKA-038)Protocol CRF Visit Date of visit Subject Number

208136/038 |___| VISIT 2 |__|__| |__|__|__| |__|__|__|__|day month year |__|__|__|__|__|

PRE-VACCINATION ASSESSMENT

Temperature : |__|__| . |__| °C � Route : [ A ] Axillary[ R ] Rectal

LABORATORY TESTS

BLOOD SAMPLE



No

15.


208136/038 |___| VISIT 2 |__|__|__|__|__|

VACCINE ADMINISTRATION

Please complete only if different from visit date : |__|__| |__|__|__| |__|__|__|__|day month year

VACCINE ADMINISTRATION(only one box must be ticked by vaccine)

Side / siteroute

Has the study vaccine been administeredaccording to the Protocol ?

MeMuRu-OKA VaccineReplacement vial (*)Wrong vial number (*)Not administered (**)

Left

Upper arm

Deltoid region

S.C.



OR

Priorix VaccineReplacement vial (*)Wrong vial number (*)Not administered (**)

Left

Upper arm

Deltoid region

S.C.



(*) : Comments : -------------------------------------------------------------------------------------------------------------------

(**) : Please complete next page

16.


208136/038 |___| VISIT 2 |__|__|__|__|__|

VACCINE ADMINISTRATION (continued)

(**) Why not administered ?

Please tick the ONE most appropriate category for non administration :

(SAE) Serious adverse event (complete the Serious Adverse Event form)


(AEX) Non-Serious adverse event (complete the Non-serious Adverse Event page)


(OTH) Other, please specify : ___________________________________________________


Please tick who took the decision : Investigator Parents/Guardians

IMMEDIATE POST-VACCINATION OBSERVATION

If any adverse events occurred during the immediate post-vaccination time (at least 30min) please fill in theSolicited Adverse Events section, the Non-Serious Adverse Events section or a Serious Adverse Eventform.

If any prophylactic medication has been administered in anticipation of study vaccine reaction,please complete the Medication section.Any other vaccines administered during the study period must be recorded in the Concomitant Vaccinationsection.

17.


208136/038 |___| VISIT 2 |__|__|__|__|__|

ADVERSE EVENTS – POST–VACCINATION OBSERVATION

Has the subject experienced any serious or non-serious unsolicited adverse events within minimum 42 dayspost-vaccination ?

[ U ] Information not retrievable

[ N A ] No Vaccine administered

[ N ] No

[ Y ] Yes, fill in the Non-Serious Adverse Event pages or Serious Adverse Event form.

18.


208136/038 |___| DOSE 2 |__|__|__|__|__|

SOLICITED ADVERSE EVENTS – LOCAL SYMPTOMSFor each vaccine, has the subject experienced any of the following signs/symptoms at the administration siteduring the solicited period?

LOCAL SYMPTOMS Day 0 Day 1 Day 2 Day 3 Ongoingafter day 3?

Date of last day of symptomsday month year

MeMuRu-OKA vaccine[ N ] No [ U ] Information not retrievable [ N A ] No vaccine administered[ Y ] Yes, please tick No/Yes for each symptom. If Yes is ticked, please complete all items.

Redness (RE)


_____ _____ _____ _____ � No � Yes � |__|__| |__|__|__| |__|__|__|__|

Swelling (SW)

� No� Yes � size (mm) : _____ _____ _____ _____

� No � Yes � |__|__| |__|__|__| |__|__|__|__|

Pain (PA)

� No� Yes � intensity : |___| |___| |___| |___|

� No � Yes � |__|__| |__|__|__| |__|__|__|__|

ORPriorix vaccine[ N ] No [ U ] Information not retrievable [ N A ] No vaccine administered[ Y ] Yes, please tick No/Yes for each symptom. If Yes is ticked, please complete all items.

Redness (RE)


_____ _____ _____ _____ � No � Yes � |__|__| |__|__|__| |__|__|__|__|

Swelling (SW)

� No� Yes � size (mm) : _____ _____ _____ _____

� No � Yes � |__|__| |__|__|__| |__|__|__|__|

Pain (PA)

� No� Yes � intensity : |___| |___| |___| |___|

� No � Yes � |__|__| |__|__|__| |__|__|__|__|

Intensity: 0 : None1 : Mild2 : Moderate3 : Severe

If any of these adverse events are serious according to Protocol definition, please report event to GSK monitor by telephone or fax within 24 hours (see Protocol) and complete the Serious Adverse Event form.

19.


208136/038 |___| DOSE 2 |__|__|__|__|__|

SOLICITED ADVERSE EVENTS – GENERAL SYMPTOMS

Has the subject experienced any of the following signs/symptoms during the solicited period?

[ U ] � Information not retrievable[ N A ] � No vaccine administered[ N ] � No[ Y ] � Yes, please tick No/Yes for each symptom. If Yes is ticked, please complete all items.

Fever� No �� Yes �

Please complete the Temperature section

General rash/ exanthema � No� Yes �

Please complete the Rash / Exanthema section

Parotid / salivary gland swelling � No� Yes �

Please complete the Parotid / Salivary GlandSwelling section

Febrile convulsions �suspected signs of meningism

� No� Yes �

Please complete the Febrile Convulsions –Suspected Signs of Meningism section

If any of these adverse events are serious according to Protocol definition, please report event to GSKmonitor by telephone or fax within 24 hours (see Protocol) and complete the Serious Adverse Event form.

20.

VISIT 3WEEK 12

42 – 56 days after Visit 2

REMINDERS

ELIMINATION CRITERIA

Please check all appropriate criteria before continuing the visit.

ADVERSE EVENTS

Please report adverse events as specified in the Protocol and fill in the Non-Serious Adverse Eventspages or the Serious Event (SAE) form, as appropriate. This SAE form must be faxed toGlaxoSmithKline within 24 hours of you becoming aware of these events.

MEDICATION

Please report medication as specified in the Protocol and fill in the Medication section.

Please report concomitant vaccination in the Concomitant Vaccination section.


208136/038 |___| VISIT 3 |__|__|__|__|__|

CHECK FOR STUDY CONTINUATION

Did the subject come at visit 3 ?

Yes, please complete the following pages.

No, please complete below :

Same reason and decision as previous visit.

Please tick the ONE most appropriate reason :



(AEX) Non-Serious adverse event

(complete the Non-serious Adverse Event page)


(OTH) Other, please specify : _______________________________________________



21.

OR

208136/038 (MeMuRu-OKA-038)Protocol CRF Visit Date of visit Subject Number

208136/038 |___| VISIT 3 |__|__| |__|__|__| |__|__|__|__|day month year |__|__|__|__|__|

LABORATORY TESTS

BLOOD SAMPLE



No

22.

TEMPERATUREVISIT 3

Post Dose 2


208136/038 |___|VISIT 3

(Post dose 2) |__|__|__|__|__|

TEMPERATURE

Please record below all temperatures within 15 days post-vaccination

Fever:Axillary > 37.5°C

Episode No Temperature not taken Causality Medical advice


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes


� No� Yes

If any antipyretics or antibiotics has been taken, please complete the Medication section.If fever occurs after the solicited period, please complete the Non-Serious Adverse Event pages.

23.


208136/038 |___|VISIT 3

(Post dose 2) |__|__|__|__|__|





� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


24.


208136/038 |___|VISIT 3

(Post dose 2) |__|__|__|__|__|





� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


� No� Yes

� No� Yes


25.

RASH / EXANTHEM


208136/038 |___| |__|__|__|__|__|

RASH / EXANTHEMPlease report any rash event that occurred during the study period.

Rash No. RA.1 RA.2Description _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _� Administration sites

[ 8 0 ] � MeMuRu-OKA vaccine[ 3 3 ] � Priorix vaccine[ 1 9 ] � Varilrix vaccine

� Non-administration site� Generalized� Localized

� Administration sites[ 8 0 ] � MeMuRu-OKA vaccine[ 3 3 ] � Priorix vaccine[ 1 9 ] � Varilrix vaccine

� Non-administration site� Generalized� Localized

ForGSKCategory: � Varicella rash

� Measles / rubella-rash� Other : _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

� Varicella rash� Measles / rubella-rash� Other : _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

Date started |__|__| |__|__|__| |__|__|__|__|day month year

|__|__| |__|__|__| |__|__|__|__|day month year

Date stopped |__|__| |__|__|__| |__|__|__|__|day month year

|__|__| |__|__|__| |__|__|__|__|day month year

Intensity [ 1 ] � 1 � 50 lesions[ 2 ] � 51 � 150 lesions[ 3 ] � > 150 lesions

[ 1 ] � 1 � 50 lesions[ 2 ] � 51 � 150 lesions[ 3 ] � > 150 lesions

Has a vesicular fluidsample been taken?

� No� Yes, if yes, date

↓|__|__| |__|__|__| |__|__|__|__|

day month year

� No� Yes, if yes, date

↓|__|__| |__|__|__| |__|__|__|__|

day month yearRelationship toinvestigational products:Is there a reasonable possibility thatthe AE may have been caused bythe investigational product?

� No� Yes

� No� Yes

Outcome

[ 1 ] � Recovered / resolved[ 2 ] � Recovering / resolving[ 3 ] � Not recovered / not resolved[ 4 ] � Recovered with sequelae /

resolved with sequelae



If you consider any of these adverse events to be serious, please report the event to the GlaxoSmithKline Biologicalsmonitor by telephone or fax within 24 hours (see protocol) and complete the Serious Adverse Event form.

26.

PAROTID /SALIVARY GLAND

SWELLING


208136/038 |___| |__|__|__|__|__|

PAROTID / SALIVARY GLAND SWELLING EVENTSPlease report any parotid / salivary gland swelling events occuring during the study period.

PS No. PS.1 PS.2Description _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ForGSKDate started |__|__| |__|__|__| |__|__|__|__|

day month year|__|__| |__|__|__| |__|__|__|__|

day month yearDate stopped |__|__| |__|__|__| |__|__|__|__|

day month year|__|__| |__|__|__| |__|__|__|__|

day month yearIntensity [ 1 ] � Swelling without difficulties to

move the jaw.[ 2 ] � Swelling with difficulties to

move the jaw.[ 3 ] � Swelling and additional

general symptoms.

[ 1 ] � Swelling without difficulties tomove the jaw.

[ 2 ] � Swelling with difficulties tomove the jaw.

[ 3 ] � Swelling and additionalgeneral symptoms.

Saliva sampleHas a saliva sample beentaken for mumps virusdetection, strain identificationand for viral culture?

� No� Yes � date

↓

|__|__| |__|__|__| |__|__|__|__|day month year

� No� Yes � date

↓

|__|__| |__|__|__| |__|__|__|__|day month year

Relationship toinvestigational products:Is there a reasonable possibilitythat the AE may have beencaused by the investigationalproduct?

� No� Yes

� No� Yes

Outcome [ 1 ] � Recovered / resolved[ 2 ] � Recovering / resolving[ 3 ] � Not recovered / not resolved[ 4 ] � Recovered with sequelae /





27.

FEBRILECONVULSIONS -

SUSPECTED SIGNSOF MENINGITIS


208136/038 |___| |__|__|__|__|__|

FEBRILE CONVULSIONS – SUSPECTED SIGNS OF MENINGITIS EVENTSPlease report any febrile convulsion and any suspected signs of meningitis occuring during the studyperiod.

FC No. FC.1 FC.2Description _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ForGSKDate started |__|__| |__|__|__| |__|__|__|__|

day month year|__|__| |__|__|__| |__|__|__|__|

day month yearDate stopped |__|__| |__|__|__| |__|__|__|__|

day month year|__|__| |__|__|__| |__|__|__|__|

day month year

Intensity [ 1 ] � Mild[ 2 ] � Moderate[ 3 ] � Severe

[ 1 ] � Mild[ 2 ] � Moderate[ 3 ] � Severe

Was a neurologicalexamination beenperformed?

� No� Yes

↓if yes, was a lumbar punctureperformed?

� No� Yes

↓if yes, please send a copyof Medical Report

� No� Yes

↓if yes, was a lumbar punctureperformed?

� No� Yes

↓if yes, please send a copyof Medical Report

Relationship toinvestigational products:Is there a reasonable possibilitythat the AE may have beencaused by the investigationalproduct?

� No� Yes

� No� Yes

Outcome [ 1 ] � Recovered / resolved[ 2 ] � Recovering / resolving[ 3 ] � Not recovered / not resolved[ 4 ] � Recovered with sequelae /





28.

CONCOMITANT

VACCINATION


VACCINATION ROUTE

CODE LABELID IntradermalIH InhalationIM IntramuscularIV IntravenousNA IntranasalOTH OtherPE ParenteralPO OralSC SubcutaneousSL SublingualTD TransdermalUNK Unknown


208136/038 |___||__|__|__|__|__|

CONCOMITANT VACCINATION

Has any vaccine other than the study vaccine(s) been administered in the period beginning 30 dayspreceding each dose and ending 42 days after each dose ?

NoYes, please record concomitant vaccination with trade name and / or generic name, and vaccineadministration date.

Trade / (Generic) Name Route Administration dateday month year

|__|__| |__|__|__| |__|__|__|__|

ForGSK

|__|__| |__|__|__| |__|__|__|__|

ForGSK

|__|__| |__|__|__| |__|__|__|__|

ForGSK

|__|__| |__|__|__| |__|__|__|__|

ForGSK

|__|__| |__|__|__| |__|__|__|__|

ForGSK

|__|__| |__|__|__| |__|__|__|__|

ForGSK

|__|__| |__|__|__| |__|__|__|__|

ForGSK

|__|__| |__|__|__| |__|__|__|__|

29.

MEDICATION


MEDICATION ROUTE

CODE LABELEXT ExternalID IntradermalIH InhalationIM IntramuscularIR IntraarticularIT IntrathecalIV IntravenousNA IntranasalOTH OtherPE ParenteralPO OralPR RectalSC SubcutaneousSL SublingualTD TransdermalTO TopicalUNK UnknownVA Vaginal

• All concomitant medication, with the exception of vitamins and/or dietary supplements, administered atANY time during the period starting with administration of each dose and ending 42 days after eachdose are to be recorded with generic name of the medication (trade names are allowed for combinationdrugs, i.e., multi-component drugs), medical indication, total daily dose, route of administration, start andend dates of treatment.

• Any treatments and/or medications specifically contraindicated, e.g., any immunoglobulins, other bloodproducts and any immune modifying drugs administered since birth or at any time until Visit 3 are to berecorded with generic name of the medication (trade names are allowed for combination drugs only),medical indication, total daily dose, route of administration, start and end dates of treatment

• Any concomitant medication administered prophylactically in anticipation of reaction to the vaccinationmust be recorded in the CRF with generic name of the medication (trade names are allowed forcombination drugs only), total daily dose, route of administration, start and end dates of treatment andcoded as �Prophylactic�.

• Concomitant medication administered for the treatment of an AE or SAE must be recorded in the CRFwith generic name of the medication (trade names are allowed for combination drugs only), medicalindication (including which AE/SAE), total daily dose, route of administration, start and end dates oftreatment.


208136/038 |___||__|__|__|__|__|

MEDICATION

Have any medications/treatments been administered during the timeframe as specified in the protocol ?

NoYes, please complete the following table.

Trade / Generic Name Medical Indication Total dailydose Route

Start and end date or tick boxif continuing at end of study

day month year

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|ForGSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|ForGSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|ForGSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|ForGSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|ForGSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|ForGSK

Prophylactic

Start: |__|__| |__|__|__| |__|__|__|__|

End: |__|__| |__|__|__| |__|__|__|__|ForGSK

30.

NON-SERIOUSADVERSEEVENTS


208136/038 |___| |__|__|__|__|__|

NON-SERIOUS ADVERSE EVENTS(Please report all serious adverse events only on the Serious Adverse Event (SAE) form).Has any non-serious adverse events occurred within one month (minimum 30 days) post-vaccination,excluding those recorded on the Solicited Adverse Events pages?

No Yes, please complete the following table.

AE No. 1 2

Description _______________________

_______________________

_______________________

_______________________

_______________________

_______________________

Administration sites[ 8 0 ] MeMuRu-OKA vaccine[ 3 3 ] Priorix vaccine[ 1 9 ] Varilrix vaccine

Non-administration site



ForGSK

Date Started|__|__| |__|__|__| |__|__|__|__|

day month year

during immediate post-vaccination period(at least 30 minutes)

|__|__| |__|__|__| |__|__|__|__|day month year


Date Stopped |__|__| |__|__|__| |__|__|__|__|day month year

|__|__| |__|__|__| |__|__|__|__|day month year

Intensity[ 1 ] Mild[ 2 ] Moderate[ 3 ] Severe

[ 1 ] Mild[ 2 ] Moderate[ 3 ] Severe

Relationship toinvestigational products:Is there a reasonablepossibility that the AE mayhave been caused by theinvestigational product?

NoYes

NoYes

Outcome

[ 1 ] Recovered / Resolved[ 2 ] Recovering / resolving[ 3 ] Not recovered / not resolved[ 4 ] Recovered with sequelae /

Resolved with sequelae



31.


208136/038 |___| |__|__|__|__|__|

NON-SERIOUS ADVERSE EVENTS (continued)

AE No. 3 4

Description _______________________

_______________________

_______________________

_______________________

_______________________

_______________________





ForGSK

Date Started|__|__| |__|__|__| |__|__|__|__|

day month year


|__|__| |__|__|__| |__|__|__|__|day month year


Date Stopped |__|__| |__|__|__| |__|__|__|__|day month year

|__|__| |__|__|__| |__|__|__|__|day month year

Intensity[ 1 ] Mild[ 2 ] Moderate[ 3 ] Severe

[ 1 ] Mild[ 2 ] Moderate[ 3 ] Severe

Relationship toinvestigational products:Is there a reasonablepossibility that the AE mayhave been caused by theinvestigational product?

NoYes

NoYes

Outcome





32.

STUDY

CONCLUSION


208136/038 |___| |__|__|__|__|__|

FOLLOW-UP STUDIES

Would the subject be willing to participate in a follow-up study?

Yes

No, please specify the reason

� Adverse Events, or Serious Adverse Events:

please specify: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

� Other:

please specify: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

33.


208136/038 |___| |__|__|__|__|__|

STUDY CONCLUSION

OCCURRENCE OF SERIOUS ADVERSE EVENTDid the subject experience any Serious Adverse Event during the study period?

Yes No

If yes, please give the total number of SAE's: |__|__|

STATUS OF TREATMENT BLINDWas the treatment blind broken during the study?

Yes No

If Yes, complete the date and tick one reason below:

|__|__| |__|__|__| |__|__|__|__|day month year

[1 ] Medical emergency requiring identification of investigational product for furthertreatments

[9 ] Other, specify: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

Complete Non-Serious Adverse Event, Investigational Product pages and/or Serious Adverse Eventform if appropriate.

ELIMINATION CRITERIADid any elimination criteria become applicable during the study?

Yes No

If Yes, please specify: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

34.


208136/038 |___| |__|__|__|__|__|

STUDY CONCLUSION (continued)Was the subject withdrawn from study?

NoYes

Please tick the ONE most appropriate category for drop out.


Please specify SAE N°: |__|__|

(AEX) Non-Serious adverse event(complete the Non-serious Adverse Event page)

Please specify AE N° (Unsol.): |__|__| or code (Solicited): |__|__|

(PTV) Protocol violation, please specify:________________________________________

(CWS) Consent withdrawal, not due to an adverse event.

(MIG) Migrated / moved from the study area

(LFU) Lost to follow-up.

(OTH) Other, please specify: ____________________________________________


Date of last contact: |__|__| |__|__|__| |__|__|__|__|day month year

Was the subject in good condition at date of last contact?No, please give details within the Adverse Events section.Yes

INVESTIGATOR'S SIGNATUREI confirm that I have reviewed the data in this Case Report Form for this subject. All information entered bymyself or my colleagues is, to the best of my knowledge, complete and accurate, as of the date below.

Investigator's signature: ___________________________ Date: |__|__| |__|__|__| |__|__|__|__|

Printed Investigator'sname: ___________________________

day month year

35.

Protocol Subject number208136/038

(MeMuRu-OKA-038)DIARY CARD

MeMuRu-OKA Vaccine DOSE 1 |__|__|__|__|__|

SOLICITED SYMPTOMS

Please fill in below and assess the occurrence of any of the following signs or symptoms according to the criteria listed hereafter:INTENSITY:Pain (at injection site):0:Absent1:Minor reaction to touch2:Cries/protests on touch3:Cries when limb is moved / spontaneously painfulSIZE: Please measure the greatest diameter (in mm).

LOCAL SYMPTOMS Day 0 Day 1Evening

Day 2Evening

Day 3Evening

Ongoingafter Day 3?

Date of last Day of Symptomsday month year

Redness! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Swelling! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Pain! intensity: |___| |___| |___| |___|

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|



Priorix + Varilrix Vaccines DOSE 1 |__|__|__|__|__|

SOLICITED SYMPTOMS

Please fill in below and assess the occurrence of any of the following signs or symptoms according to the criteria listed hereafter:INTENSITY:Pain (at injection site):0:Absent1:Minor reaction to touch2:Cries/protests on touch3:Cries when limb is moved / spontaneously painfulSIZE: Please measure the greatest diameter (in mm).For investigator only: Could you please check the appropriate box (side / site) for assessment.

for investigator only LOCALSYMPTOMS

Day 0 Day 1Evening

Day 2Evening

Day 3Evening

Ongoingafter Day 3?


Priorix Vaccine

Redness! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Swelling! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Side Upper left Lower left Upper right Lower right

Site Arm Thigh Buttock

Pain! intensity: |___| |___| |___| |___|

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Varilrix Vaccine

Redness! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Swelling! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Side Upper left Lower left Upper right Lower right

Site Arm Thigh Buttock

Pain! intensity: |___| |___| |___| |___|

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|


(MeMuRu-OKA-038)DIARY CARD DOSE 1 |__|__|__|__|__|

UNSOLICITED SYMPTOMSINTENSITY : Other symptoms:1:Mild: An adverse event which is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.2:Moderate: An adverse event which is sufficiently discomforting to interfere with normal everyday activities.3:Severe: An adverse event which prevents normal, everyday activities. (In a young child, such an adverse event would, for example, prevent

attendance at school/kindergarten/a day-care center and would cause the parents/guardians to seek medical advice).

OTHER SYMPTOMS (day 0 – 42) Please give details belowStart date End date or check box if continuingDescription - please specify side(s) and site(s) Intensity day month year day month year

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

MEDICATION Please fill in below if any medication has been taken since the vaccinationStart date End date or check box if continuingTrade/Generic name Reason Total Daily

Dose day month year day month year

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

PLEASE DO NOT FORGET TO BRING BACK THE DIARY CARD ON |__|__| |__|__|__|

|__|__|__|__|

IN CASE OF HOSPITALISATION, PLEASE INFORM …..…....………………………………………… ": …..…....……………………………………..…………



DAY 0 TO DAY 14

Please record temperature daily from day 0 to day 14after vaccination at bedtime.Fever : Axillary (> 37.5°C)

If multiple measures, take the maximum value.

Episode No Temperature! °C

Medicaladvice

Day 0 ___.__ ! No! Yes

Day 1 ___.__ ! No! Yes

Day 2 ___.__ ! No! Yes

Day 3 ___.__ ! No! Yes

Day 4 ___.__ ! No! Yes

Day 5 ___.__ ! No! Yes

Day 6 ___.__ ! No! Yes

Day 7 ___.__ ! No! Yes

Day 8 ___.__ ! No! Yes

Day 9 ___.__ ! No! Yes

Day 10 ___.__ ! No! Yes

Day 11 ___.__ ! No! Yes

Day 12 ___.__ ! No! Yes

Day 13 ___.__ ! No! Yes

Day 14 ___.__ ! No! Yes


|__|__|__|__|


TEMPERATURE



DAY 15 TO DAY 42

Please screen temperature daily from day 15 to 42please use the temperature sensitive pad orthermometer. If fever is indicated, please take thechild’s temperature using a thermometer and reportmeasurement below.

Fever : Axillary (> 37.5°C)


DAY Fever Temperature! °C

Medicaladvice DAY Fever Temperature

! °CMedicaladvice

15! No! Yes ___.__

! No! Yes

29 ! No! Yes ___.__

! No! Yes

16! No! Yes ___.__

! No! Yes

30 ! No! Yes ___.__

! No! Yes

17! No! Yes ___.__

! No! Yes

31 ! No! Yes ___.__

! No! Yes

18! No! Yes ___.__

! No! Yes

32 ! No! Yes ___.__

! No! Yes

19! No! Yes ___.__

! No! Yes

33 ! No! Yes ___.__

! No! Yes

20! No! Yes ___.__

! No! Yes

34 ! No! Yes ___.__

! No! Yes

21! No! Yes ___.__

! No! Yes

35 ! No! Yes ___.__

! No! Yes

22! No! Yes ___.__

! No! Yes

36 ! No! Yes ___.__

! No! Yes

23! No! Yes ___.__

! No! Yes

37 ! No! Yes ___.__

! No! Yes

24! No! Yes ___.__

! No! Yes

38 ! No! Yes ___.__

! No! Yes

25! No! Yes ___.__

! No! Yes

39 ! No! Yes ___.__

! No! Yes

26! No! Yes ___.__

! No! Yes

40 ! No! Yes ___.__

! No! Yes

27! No! Yes ___.__

! No! Yes

41 ! No! Yes ___.__

! No! Yes

28! No! Yes ___.__

! No! Yes

42 ! No! Yes ___.__

! No! Yes


|__|__|__|__|


TEMPERATURE



In case Rash/exanthem and/or Parotid/Salivary gland swellingand/or Febrile convulsions – Suspected signs ofmeningism

Day 0 – Day 42

is (are) observed, the parents/guardians are instructed to bring the child to visit the investigatorfor complete clinical examination, further assessments and/or appropriate treatment

If rash occurs, please also record the event here

Rash Episode No. RA 1. RA 2. RA 3

RASH /EXANTHEMDescription

_________________

_________________

_________________

_________________

_________________

_________________

_________________

_________________

_________________

_________________

_________________

_________________

! Vaccination site! Left arm! Right arm

! Non-administrationsite





Date Started: |__|__| |__|__|__| |__|__|__|__|day month year

|__|__| |__|__|__| |__|__|__|__|day month year

|__|__| |__|__|__| |__|__|__|__|day month year

Date Stopped: |__|__| |__|__|__| |__|__|__|__|day month year

|__|__| |__|__|__| |__|__|__|__|day month year

|__|__| |__|__|__| |__|__|__|__|day month year

Intensity: ! 1 1 – 50 lesions! 2 51 – 150 lesions! 3 > 150 lesions

! 1 1 – 50 lesions! 2 51 – 150 lesions! 3 > 150 lesions


Temperature: Please complete the “Temperature” diary card.


|__|__|__|__|




MeMuRu-OKA or Priorix Vaccine DOSE 2 |__|__|__|__|__|

SOLICITED SYMPTOMS

Please fill in below and assess the occurrence of any of the following signs or symptoms according to the criteria listed hereafter:INTENSITY:Pain (at injection site):0:Absent1:Minor reaction to touch2:Cries/protests on touch3:Cries when limb is moved / spontaneously painfulSIZE: Please measure the greatest diameter (in mm).

LOCAL SYMPTOMS Day 0 Day 1Evening

Day 2Evening

Day 3Evening

Ongoingafter Day 3?


Redness! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Swelling! size (mm): _____ _____ _____ _____

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|

Pain! intensity: |___| |___| |___| |___|

! No! Yes ! |__|__| |__|__|__| |__|__|__|__|



UNSOLICITED SYMPTOMSINTENSITY : Other symptoms:1:Mild: An adverse event which is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.2:Moderate: An adverse event which is sufficiently discomforting to interfere with normal everyday activities.3:Severe: An adverse event which prevents normal, everyday activities. (In a young child, such an adverse event would, for example, prevent

attendance at school/kindergarten/a day-care center and would cause the parents/guardians to seek medical advice).

OTHER SYMPTOMS (day 0 – 42) Please give details belowStart date End date or check box if continuingDescription - please specify side(s) and site(s) Intensity day month year day month year

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|___| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

MEDICATION Please fill in below if any medication has been taken since the vaccinationStart date End date or check box if continuingTrade/Generic name Reason Total Daily

Dose day month year day month year

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| !


|__|__|__|__|




DAY 0 TO DAY 14

Please record temperature daily from day 0 to day 14after vaccination at bedtime.Fever : Axillary (> 37.5°C)


Episode No Temperature! °C

Medicaladvice

Day 0 ___.__ ! No! Yes

Day 1 ___.__ ! No! Yes

Day 2 ___.__ ! No! Yes

Day 3 ___.__ ! No! Yes

Day 4 ___.__ ! No! Yes

Day 5 ___.__ ! No! Yes

Day 6 ___.__ ! No! Yes

Day 7 ___.__ ! No! Yes

Day 8 ___.__ ! No! Yes

Day 9 ___.__ ! No! Yes

Day 10 ___.__ ! No! Yes

Day 11 ___.__ ! No! Yes

Day 12 ___.__ ! No! Yes

Day 13 ___.__ ! No! Yes

Day 14 ___.__ ! No! Yes


|__|__|__|__|


TEMPERATURE



DAY 15 TO DAY 42

Please screen temperature daily from day 15 to 42please use the temperature sensitive pad orthermometer. If fever is indicated, please take thechild’s temperature using a thermometer and reportmeasurement below.

Fever : Axillary (> 37.5°C)


DAY Fever Temperature! °C

Medicaladvice DAY Fever Temperature

! °CMedicaladvice

15! No! Yes ___.__

! No! Yes

29 ! No! Yes ___.__

! No! Yes

16! No! Yes ___.__

! No! Yes

30 ! No! Yes ___.__

! No! Yes

17! No! Yes ___.__

! No! Yes

31 ! No! Yes ___.__

! No! Yes

18! No! Yes ___.__

! No! Yes

32 ! No! Yes ___.__

! No! Yes

19! No! Yes ___.__

! No! Yes

33 ! No! Yes ___.__

! No! Yes

20! No! Yes ___.__

! No! Yes

34 ! No! Yes ___.__

! No! Yes

21! No! Yes ___.__

! No! Yes

35 ! No! Yes ___.__

! No! Yes

22! No! Yes ___.__

! No! Yes

36 ! No! Yes ___.__

! No! Yes

23! No! Yes ___.__

! No! Yes

37 ! No! Yes ___.__

! No! Yes

24! No! Yes ___.__

! No! Yes

38 ! No! Yes ___.__

! No! Yes

25! No! Yes ___.__

! No! Yes

39 ! No! Yes ___.__

! No! Yes

26! No! Yes ___.__

! No! Yes

40 ! No! Yes ___.__

! No! Yes

27! No! Yes ___.__

! No! Yes

41 ! No! Yes ___.__

! No! Yes

28! No! Yes ___.__

! No! Yes

42 ! No! Yes ___.__

! No! Yes


|__|__|__|__|


TEMPERATURE



In case Rash/exanthem and/or Parotid/Salivary gland swellingand/or Febrile convulsions – Suspected signs ofmeningism

Day 0 – Day 42

is (are) observed, the parents/guardians are instructed to bring the child to visit the investigatorfor complete clinical examination, further assessments and/or appropriate treatment

If rash occurs, please also record the event here

Rash Episode No. RA 1. RA 2. RA 3

RASH /EXANTHEMDescription

_________________

_________________

_________________

_________________

_________________

_________________

_________________

_________________

_________________

_________________

_________________

_________________







Date Started: |__|__| |__|__|__| |__|__|__|__|day month year

|__|__| |__|__|__| |__|__|__|__|day month year

|__|__| |__|__|__| |__|__|__|__|day month year

Date Stopped: |__|__| |__|__|__| |__|__|__|__|day month year

|__|__| |__|__|__| |__|__|__|__|day month year

|__|__| |__|__|__| |__|__|__|__|day month year

Intensity: ! 1 1 – 50 lesions! 2 51 – 150 lesions! 3 > 150 lesions



Temperature: Please complete the “Temperature” diary card.


|__|__|__|__|


Randomisation List

RIX\RDE\ENABLE Randomisation list

MMRV-038 (A.25FEB2004)

Subjects from Group : MMRV_1 Lot MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)-------------------------------------------------------------------

Sub. Bl. Sub. Bl.No. nb No. nb-------- --------

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MMRV-038 (A.25FEB2004)

Subjects from Group : MMRV_1 Lot MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)-------------------------------------------------------------------


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MMRV-038 (A.25FEB2004)

Subjects from Group : MMRV_2 Lot MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)-------------------------------------------------------------------


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MMRV-038 (A.25FEB2004)

Subjects from Group : MMRV_2 Lot MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)-------------------------------------------------------------------


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MMRV-038 (A.25FEB2004)

Subjects from Group : MMRV_3 Lot MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)-------------------------------------------------------------------


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MMRV-038 (A.25FEB2004)

Subjects from Group : MMRV_3 Lot MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)-------------------------------------------------------------------


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MMRV-038 (A.25FEB2004)

Subjects from Group : MMR_V Lot #1 MJR vaccine(MJR622A44) mix Diluent for MJR(03A10/585) sep Varicella vaccine(VA271A43) mix Dil. for Varicella(02E07/511)#2 MJR v-------------------------------------------------------------------


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MMRV-038 (A.25FEB2004)

Subjects from Group : MMR_V Lot #1 MJR vaccine(MJR622A44) mix Diluent for MJR(03A10/585) sep Varicella vaccine(VA271A43) mix Dil. for Varicella(02E07/511)#2 MJR v-------------------------------------------------------------------


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Investigator CV

This section contained Principal Investigator’s Curriculum Vitae and has been excluded to

protect Principal Investigator privacy.

This section contained journal publication(s), which are protected by copyright laws and therefore have been excluded.

GlaxoSmithKline Biologicals Rue de l’Institut 89

1330 Rixensart, Belgium

CONFIDENTIAL

Study Reporting and Analysis Plan for clinical trial 208136/038 (MeMuRu-OKA-038)

Title : A phase III, randomised, controlled study to evaluate the immunogenicity and safety of three production lots of GlaxoSmithKline Biologicals’ combined measles-mumps-rubella-varicella (MeMuRu-OKA) candidate vaccine given on a two-dose schedule to healthy children in their second year of life, as compared to separate administration of GlaxoSmithKline Biologicals’ measles-mumps-rubella vaccine (Priorix®) and varicella vaccine (Varilrix®).

This Study RAP is to be considered with respect to the MeMuRu-OKA Project RAP

CPMS Study No. 208136/038 (MEMURU-OKA-038)

Date February 18, 2004

Version Final

Authors Statistician

February 18, 2004-Final GlaxoSmithKline Biologicals i Study Reporting and Analysis Plan 208136/038 (MEMURU-OKA-038)


Table of contents

1 INTRODUCTION ................................................................................................................ 1

2 STUDY OBJECTIVES, ENDPOINTS AND ANALYSIS VARIABLES ......................... 1

2.1 OBJECTIVES ........................................................................................................................ 1 2.1.1 Primary objectives .................................................................................................... 1 2.1.2 Secondary objectives ................................................................................................ 1

2.2 PRIMARY ENDPOINTS .......................................................................................................... 2 2.2.1 Active phase of the study .......................................................................................... 2

2.2.1.1 Co-primary endpoints ...................................................................... 2 2.2.1.2 Secondary endpoints ........................................................................ 2

2.3 ANALYSIS VARIABLES ........................................................................................................ 3

3 STUDY DESIGN OVERVIEW ........................................................................................... 3

4 STUDY COHORTS/DATASETS TO BE EVALUATED ................................................. 4

4.1 TOTAL VACCINATED COHORT ............................................................................................ 4 4.2 ACCORDING-TO-PROTOCOL (ATP) SAFETY COHORT ......................................................... 5 4.3 ACCORDING-TO-PROTOCOL IMMUNOLOGY COHORT.......................................................... 5

5 INTERIM ANALYSIS ......................................................................................................... 5

6 FINAL ANALYSIS ............................................................................................................... 6

6.1 CHANGES FROM THE PROTOCOL.......................................................................................... 6 6.2 FINAL INTEGRATED STUDY REPORT ................................................................................... 6

6.2.1 Study cohorts and demography analysis .................................................................. 7 6.2.1.1 Number of subjects and cohort distribution .................................... 7 6.2.1.2 Number of subjects at each visit and list of dropped-out subjects .. 8 6.2.1.3 Number of dropped-out subjects and reasons for drop-out ............. 9 6.2.1.4 Compliance with respect to documenting safety ........................... 10 6.2.1.5 Deviations from specifications for age and intervals between study visits. 11 6.2.1.6 Number of subjects by country ...................................................... 12

6.2.2 Demography ........................................................................................................... 13 6.2.2.1 Summary of demographic characteristics ...................................... 13

6.2.3 Immunogenicity analysis ........................................................................................ 14 6.2.3.1 Summary of immunogenicity ........................................................ 14 6.2.3.2 Antibody titers distribution ............................................................ 16

Presentation for the clinical report ....................................................................................... 25 Immunogenicity results will be presented in 2 different sections: ........................................ 25

February 18, 2004-Final GlaxoSmithKline Biologicals ii Study Reporting and Analysis Plan 208136/038 (MEMURU-OKA-038)


- First part will present the consistency between the 3 MeMuRu-OKA lots. So, in this section, the 3 consistency lots will be kept separately. ......................................................... 25 Safety .................................................................................................................................... 26 6.2.4 List of tables and figures ........................................................................................ 26

Glossary • A seronegative subject is a subject whose titre is below the assay cut-off value

(see cut-off values in protocol). • A seropositive subject is a subject whose titre is greater than or equal to the

assay cut-off value. • Seroconversion is defined as the appearance of antibodies (i.e. titre ≥ cut-off )

in the serum of subjects seronegative before vaccination. • The Geometric Mean Titre (GMT) calculations are performed by taking the

anti-log of the mean of the log-transformed titres. Antibody titres below the cut-off of the assay will be given an arbitrary value of half the cut-off for the purpose of GMT calculation.

February, 2004- Final GlaxoSmithKline Biologicals Study Reporting and Analysis Plan 208136/038 (MEMURU-OKA-038)


1

1 Introduction This Study Reporting and Analysis Plan (StRAP) briefly describes the context of the clinical study 208136/038 (MEMURU-OKA-038), in terms of objectives, endpoints and analysis variables (Section 2) and in terms of study design and procedures (section 3), as stated in the protocol. Subjects (cohorts) included in the analyses are described in Section 4. The final descriptive analyses of demography, safety, reactogenicity and immunogenicity (Section 6) will be based on the 208136/038 (MEMURU-OKA-038) Project Reporting and Analysis Plan (PjRAP). The list of all tables and figures foreseen in this StRAP is provided in Section 6.2.4. Deviations from the Project RAP, due to particularities of the study, are described in the present StRAP. The main characteristic of study MEMURU-OKA-038 is that it is a 2-dose study. This study RAP is limited to the active phase.

2 Study objectives, endpoints and analysis variables

2.1 Objectives

2.1.1 Primary objectives

• To demonstrate the consistency of three production lots of MeMuRu-OKA candidate vaccine in terms of measles, mumps, rubella and varicella seroconversion, 42-56 days after the second dose.

• To demonstrate the non-inferiority of MeMuRu-OKA candidate vaccine to separate administration of Priorix and Varilrix vaccines in terms of measles, mumps, rubella and varicella seroconversion, 42-56 days after the second dose.

2.1.2 Secondary objectives

• To assess the immunogenicity of the study vaccines in terms of antibody titres to each vaccine component, 42-56 days after the second dose.

• To assess the immunogenicity of the study vaccines in terms of seroconversion and antibody titres to each vaccine component, 42-56 days after the first dose.

• To assess the safety of the study vaccines after the first and the second dose.



2

2.2 Primary Endpoints

2.2.1 Active phase of the study

2.2.1.1 Co-primary endpoints

• Measles, mumps, rubella and varicella seroconversion rates at 42-56 days after the second dose.

2.2.1.2 Secondary endpoints

Immunogenicity

• Measles, mumps, rubella and varicella antibody titres at 42-56 days after the first dose and 42-56 days after the second dose.

• Measles, mumps, rubella and varicella seroconversion rates at 42-56 days after the first dose.



3

Safety

• Occurrence of any fever and grade 3 fever (defined as axillary temperature >39.0°C) within 15 days after each vaccination (Day 0-14).

• Occurrence of any and grade 3 solicited local symptoms within 4 days after each vaccination (Day 0-3).

• Occurrence of any and grade 3 solicited general symptoms (fever, rash, any sign of meningitis including febrile convulsion, parotid gland swelling) within 43 days after each vaccination (Day 0-42).

• Occurrence, intensity and relationship to vaccination of unsolicited symptoms within 43 days after each vaccination (Day 0-42).

• Occurrence of SAEs throughout the entire study up to and including 42 days after vaccination.

2.3 Analysis variables

The demographic, reactogenicity and immunogenicity variables are described in Section 3 of the 208136/038 (MEMURU-OKA-038) Project RAP.

3 Study design overview

Visit 1, Day 0 Visit 2, Week 6 Visit 3, Week 12 Visit 4/ Visit 5/ Visit 6/Vaccination 1 Vaccination 2 Year 1* Year 2* Year 3*

Randomisation (1:1:1:1)

Group MeMuRu-OKA lot A (N=120)

Group MeMuRu-OKA lot C (N=120)

Group MeMuRu-OKA lot B (N=120)

Group Priorix + Varilrix (N=120)

Follow-up visits

* Year 1, year 2 and year 3 visits are identified as CPMS N° 208136/039, 208136/040, 208136/041 respectively.



4

• Phase III, randomised (1:1:1:1), controlled study with four parallel groups:

Subjects in Group MeMuRu-OKA lot A will receive two doses of GSK Biologicals’ MeMuRu-OKA vaccine lot A administered at Visit 1/Day 0 and Visit 2/Week 6

Subjects in Group MeMuRu-OKA lot B will receive two doses of GSK Biologicals’ MeMuRu-OKA vaccine lot B administered at Visit 1/Day 0 and Visit 2/Week 6

Subjects in Group MeMuRu-OKA lot C will receive two doses of GSK Biologicals’ MeMuRu-OKA vaccine lot C administered at Visit 1/Day 0 and Visit 2/Week 6

Subjects in Group Priorix + Varilrix will receive one dose of GSK Biologicals’ licensed measles-mumps-rubella vaccine administered concomitantly with one dose of varicella (Varilrix) vaccine at Visit 1/Day 0 and a second dose of Priorix administered at Visit 2/Week 6.

• All vaccines will be administered subcutaneously to healthy infants in their second year of life (6 weeks apart).

• Blinding: The study will be conducted double-blind for Groups MeMuRu-OKA lots A-B-C and open for Groups MeMuRu-OKA lots A-B-C versus Group Priorix + Varilrix.

• Four millilitres (4 mL) of blood will be collected for all subjects at each time point as follows: Pre-vaccination (Visit1/Day 0), post-dose 1 (Visit 2/ Week 6) and post-dose 2 (Visit 3/Week 12). Three additional blood samples will also be collected during the 3-year follow-up period (4 mL of blood sample per year) for the assessment of antibody persistence at Visit 4/Year 1, Visit 5/Year 2 and Visit 6/Year 3.

• The study duration for each subject will be approximately 12 weeks for the active phase of the study and 3 years for the whole study, including the long-term follow-up.

• All subjects should be enrolled within a period of 8 weeks

• Data Collection: Electronic Case Report Forms (eCRF) or Remote Data Entry (RDE).


4 Study cohorts/Datasets to be evaluated

The target population consists of healthy male and female children of 12 to 18 months of age at the time of the first vaccine dose. Subjects older than 18 months may be enrolled in the study if the investigator can ensure these subjects receive the second vaccination planned in the study before the subjects is 24 months old (i.e., before the subject’s second year’s birthday). Inclusion and exclusion criteria are as defined in the protocol (Section 4.2 and 4.3). Proposition for elimination code is annexed.

4.1 Total Vaccinated Cohort

The Total Vaccinated Cohort will includes all vaccinated subjects.



5

• For the total analysis of safety, this will include all subjects with at least one vaccine administration documented.

• For the total analysis of immunogenicity, this will include vaccinated subjects for whom data concerning immunogenicity endpoints are available.

Total vaccinated cohort analyses will be performed per treatment actually administered.

4.2 According-To-Protocol (ATP) Safety Cohort

The protocol-defined cohort for analysis of safety will include subjects: • who have received two doses of study vaccine according to the randomisation list. • who only received vaccine specified or allowed in the protocol protocol, • who have not received a replacement vial (will only apply to MeMuRu-OKA groups),

except if the appropriate vaccine is administered in “double-blind replacement”. • for whom randomization code has not been broken by the investigator (will only to

MeMuRu-OKA groups). • for whom study vaccine dose has been administered according to protocol

(for whom the administration site, side and route of study vaccine(s) is/are known,…)

4.3 According-To-Protocol Immunology Cohort

The protocol-defined cohort for analysis of immunogenicity will include eligible subjects in the protocol-defined cohort for safety: • with blood samples available for pre and post dose 1 or post dose 2 timepoints. Who

complied with all protocol procedures (e.g., the time schedule for post-vaccination blood sample should be between Day 35 and Day 77 after the pre-vaccination blood sample/ previous dose)

• who are seronegative for antibodies to all four antigens (i.e., measles, mumps, rubella and varicella) at baseline (elimination code 2020 if condition is not fulfilled).

• whose post-vaccination serology data are available for at least one of the vaccine antigens and taken within 35-77 days after vaccination.

• who have not received any medication forbidden by the protocol • with no underlying medical condition forbidden by the protocol In practice, the ATP cohort for analysis of immunogenicity will include all vaccinated subjects with no elimination codes beginning with 10XX or 2XXX (with no elimination codes at all). All subjects who are not seronegative for all vaccine antigens before the first vaccination will be excluded from the ATP immunogenicity cohort.

5 Interim Analysis No interim analysis planned.



6

6 Final Analysis

6.1 Changes from the protocol

- Some changes will occur as compared to what was initially planned in the protocol: The Total Vaccinated Cohort includes all vaccinated subjects. For the total analysis of safety, this includes all vaccinated subjects with at least one vaccine administration documented rather than for whom safety data are available as planned in the protocol. Doses documented without any documentation of safety data are considered as doses not followed by any symptoms. Analysis on safety will be based on the Total Vaccinated cohort. In case of significant (5%) non-compliance with study procedures for reporting symptoms, additional analyses will be made excluding all doses for which no data on solicited symptoms are available.

- The Total Vaccinated Cohort is therefore defined to include all subjects enrolled and vaccinated, instead of subjects enrolled for whom data are available. Hence, subjects who did not receive any vaccine dose will not be included in safety nor immunogenicity analysis.

- GMT ratio Post dose 2 over Post dose 1 will be performed as an exploratory analysis. - Fisher’s Exact tests for safety endpoints will be produced as an exploratory analysis. - The verbatim reports of unsolicited symptoms was planned to be coded according to

MedDRA, the Medical Dictinary for Regulatory Activities. As MMRV-038 is the last study for a file that has been used on WHO, the team decide to keep WHO dictionary for this study.

6.2 Final Integrated Study Report

The final analysis will be performed with all data until study conclusion of the active phase period (i.e., until Visit 3 as described in the Outline of study procedures in Section 5.2.1 from the protocol).

The primary analysis of immunogenicity will be based on the ATP cohort. If the percentage of enrolled subjects excluded from this ATP cohort is more than 5%, a second analysis based on the Total vaccinated cohort will be performed to complement the ATP analysis.

All descriptive analyses will be performed by the individual study group (each MeMuRu-OKA lot and Group Priorix+Varilrix) and by vaccine group (pooled MeMuRu-OKA lots compared to Group Priorix+Varilrix).



7

6.2.1 Study cohorts and demography analysis

6.2.1.1 Number of subjects and cohort distribution

The number of subjects and the percentage of subjects included in the Total cohort, ATP safety cohort and ATP immunogenicity cohort will be presented with reasons for elimination (Table 1).

Table 1 : Number of subjects enrolled into the study and the number of subjects excluded from ATP analyses with reasons for exclusion

Title Total % MeMuRu-

OKA – lot A

MeMuRu-OKA –

lot B

MeMuRu-OKA – lot C

Pooled lots

Priorix + Varilrix

Number of subjects planned Subjects or vaccine number not allocated (code 1010) Number of subjects enrolled All vaccine not administered (code 1030) Number of subjects vaccinated (Total Vaccinated cohort)

Study vaccine dose not administered according to protocol (code 1070)

“Reasons for elimination..."(Other Code 1XXX) Number of subjects in the ATP cohort for safety "Reasons for elimination..."(Code 2XXX) Number of subjects in the ATP cohort for immunogenicity

% = percentage of subjects in the considered ATP cohort relative to the Total Vaccinated Cohort. Subjects may have one or more elimination code(s) assigned in which case the lowest code number is listed in the figure. Codes are listed based on a ranking order. Individual subjects' data can be found in Appendix Table IA

In case of more than one reason for elimination (more than one code), the lowest code is chosen for the purpose of this table.



8

6.2.1.2 Number of subjects at each visit and list of dropped-out subjects

For each group, the number of subjects who have dropped out (along with their identification numbers) and the number of subjects who came back at each visit will be described (see Table 2). From an analysis perspective, a “drop-out” is any subject who did not come back for the concluding visit/contact foreseen in the protocol for the active phase of the study. A subject who returns for the concluding visit/contact foreseen in the protocol is considered to have completed the study even if all study procedures (e.g. blood sampling) were not performed.

Table 2 Number of subjects at each visit and list of dropped-out subjects (Total Vaccinated cohort)

Visit 1 Pid Visit 2 Pid Visit 3 MMRV-lot A VC1 VC2 BS3

Number of subjects XX XX XX Dropped-out subject number N°xxx

N°xxx N°xxx

N°xxx

MMRV-lot B


N°xxx N°xxx

N°xxx

MMRV-lot C


N°xxx N°xxx

N°xxx

Priorix + Varilrix


N°xxx N°xxx

N°xxx

Source : Appendix Table I.e Notes : N° = subject identification of drop-out.

VC1= First Vaccination VC2= Second Vaccination BS3= Blood sampling at PI(D84)



9

6.2.1.3 Number of dropped-out subjects and reasons for drop-out

The reasons for drop out are further summarised by group (see Table 3).

The “number of subjects completed” is the number of subjects who completed the last study visit of the active phase. The “number of subjects dropped-out” is the number of subjects who did not come back for the last study visit of the active phase.

Table 3 Number of subjects enrolled completed and dropped-out and reasons for drop-out (Total Vaccinated cohort)

MeMuRu-

OKA- lot A

MeMuRu-OKA- lot B

MeMuRu-OKA- lot C

Pooled lots

Priorix +

Varilrix

Total

Number of subjects enrolled and vaccinated Number of subjects completed Number of subjects dropped-out Reasons for dropped-out: Serious adverse event Non-serious adverse event Protocol violation Consent withdrawal (not due to an adverse event) Migrated/moved from study area Lost to follow-up (subjects with incomplete vaccination course)

Lost to follow-up (subjects with complete vaccination course)

Others Enrolled = number of subjects who where enrolled in the study Completed = number of subjects who completed the last study visit Dropped-out = number of subjects who did not come back for the last visit Individual subjects data can be found in Appendix Table IE



10

6.2.1.4 Compliance with respect to documenting safety

The number of doses injected, the number of doses not given according to protocol, the number of symptom sheets (SS) transcribed for solicited local and general symptoms and the compliance for solicited local and general symptoms will be tabulated by group for the Total Vaccinated Cohort (see Table 4).

Compliance is defined as the number of general (local) symptom sheets completed divided by the number of doses administered for a specified vaccination (dose) and group. Doses not given according to protocol are those injected at the wrong site and/or side, or injected using the wrong route as defined in each study protocol for each study vaccine. This number is issued from the following question in the vaccine administration sheet of the CRF: “Has the study vaccine been administered according-to-protocol?” Note that subjects who received the study vaccines at the wrong side will not be excluded from the ATP analyses. Table 4 Number of doses and compliance with respect to documenting safety

(Total Vaccinated cohort)

Dose Group Number

of Doses

Doses NOT

according to protocol*

Number of

general SS

Compliance (%)

general

Number of

local SS

Compliance (%) local

1 MeMuRu-OKA-lot A MeMuRu-OKA-lot B MeMuRu-OKA-lot C Pooled MMRV lots Priorix + Varilrix 2 MeMuRu-OKA-lot A MeMuRu-OKA-lot B MeMuRu-OKA-lot C Pooled MMRV lots Priorix + Varilrix Total MeMuRu-OKA-lot A MeMuRu-OKA-lot B MeMuRu-OKA-lot C Pooled MMRV lots Priorix + Varilrix Notes : SS=Symptom Sheet Compliance % = (number of SS / number of doses)x100 *The number of doses not given according to protocol is issued from the following question in the vaccine administration sheet of the CRF: "Has the study vaccine been administred according-to-protocol?"



11

6.2.1.5 Deviations from specifications for age and intervals between study visits.

The age at vaccination/enrolment and the intervals between visits (42-56 days) defined in the protocol should be followed as closely as possible. However this does not necessarily lead to the exclusion of the subject(s) from analysis. An adapted window between day 35 to day 77 after vaccination will actually be used for exclusion from the ATP immunogenicity cohort.

For each group, the number and percentage of subjects (with a list of these subjects ) being out of the limits defined above will be provided (see Table 5). In addition, this table will include the minimum and maximum values for subjects out of the limits and the number of subjects with missing values.

Note that the denominator used to calculate the percentage is for: - AGE: the number of enrolled subjects and - between visits: the number of subjects coming back for the 2 considered visits. In addition, the table reports the minimum and maximum values for subjects out of the limits. Table 5 Deviations from protocol specifications for age and intervals between

study visits (Total Vaccinated cohort)

Group

Age VC_1-VC_2 VC_2-BS_3 Protocol Adapted Protocol Adapted Protocol Adapted from 12 to 18 M

from 12 to 21.5 M

from 42 to 56 D

from 35 to 77 D

from 42 to 56 D

from 35 to 77 D

MeMuRu-OKA- lot A

n=x subjects (from xx to xx M)

n=x subjects (from xx to xx M)

n=x subjects (from xx to xx D)

n=x subjects (from xx to xx D)

… …

xx% of xx xx% of xx xx% of xx xx% of xx … … (xxx subjects with

empty value) (xxx subjects with



empty value) … …

MeMuRu-OKA- lot B

… … … … … …

… … … … … … … … … … … …

MeMuRu-OKA- lot C

… … … … … …

… … … … … … … … … … … …

Priorix + Varilrix

… … … … … … … … … … … … … … … … … …

VC = Vaccination Visit BS = Post vaccination blood sampling D = Days, M= Months n = number of subjects out of the specified interval. % = proportion of subjects out of the specified interval among subjects present at the considered visits. % (for age) = proportion of subjects out of the specified interval using as denominator the number of subjects enrolled. Individual subjects data can be found in Appendix Table IC



12

An additional table such as Working Table 1 provides, for each visit, the earliest and latest date among all subjects. Working Table 1: Minimum and maximum visit dates

Total Vaccinated Cohort Visit number Activity

Number Minimum Date Maximum Date

1 10 ddmmyy ddmmyy 2 20

… … Source : Appendix Table I.C Interval between the 2 doses will be tabulated (see working table 2) Working Table 1: Interval between 2 doses (Days)-Total Vaccinated cohort

Each Group Total

Parameters or (N =XXX) (N =XXX)

Characteristics Categories Value Value

Interval between 2 doses

Mean

(days) SD Median Minimum Maximum Unknown

Source : Appendix Table I.C Treatment Groups : Group 1 =… Notes : N= total number of subjects by group or in total (sum for all groups) Value = value of the considered parameter SD= standard deviation

6.2.1.6 Number of subjects by country

The number and percentage of subjects enrolled by group, by country will be tabulated (see Table 6) in order to check the randomization ratio by country.

Table 6 The number of subjects enrolled at each country by group (Total Vaccinated cohort)

Center

MeMuRu-OKA- lot A (N=)

MeMuRu-OKA- lot B (N=)

MeMuRu-OKA- lot C (N=)

Priorix + Varilrix (N=)

Total (N =)

n n n n n % Germany Austria

Source : Appendix Table I.b Notes: N = number of subjects in the Total Cohort

n / % = number / percentage of subjects by country



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6.2.2 Demography

6.2.2.1 Summary of demographic characteristics

Main demographic characteristics (age descriptive statistics, gender and racial distribution) of the studied cohort will be presented. According to the primary objective of the study, only the table of the associated cohort will be included in the core of the clinical report (i.e. ATP cohort of immunogenicity). Table 7 Summary of demographic characteristics (ATP immunogenicity cohort)

Characteristics

Parameters or Categories

MeMuRu-OKA-lot A

MeMuRu-OKA-lot B

MeMuRu-OKA-lot C

Priorix + Varilrix Total

N= N= N= N= N= Value or n

% Value or n

% Value or n % Value

or n % Value or n

%

Age (Months)

Mean - - - - SD - - - -

Median - - - - Minimum - - - - Maximum - - - -

Gender Male Female

Race White Black

Oriental Other

Unknown Source : Appendix Table I.b Notes: N = total number of subjects

n = number of subjects in a given category Value = value of the considered parameter % = n / Number of subjects with available results x 100 SD= standard deviation



14

6.2.3 Immunogenicity analysis

6.2.3.1 Summary of immunogenicity

6.2.3.1.1 Pre-vaccination serological status

The number and percentage of subjects initially (i.e., before the first vaccination) seropositive (subjects with titers ≥ cut-off), seronegative (subjects with titers < cut-off) and with unknown status (blood sample not available or not tested) will be summarized by vaccine antigen (see Table 8). Table 8 Initial serological status before dose 1 – Total Vaccinated cohort

Antibody Pre-vacc. Status

MeMuRu-OKA- lot A (N= )

MeMuRu-OKA- lot B (N= )

MeMuRu-OKA- lot C (N= )

MeMuRu pooled lots

(N= )

Priorix + Varilrix

(N= )

Total (N=)

n % n % n % n % n % n % Anti-Measles S-

S+ Unknown

Anti-Mumps S- S+ Unknown

Anti-Rubella S- S+ Unknown

Anti-Varicella S- S+ Unknown

Source : Appendix Table III.a Notes : N = number of subjects in the selected cohort regardless of whether there is a result (sum of S-, S+ and Unknown).

S-/S+ = seronegative/seropositive subjects at prevaccination. n = number of subjects with the considered prevaccination status. % = n / (seronegative + seropositive). Total = sum on all groups. Cut-off values: Measles: 150 mIU/ml, Mumps: 231 U/ml, Rubella: 4 IU/ml, Varicella: 4 [dil-1]



15

6.2.3.1.2 Anti-(antigen) Seroconversion/seropositivity rates and GMTs (calculated on all subjects) for initially seronegative subjects

For initially seronegative subjects, GMTs and seroconversion/seropositivity rates will be calculated, for each group, at Day 0 (pre-vaccination) at Day 42 and at Day 84 post vaccination. Day 0 GMTs will only be calculated for the total vaccinated cohort since all subjects within the ATP cohort are initially seronegative for all antigens. These descriptive statistics will be tabulated with their 95% confidence interval (CI) (see Table 9).

GMTs will be computed on all subjects by giving an arbitrary value of half the cut-off for non-detectable titers. The 95% CI limits for GMTs are calculated by taking the antilog of the 95% confidence interval limits of the mean log10 antibody titre. These latter limits are calculated under the assumption of normal distribution of the log10 antibody titre but unknown variance.

Table 9 Anti-(antigen) seroconversion/seropositivity rates and GMTs (calculated on all subjects) in initially seronegative subjects - ATP cohort for immunogenicity

Seroconversion/

seropositivity GMTs (unit) MIN MAX

95% CI 95% CI Antibody Group Timing N n % LL UL GMT LL UL

antigen MeMuRu-OKA-lot A

PRE PI(D42) PII(D84)

MeMuRu-OKA-lot B


MeMuRu-OKA-lot C


MeMuRu-OKA pooled lots


Priorix+ Varilrix


Source: Appendix Table III.a Notes: N = number of subjects n / % = number / percentage of subjects with the specified pre-vaccination serological status LL/UL=lower/upper limit of 95%CI. Min=Minimum, Max=Maximum. Cut-off values: Measles: 150 mIU/ml, Mumps: 231 U/ml, Rubella: 4 IU/ml, Varicella: 4 [dil-1].



16

6.2.3.2 Antibody titers distribution

6.2.3.2.1 Distribution of individual antibody titers in initially seronegative subjects

The distribution of antibody titres will be tabulated as the number and the proportion of subjects with antibody titers equal to or higher than pre-specified limits, for each group and each timepoint (see Table10, Table 11, Table12 and Table 13). The limits that will be used are the following:

- Varicella : 4, 8, 16, 32, 64, and 128 - Measles : 150, 300, 600 and 1200 - Mumps : 231, 460 and 920 - Rubella : 4, 10, 16, 32 and 64

Only initially seronegative subjects, for the studied vaccine component, will be considered.

The denominator used to calculate the proportion is the number of subjects with available results for the specified vaccine component. Table 10 Distribution of anti-measles antibody titre in initially seronegative

subjects - ATP cohort for immunogenicity

Group Timing N <150 mIU/mL >=150 mIU/mL >=300 mIU/mL

>=600 mIU/mL

>=1200 mIU/mL

n % n % n % n % n % MeMuRu-OKA-

lot A PI(D42) PII(D84)

MeMuRu-OKA-lot B

PI(D42) PII(D84)

MeMuRu-OKA-lot C

PI(D42) PII(D84)

MeMuRu-OKA-pooled

lots

PI(D42) PII(D84)

Priorix + Varilrix

PI(D42) PII(D84)

Source: Appendix Table III.a Notes: N = number of subjects with available data n / % = number / percentage of subjects with specified pre-vaccination status within the specified range PI(D42) = post-vaccination blood sample at Day 42 PII(D84) = post-vaccination blood sample at Day 84



17

Table 11 Distribution of anti-mumps antibody titre in initially seronegative

subjects - ATP cohort for immunogenicity

Group Timing N <231 U/mL >=231 U/mL >=460 U/mL >=920 U/mL n % n % n % n %

MeMuRu-OKA-lot A

PI(D42) PII(D84)

MeMuRu-OKA-lot B

PI(D42) PII(D84)

MuMuRu-OKA-lot C

PI(D42) PII(D84)

MeMuRu-OKA-pooled

lots

PI(D42) PII(D84)

Priorix + Varilrix

PI(D42) PII(D84)

Source: Appendix Table III.a Notes: N = number of subjects with available data

n / % = number / percentage of subjects with specified pre-vaccination status within the specified range PI(D42) = post-vaccination blood sample at Day 42 PII(D84) = post-vaccination blood sample at Day 84

Table 12 Distribution of anti-rubella antibody titre distribution in initially seronegative subjects - ATP cohort for immunogenicity

Group Timing N <4 IU/mL >=4 IU/mL >=10 IU/mL >=16 IU/mL >=32 IU/mL >=64 IU/mL n % n % n % n % n % n %

MeMuRu-OKA -lot A

PI(D42) PII(D84)

MeMuRu-OKA -lot B

PI(D42) PII(D84)

MeMuRu-OKA -lot C

PI(D42) PII(D84)

MeMuRu-OKA-pooled

PI(D42) PII(D84)

Priorix + Varilrix

PI(D42) PII(D84)

Source: Appendix Table III.a Notes: N = number of subjects with available data n / % = number / percentage of subjects with specified pre-vaccination status within the specified range PI(D42) = post-vaccination blood sample at Day 42 PII(D84) = post-vaccination blood sample at Day 84



18

Table 13 Distribution of anti-varicella antibody titre initially seronegative subjects

- ATP cohort for immunogenicity

Group Timing N <4 Dil-1 >=4 Dil-1 >=8 Dil-1 >=16 Dil-1 >=32 Dil-1 >=64 Dil-1 >=128 Dil-1

n % n % n % n % n % n % n % MeMuRu-OKA -

lot A PI(D42) PII(D84)

MeMuRu-OKA -lot B

PI(D42) PII(D84)

MeMuRu-OKA -lot C

PI(D42) PII(D84)

MeMuRu-OKA-pooled

PI(D42) PII(D84)

Priorix + Varilrix

PI(D42) PII(D84)

Source: Appendix Table III.a Notes: N = number of subjects with available data

n / % = number / percentage of subjects with specified pre-vaccination status within the specified range PI(D42) = post-vaccination blood sample at Day 42 PII(D84) = post-vaccination blood sample at Day 84

6.2.3.2.2 Reverse cumulative curves for anti- (each vaccine antigen) antibody concentrations in initially seronegative subjects

Distribution of antibody titers at Day 42 (post dose 1) and Day 84 (post dose 2) will also be presented graphically using reverse cumulative curves

- for each consistency lots and at Day 84 (post dose 2) as working figure.

- for the pooled lots versus Priorix + Varilrix group at Day 42 (post dose 1) and Day 84 (post dose 2).

As for distribution table, only initially seronegative subjects will be considered (see Figure 1).

Figure 1: anti-(antigen) Reverse Cumulative Curve post dose X (ATP immunogenicity).

Source: Appendix Table III.a Treatment: Group 1 = MeMuRu-OKA pooled Group MMR_V = Priorix + Varilrix



19

6.2.3.2.3 Evaluation of primary objectives

Consistency between MeMuRu-OKA lots Beside the tables and figures described below, the MeMuRu-OKA lot-to-lot consistency 42-56 days after the second dose will be demonstrated by showing that the seroconversion rates of the three MeMuRu-OKA lots (Groups A, B, C) are clinically equivalent. This will be achieved by computing the 90% CI for each pairwise MeMuRu-OKA lot differences using standardized asymptotic CI for the difference of 2 proportions in StatXact (%SP_CI standard SAS macro). If, for each antigen, the CI for all pairwise differences is included in [-10%,+10%], it will be concluded that the 3 production lots of MeMuRu-OKA are consistent in terms of immunogenicity (see Table 14).

Table 14 Difference between the 3 MeMuRu-OKA production lots in terms of measles, mumps, rubella and varicella seropositivity rates 42 days after the second dose - ATP cohort for immunogenicity

Difference in seropositivity rates S+ S+ Value 90% CI Group N % Group N % Groups % LL UL

Measles MeMuRu-OKA- lot A MeMuRu-OKA -lot B MeMuRu-OKA- lot A minus MeMuRu-OKA-lot B MeMuRu-OKA -lot A MeMuRu-OKA -lot C MeMuRu-OKA- lot A minus MeMuRu-OKA-lot C MeMuRu-OKA- lot B MeMuRu-OKA -lot C MeMuRu-OKA- lot B minus MeMuRu-OKA-lot C

Mumps MeMuRu-OKA- lot A MeMuRu-OKA -lot B MeMuRu-OKA- lot A minus MeMuRu-OKA-lot B MeMuRu-OKA -lot A MeMuRu-OKA -lot C MeMuRu-OKA- lot A minus MeMuRu-OKA-lot C MeMuRu-OKA- lot B MeMuRu-OKA -lot C MeMuRu-OKA- lot B minus MeMuRu-OKA-lot C

Rubella MeMuRu-OKA- lot A MeMuRu-OKA -lot B MeMuRu-OKA- lot A minus MeMuRu-OKA-lot B MeMuRu-OKA -lot A MeMuRu-OKA -lot C MeMuRu-OKA- lot A minus MeMuRu-OKA-lot C MeMuRu-OKA- lot B MeMuRu-OKA -lot C MeMuRu-OKA- lot B minus MeMuRu-OKA-lot C

Varicella MeMuRu-OKA- lot A MeMuRu-OKA -lot B MeMuRu-OKA- lot A minus MeMuRu-OKA-lot B MeMuRu-OKA -lot A MeMuRu-OKA -lot C MeMuRu-OKA- lot A minus MeMuRu-OKA-lot C MeMuRu-OKA- lot B MeMuRu-OKA -lot C MeMuRu-OKA- lot B minus MeMuRu-OKA-lot C

Source: Appendix III.A N = number of subjects with available results % = percentage of subjects with titer >=cut-off (seroconversion) CI = standardized asymptotic confidence interval, LL = lower limit, UL = upper limit S+ = seropositive subjects



20

Exploratory analysis As supportive analysis to demonstrate lot-to-lot consistency, the 90% CI for GMT ratios between groups will also be computed using a one-way ANOVA model on the logarithm 10 transformation of the titres. The ANOVA model will be adjusted to data from groups A, B & C only and will include the vaccine group effect. The GMT ratio will be derived from the contrast on the vaccine group effect (%BIOGMT standard SAS macro) (see Table 15) .

Table 15 GMT ratios between the 3 MeMuRu-OKA lots for measles, mumps,

rubella and varicella antibody titers 42 days after the second dose - ATP cohort for immunogenicity

GMT ratio Value 90% CI Group N GMT Group N GMT Groups LL UL

Measles MeMuRu-OKA- lot A MeMuRu-OKA -lot B MeMuRu-OKA- lot A over MeMuRu-OKA-lot B MeMuRu-OKA -lot A MeMuRu-OKA -lot C MeMuRu-OKA- lot A over MeMuRu-OKA-lot C MeMuRu-OKA- lot B MeMuRu-OKA -lot C MeMuRu-OKA- lot B over MeMuRu-OKA-lot C

Mumps MeMuRu-OKA- lot A MeMuRu-OKA -lot B MeMuRu-OKA- lot A over MeMuRu-OKA-lot B MeMuRu-OKA -lot A MeMuRu-OKA -lot C MeMuRu-OKA- lot A over MeMuRu-OKA-lot C MeMuRu-OKA- lot B MeMuRu-OKA -lot C MeMuRu-OKA- lot B over MeMuRu-OKA-lot C

Rubella MeMuRu-OKA- lot A MeMuRu-OKA -lot B MeMuRu-OKA- lot A over MeMuRu-OKA-lot B MeMuRu-OKA -lot A MeMuRu-OKA -lot C MeMuRu-OKA- lot A over MeMuRu-OKA-lot C MeMuRu-OKA- lot B MeMuRu-OKA -lot C MeMuRu-OKA- lot B over MeMuRu-OKA-lot C

Varicella MeMuRu-OKA- lot A MeMuRu-OKA -lot B MeMuRu-OKA- lot A over MeMuRu-OKA-lot B MeMuRu-OKA -lot A MeMuRu-OKA -lot C MeMuRu-OKA- lot A over MeMuRu-OKA-lot C MeMuRu-OKA- lot B MeMuRu-OKA -lot C MeMuRu-OKA- lot B over MeMuRu-OKA-lot C

Source: Appendix III.A N = number of subjects with available results 90%CI= 90% confidence interval, LL/UL = lower/upper limit of 90%CI GMT ratio was calculated using a one-way ANOVA model on log-transformed antibody titers.



21

Non-inferiority of the MeMuRu-OKA candidate vaccine vs Priorix + varilrix The second co-primary objective consists in showing that the pooled MeMuRu-OKA lots (i.e., groups A, B, C) are not clinically inferior to Priorix+Varilrix group (separate injections of Priorix and Varilrix) in terms of seroconversion rates at 42-56 days after the second dose. For each of the antigens, the 95% CI for treatment difference will be computed using standardized asymptotic CI for the difference of 2 proportions in StatXact (%SP_CI standard SAS macro) (see Table 16).

If for each antigen, the lower limit of the CI for treatment difference (‘MeMuRu-OKA pooled lots’ minus 'Priorix+Varilrix’) is [-10%] or higher, it will be concluded that the immunogenicity in MeMuRu-OKA groups is clinically non-inferior to the immunogenicity in the group receiving Priorix and Varilrix vaccines concomitantly. This criterion is only applicable as long as the consistency criterion has been met.

Table 16 Anti-(antigens) seropositivity rate difference between pooled MeMuRu-OKA lots and Priorix + Varilrix 42-56 days after dose 2 in initially (before dose 1) seronegative subjects - ATP Immunogenicity Cohort

Pooled MeMuRu-OKA lots Priorix + Varilrix

Difference Pooled MeMuRu-OKA lots minus

Group Priorix+ Varilrix

Endpoints N S+ (%) N S+ (%) Value (%)

95% CI LL UL

Anti-measles Anti-mumps Anti-rubella Anti-varicella

Source: Appendix Table III.a Notes: N = number of subjects with available results S+ (%) = Seropositivity rate (percentage of subjects with titer >=cut-off) CI = standardized asymptotic confidence interval; LL = Lower Limit; UL = Upper Limit



22

Exploratory analysis Finally and as long as consistency criteria is met, the 95% CI for GMT ratio between pooled MeMuRu-OKA lots and the Priorix+Varilrix group will be computed using a one-way ANOVA model on the logarithm 10 transformation of the titres. The ANOVA model will include the vaccine group effect (see Table 17).

The GMT ratio will be derived from the contrast on the vaccine group effect (%BIOGMT standard SAS macro).

Table 17 Anti-(antigens) GMT ratios between between MeMuRu-OKA pooled lots and Priorix + Varilrix 42-56 days after dose 2 in initially (before dose 1) seronegative subjects - ATP immunogenicity cohort

Pooled MeMuRu-OKA lots* Priorix+ Varilrix

Ratio Pooled MeMuRu-OKA lots over


Endpoints N GMT N GMT Value 95% CI LL UL


Source: Appendix III Note: GMT ratio was calculated using a one-way ANOVA model on log-transformed antibody titers



23

6.2.3.2.4 Evaluation of secondary objectives

Immunogenicity • Seroconversion after the first vaccine dose for each of the vaccine components: measles,

mumps, rubella and varicella. In addition to the descriptive tables and graphs depicted in the Project RAP and presented previously (see section 6.2.3.1.2), the 95% CI for the difference in seroconversion rates between the vaccine groups (MeMuRu-OKA pooled lots versus Priorix + Varilrix) will be computed using standardized asymptotic CI for the difference of 2 proportions in StatXact (%SP_CI standard SAS macro) (see Table 18).

Table 18 Anti-(antigen) seroconversion rate difference between pooled MeMuRu-

OKA lots and Priorix + Varilrix 42-56 days after dose 1 in initially seronegative subjects - ATP Immunogenicity Cohort

Pooled MeMuRu-OKA lots Priorix + Varilrix

Difference Pooled MeMuRu-OKA lots minus


Endpoints N SC (%) N SC (%) Value 95% CI LL UL


Source: Appendix Table III.a Notes: N = number of subjects with available results SC (%) = Seroconversion rate (percentage of subjects with titer >=cut-off) CI = standardized asymptotic confidence interval; LL = Lower Limit; UL = Upper Limit • Anti-measles, mumps, rubella and varicella titres after the first vaccine dose.

After the first vaccine dose, the 95% CI for GMT ratio between groups (group A and B) will be computed using a one-way ANOVA model on the logarithm 10 transformation of the titres. The ANOVA model will include the vaccine group effect. The GMT ratio will be derived from the contrast on the vaccine group effect (%BIOGMT standard SAS macro) (see Table 19).



24

Table 19 Anti-(antigens) GMT ratio between MeMuRu-OKA pooled lots and Priorix + Varilrix 42-56 days after dose 1 in initially (before dose 1) seronegative subjects - ATP immunogenicity cohort

Pooled MeMuRu-OKA lots* Priorix+ Varilrix

Ratio Pooled MeMuRu-OKA lots over


Endpoints N GMT N GMT Value 95% CI LL UL


Source: Appendix III Note: GMT ratio was calculated using a one-way ANOVA model on log-transformed antibody titers LL/UL=lower/upper 95%CI *For the pooled MMRV group, the GMT ratio is derived as the geometric mean of the 3 individual GMT ratios

• In addition to what was described in the protocol, the Geometric Means of the ratio of

post-dose 2 over post-dose 1 and their 95% CI will be tabulated by group. These calculations will be done for subjects who seroconverted after dose 1, assuming a log-normal distribution of titers (%GMRTIM SAS macro).

Table 20 Anti-(antigen) GM ratio of post-dose 2 over post-dose 1 titer in

seroconverters post dose 1- ATP immunogenicity cohort

Dose 1 Dose 2 Dose 2 / Dose 1 Antigen Group N Timepoint GMT Timepoint GMT 95% CI

Ratio LL UL MeMuRu-OKA

Pooled lots PI(d42) PII(d84)

Priorix + Varilrix

PI(d42) PII(d84)

Source: Appendix III Note: N = Number of subjects with serological data available at both Dose 1 and Dose 2

LL/UL=lower/upper 95%CI



25

• In addition to what was described in the protocol, the seroconversion rate and GMTs will

be calculated, for each group after post-dose 2, at day 84 post vaccination for subjects who were still seronegative after dose 1.

Table 21 Anti-(antigen) seroprotection/seropositivity rates and GMT (calculated

on all subjects) in seronegative subjects after dose 1- ATP cohort for immunogenicity

Seroconversion/

seropositivity GMTs (unit) MIN MAX

95% CI 95% CI Antibody Group Timing N n % LL UL GMT LL UL

antigen MeMuRu-OKA-lot A


MeMuRu-OKA-lot B


MeMuRu-OKA-lot C


MeMuRu-OKA pooled lots


Priorix+ Varilrix


Source: Appendix Table III.a Notes: N = number of subjects n / % = number / percentage of subjects with the specified pre-vaccination serological status S- = initially seronegative LL/UL=lower/upper limit of 95%CI. Min=Minimum, Max=Maximum. Cut-off values: Measles: 150 mIU/ml, Mumps: 231 U/ml, Rubella: 4 IU/ml, Varicella: 4 [dil-1].

Presentation for the clinical report

Immunogenicity results will be presented in 2 different sections:

- First part will present the consistency between the 3 MeMuRu-OKA lots. So, in this section, the 3 consistency lots will be kept separately.

- Second part will present the non inferiority between MeMuRu-OKA pooled lots versus Priorix+Varilrix. So, the 3 lots will not be kept and only one pooled group will be presented.



26

Safety

All analyses will be done by dose, for each MeMuRu-OKA lot, for the pooled MeMuRu-OKA lots group and for the Priorix+Varilrix group. Graph presented in the Project RAP will be done for pooled MeMuRu-OKA lots group and Priorix+Varilrix group only. Beside the tables described in the Project RAP and summarized in section 6.2.4, the difference between groups (for each lot first and then, for pooled MeMuRu-OKA lots versus Priorix+Varilrix group) will be explored using a two-sided Fisher’s Exact Test on the following endpoints (if consistency objective is reach):

- Incidence of grade 3 fever (defined as rectal temperature >39.5°C) within 15 days after vaccination (Days 0-14);

- Incidence of any fever (defined as rectal temperature ≥38.0°C) within 15 days after vaccination (Days 0-14);

- Incidence of each solicited local symptoms (Redness, Swelling and Pain, globally whatever the injection site) within 4 days after vaccination (Days 0-3);

- Incidence of generalized rash within 43 days after vaccination (Days 0-42); Statistically significant differences (p-value <0.05) should be interpreted with caution due to the number of endpoints, since the differences observed in this study are likely to occur by chance alone.

Dictionary to be used for the reporting of adverse events: In view of the file preparation and the likelihood of pooling AEs results of MMRV 038 with other earlier MMRV studies (007, 013, 018, 022). WHO dictionary will be used for the recording of adverse event in this study.

6.2.4 List of tables and figures

In the following summary of tables and figures to be included in the analysis (already described in the Project Rap), the following abbreviations are used: CR = Core Report, ST = Supplement Table, WT = Working Table, App. = Appendix.

Denomination Total Vaccin

ated

ATP Safety

ATP Immuno

Macro

4.1 Study cohorts and demography analysis

4.1.1 Study Cohorts

4.1.1.1 Number of subjects and cohorts definition CR %ELIMLIST

4.1.1.2 Number of subjects at each visit and list of dropped-out subjects

WT %DROPOUT

4.1.1.3 Number of dropped-out subjects and reasons for drop-out CR %DROP_SUM

4.1.1.4 Compliance with respect to documenting safety1 ST WT %COMPLI

4.1.1.5 Deviations from specifications for age1 and intervals between study visits

WT %INT_VAL

4.1.1.6 Number of subjects by center ST %BLOCK_CK

4.1.2 Demography

4.1.2.1 Summary of demographic characteristics1 ST ST CR %DEMOGRA

4.1.3 Individual Data Listings* App.

NOTE: CR = Core Report, ST = Supplement Table, WT = Working Table, App. = Appendix 1 : by dose



27

If less than 5% of the vaccinated subjects are excluded from the ATP safety cohort, results on the ATP safety cohort will be considered as Working tables.


ated

ATP Safety

ATP Immuno

Macro

4.2 Reactogenicity / Safety analysis

4.2.1 Exposure to the vaccination

4.2.1.1 Number and percentage of subjects who received vaccine dose(s)1

ST

%EXPO

4.2.2 All Symptoms

4.2.2.1 Incidence and nature of reported (solicited and unsolicited) symptoms (Day 0 to day 42)1

CR ST %LOCGEN

4.2.2.2 Follow-up duration (days) distribution1 WT WT %FU_DUR

4.2.3 Solicited Local Symptoms

4.2.3.1 Incidence of solicited local symptoms after vaccination (Day 0 to day 3) 1

CR ST %FREQ

4.2.3.2 Incidence of grade 3 solicited local symptoms after vaccination (Day 0 to day 3) 1

CR ST %FREQ

4.2.4 Solicited General Symptoms

4.2.4.1 Incidence of fever after vaccination (Day 0 to day 14) 1

Incidence of fever causally related after vaccination (Day 0 to day 14)

Incidence of fever with medical advice after vaccination (Day 0 to day 14)

Incidence of fever per half degree (Day 0 to Day 14)

Incidence of fever after vaccination (Day 0 to day 42) 1

Incidence of fever causally related after vaccination (Day 0 to day 42)

Incidence of fever with medical advice after vaccination (Day 0 to day 42)

CR

ST

ST

ST

ST

ST

ST

ST

ST

%FREQ

4.2.3.2 Number of days with any fever (Day 0 to day 42) 1

Number of days with grade 3 fever (Day 0 to day 42) 1

WT

ST

%FEV_NDAY

4.2.3.3 Prevalence of any fever by day (Day 0 to day 42) 1

Prevalence of grade 3 fever by day (Day 0 to day 42) 1

ST

ST

%SYMPLOT

4.2.3.4 Incidence of generalized rash after vaccination (Day 0 to 42) 1 ST WT %RAS_INC

4.2.3.5 Number of days with generalized rashes (Day 0 to day 42)1 WT %RAS_NDAY

4.2.3.6 Prevalence of generalized rash by day after vaccination (Day 0 to day 42) 1

ST %SYMPLOT

New Differences in safety between pooled MeMuRu-OKA lots and Varilrix+Priorix1

ST

4.2.4 Unsolicited Symptoms

4.2.4.1 Incidence of unsolicited symptoms after vaccination (Day 0 to day 42) by body system and preferred term1

Incidence of unsolicited symptoms grade 3 after vaccination (Day 0 to day 42) by body system and preferred term1

Incidence of unsolicited symptoms after vaccination (Day 0 to day 42) considered to be related to the vaccination by body system and preferred term1

ST

CR

CR

%UNSOL



28


ated

ATP Safety

ATP Immuno

Macro

4.2.6 Concomitant medications/vaccinations 4.2.6.1 Number and percentage of subjects who took at least one

concomitant medication by type (Day 0 to day 42) 1 ST %CMED_INC

4.2.6.2 Number and percentage of subjects who took at least one medication before vaccination1

WT %CMED_INC

4.2.6.4 Percentage of subjects who took antipyretic by day after vaccination (Day 0 to day 42) 1

ST %PYR_PRVD

4.2.7 Individual Data Listings App.

NOTE: CR = Core Report, ST = Supplement Table, WT = Working Table, App. = Appendix 1: by dose 2: by dose and overall

If less than 5% of the vaccinated subjects are excluded from the ATP immunogenicity cohort, results on the vaccinated cohort will be considered as Working tables.

Denomination Total ATP Safety

ATP Immuno

Macro

4.3 Immunogenicity analysis

4.3.1 Summary of antibody titres level 4.3.1.1 Prevaccination serological status

- dose 1 - dose 2

ST WT

CR WT

%STATUSBV %STATUSBV

4.3.1.2 Seroconversion / Seropositivity rates and Anti-(each vaccine antigen) GMTs1

ST CR %GMT

4.3.1.3 Seroconversion rates to all 4 MeMuRu-OKA components by group Not requested (?)

New Seroconversion rate difference between MeMuRu-OKA lots

ST CR %SP_CI

New Measles, Mumps, Rubella and Varicella GMT's ratio between MeMuRu-OKA lots

ST CR %BIOGMT

New Seroconversion rate difference between pooled MeMuRu-OKA lots and Priorix +Varilrix 2

ST CR %SP_CI

New GMT's ratio between pooled MeMuRu-OKA lots and Priorix +Varilrix 2

ST CR %BIOGMT

New GM ratio of post-dose 2 over post-dose 1 titer for anti-measles <Mumps, Rubella, Varicella> in post-dose 1 seropositive subjects

ST ST %GMRTIM

New Seroconversion rate and GMT for each anti-(antigen) for seronegative subjects after dose 1

ST ST %GMT

4.3.2 Antibody titres distribution 4.3.2.1 Distribution of individual anti-(each vaccine antigen)

antibody concentrations2 ST ST %DIS

4.3.2.2 Reverse cumulative curves for anti- (each vaccine antigen) antibody concentrations2

ST ST %REVCUM

4.3.3 Individual Data Listings App.

NOTE: CR = Core Report, ST = Supplement Table, WT = Working Table, App. = Appendix 1: Seroconversion after dose 1 and Seropositivity after dose 2 on initially (before dose 1) seronegative subjects 2: on initially (before dose 1) seronegative subjects and by dose.

Final Study ReportAnnex 1

( )

MeMuRu-OKA-038208136/038

August 2005

CONFIDENTIAL

- 1 –CARS Id : CLIN_200409_285/ Version : 1.5,Admin. QC/ Modify Date : 29/09/2005


Study Title: A phase III, randomized, controlled study to evaluate theimmunogenicity and safety of three production lots of GlaxoSmithKline Biologicals’combined measles-mumps-rubella-varicella (MeMuRu-OKA) candidate vaccine givenon a two-dose schedule to healthy children in their second year of life, as compared toseparate administration of GlaxoSmithKline Biologicals’ measles-mumps-rubellavaccine (Priorix®) and varicella vaccine (Varilrix®).

This report presents the analysis of mumps antibodies by neutralisation assay 42days after each vaccination.

Clinical Study Report Annex 1 for Study208136/038 (MeMuRu-OKA-038)(Development Phase III)

Indication Studied: Active immunization of healthy children during their secondyear of life against measles, mumps, rubella and varicella diseases

Study Initiation Date: 16 July 2003

Study Completion Date: 09 January 2004

Date of Annex Report August 2005

Earlier Clinical StudyReport (Main Report)

28 April 2004

Sponsor Signatory: MD.Clinical Research and DevelopmentGlaxoSmithKline Biologicals

This study was performed in compliance with Good Clinical Practices including thearchiving of essential documents.

Copyright 2002 the GlaxoSmithKline group of companies. All rights reserved.Unauthorised copying or use of this information is prohibited.

CONFIDENTIAL 208136/038Annex 1


SynopsisName of Company: GlaxoSmithKlineBiologicals, Rixensart, BelgiumName of Finished Product:Name of active substance: Live attenuatedmeasles, mumps, rubella and varicellavaccine

TABULAR FORMATREFERRING TO PART OFTHE DOSSIERVolume:Page:

(for national authorityonly)

Title of the study : A phase III, randomized, controlled study to evaluate the immunogenicity and safety ofthree production lots of GlaxoSmithKline Biologicals’ combined measles-mumps-rubella-varicella(MeMuRu-OKA) candidate vaccine given on a two-dose schedule to healthy children in their second year oflife, as compared to separate administration of GlaxoSmithKline Biologicals’ measles-mumps-rubellavaccine (Priorix®) and varicella vaccine (Varilrix®).This report presents the analysis of mumps antibodies by neutralisation assay 42 days after eachvaccination.Principal Investigators: Prof. Dr. Germany; Dr.

Austria; Dr. Austria; Dr. Austria & Dr.

Austria.Study Centre(s): Multiple centres in Germany and Austria.Publication (reference): Not published as of August 2005Study period: Initiated on 16 July 2003; Completed on 09 January 2004 Clinical phase: IIIObjectives, Methodology and design of the study: Please refer to 208136 (MeMuRu-OKA) 038 StudyReport Part I Main for details.Number of subjects:From the 494 subjects included in Total vaccinated cohort, 246 were included in the random subset (123subjects in pooled MeMuRu-OKA groups and all 123 subjects in Priorix+Varilrix group) and 248 were notincluded in the random subset (all from pooled MeMuRu-OKA groups).Criteria for evaluation:Mumps immunogenicity:Measurement of antibody level against mumps was performed by neutralisation assay (cut-off: mumps: 1/28dilution) in serum samples collected at Day 0, Day 42 and Day 84. Seropositivity was defined as antibodytitre ≥ assay cut-off. Seroconversion was defined as the appearance of antibody titre ≥assay cut-off inpreviously seronegative subject (i.e., titre < assay cut-off).Statistical methods:Statistical analyses were performed on the Total vaccinated cohort and on the ATP immunogenicity cohort(see Section 4.1 for study cohorts’ definitions). In this annex report, the primary analyses on mumpsimmunogenicity were based on the Total vaccinated cohort.Analysis of mumps immunogenicity:All analyses were descriptive.For each group (subjects with pre-vaccination serological status available), mumps immunogenicity aftereach vaccination was evaluated in terms of GMTs and seroconversion/seropositivity rates (PRNT) with their95% confidence intervals (CIs). Distribution of antibody titres was displayed by using reverse cumulativecurves (RCCs) on initially seronegative subjects after each dose.The results are presented for subjects who were included in the random subset (sera tested in 2004) and forsubjects who were included in the non-random subset (sera tested in 2005).Summary:The read-out for mumps immune response by neutralisation assay was performed at two different periods. Arandom subset of samples, assayed in 2004, included 33% of subjects from each of the three MeMuRu-OKAgroups (total = 123 subjects) and all subjects in the control Priorix+Varilrix group (123 subjects). In thissubset, the overall mumps seroconversion rate was 96.2% [95% CIs: 90.5; 99.0] after the first dose and100% [95% CIs: 96.5; 100] after the second dose in the MeMuRu-OKA pooled groups (Total vaccinatedcohort). The mumps seroconversion rate in the control Priorix+Varilrix group was ∼ 99.0% after eachvaccination.Serum samples from the remaining subjects in MeMuRu-OKA groups (about 67%) not included in therandom subset (i.e. non-random subset) were assayed in 2005. The overall mumps seroconversion rates forthese subjects were 92.5% [95% CIs: 88.3; 95.6] and 96.5% [95% CIs: 93.2; 98.5] after the first and afterthe second dose, respectively. Date of annex report: August 2005

Synopsis of Final Study Report Annex 1 208136/038 (MeMuRu-OKA-038) Page 1



TABLE OF CONTENTS

SYNOPSIS .................................................................................................................... 2

1. BACKGROUND OF THE STUDY............................................................................ 7

2. STUDY DESIGN AND METHODOLOGY ................................................................ 7

3. LABORATORY ASSAY ........................................................................................... 7

4. STATISTICAL CONSIDERATIONS......................................................................... 84.1. Study cohorts ............................................................................................... 8

5. RESULTS................................................................................................................ 95.1. Mumps immune response by neutralisation assay ......................................10

5.1.1. Random subset............................................................................105.1.2. Non-random subset......................................................................12

6. SUPPLEMENTS.....................................................................................................146.1. Random subset...........................................................................................146.2. Non-random subset.....................................................................................23

7. REFERENCES.......................................................................................................32

8. STUDY REPORT AUTHORS/ CONTRIBUTING AUTHORS ..................................33

9. APPENDICES ........................................................................................................34List of Appendices available for the annex report....................................................34

CONTENTS: REPORT TABLES

Table 1 Number of subjects enrolled into the study as well as thenumber of subjects excluded from the neutralisation analyses withreasons for exclusion .............................................................................................. 9

Table 2 Pre-vaccination status (PRE) for mumps by neutralisationassay (Total Vaccinated Cohort, subjects included in random subset) ...................10

Table 3 Seroconversion rates and geometric mean titres (GMT) forANTI-MUMPS (PRNT) antibody titres (Total vaccinated cohort, initiallyseronegative subjects included in random subset).................................................11

Table 4 Pre-vaccination status (PRE) for mumps by neutralisationassay (Total Vaccinated Cohort, subjects included in non-randomsubset; tested in 2005)...........................................................................................12

Table 5 Seroconversion rates and GMTs for ANTI-MUMPS (PRNT)antibodies by pre-vaccination status (Total Vaccinated Cohort, initiallyseronegative subjects included in non-random subset; tested in 2005)..................13



CONTENTS: SUPPLEMENTSSupplement 1 Pre-vaccination status (PRE) for mumps by

neutralisation assay (ATP cohort for immunogenicity, subjectsincluded in random subset) ....................................................................................14

Supplement 2 Seroconversion rates and geometric mean titres(GMTs) for ANTI-MUMPS (PRNT) antibody titres (Total vaccinatedcohort, subjects included in random subset) ..........................................................15

Supplement 3 Seroconversion rates and geometric mean titres(GMT) for ANTI-MUMPS (PRNT) antibody titres (ATP cohort forimmunogenicity, subjects included in random subset)............................................16

Supplement 4 Distribution of ANTI-MUMPS (PRNT) antibody titresby pre-vaccination status (Total Vaccinated Cohort, subjects includedin random subset) ..................................................................................................17

Supplement 5 Reverse Cumulative Curve of anti-Mumps antibodytitres post dose 1 in intially seronegative subjects (Total vaccinatedcohort, subjects included in random subset) ..........................................................18

Supplement 6 Reverse Cumulative Curve of anti-Mumps antibodytitres post dose 2 in intially seronegative subjects (Total vaccinatedcohort, subjects included in random subset) ..........................................................19

Supplement 7 Distribution of ANTI-MUMPS (PRNT) antibody titre bypre-vaccination status (ATP cohort for immunogenicity, subjectsincluded in random subset) ....................................................................................20

Supplement 8 Reverse Cumulative Curve of anti-Mumps antibodytitres post dose 1 in intially seronegative subjects (ATP cohort forimmunogenicity, subjects included in random subset)............................................21

Supplement 9 Reverse Cumulative Curve of anti-Mumps antibodytitres post dose 2 in intially seronegative subjects (ATP cohort forimmunogenicity, subjects included in random subset)............................................22

Supplement 10 Pre-vaccination status (PRE) for mumps byneutralisation assay (ATP cohort for immunogenicity, subjectsincluded in non-random subset; tested in 2005).....................................................23

Supplement 11 Seroconversion rates and GMTs for ANTI-MUMPS(PRNT) antibodies by pre-vaccination status (Total Vaccinated Cohort,subjects included in non-random subset; tested in 2005).......................................24

Supplement 12 Seroconversion rates and GMTs for ANTI-MUMPS(PRNT) antibodies by pre-vaccination status (ATP cohort forimmunogenicity, subjects included in non-random subset; tested in2005) .....................................................................................................25

Supplement 13 Distribution of ANTI-MUMPS (PRNT) antibody titre bypre-vaccination (Total Vaccinated Cohort, subjects included in non-random subset; tested in 2005)..............................................................................26

Supplement 14 Reverse Cumulative Curve of anti-Mumps antibodytitres post dose 1 in intially seronegative subjects (Total VaccinatedCohort, subjects included in non-random subset; tested in 2005) ..........................27

Supplement 15 Reverse Cumulative Curve of anti-Mumps antibodytitres post dose 2 in intially seronegative subjects (Total VaccinatedCohort, subjects included in non-random subset; tested in 2005) ..........................28

Supplement 16 Distribution of ANTI-MUMPS (PRNT) antibody titre bypre-vaccination status (ATP cohort for immunogenicity, subjectsincluded in non-random subset; tested in 2005).....................................................29

Supplement 17 Reverse Cumulative Curve of anti-Mumps antibodytitres post dose 1 in intially seronegative subjects status (ATP cohortfor immunogenicity, subjects included in non-random subset; tested in2005) .....................................................................................................30



Supplement 18 Reverse Cumulative Curve of anti-Mumps antibodytitres post dose 2 in intially seronegative subjects status (ATP cohortfor immunogenicity, subjects included in non-random subset; tested in2005) .....................................................................................................31



LIST OF ABBREVIATIONSATP According-to-protocol

CI Confidence interval

GMT Geometric mean titre

GSK GlaxoSmithKline

IEC Independent Ethics Committee

IRB Institutional Review Board

Glossary of Terms

Completed: Subjects who completed the last study visit.

Eligible: Qualified for enrolment into the study based upon strict adherence toinclusion/exclusion criteria.

Evaluable: Meeting all eligibility criteria, complying with the proceduresdefined in the protocol, and, therefore, included in the analysis.

Subject(s): Term used throughout the protocol to denote an individual that hasbeen contacted in order to participate in the clinical study, either as arecipient of the investigational product(s) or as a control) .



1. BACKGROUND OF THE STUDY

This study was performed to evaluate the consistency of three production lots ofMeMuRu-OKA, as well as the non-inferiority of MeMuRu-OKA in terms ofimmunogenicity when administered according to a two-dose schedule to healthy childrenin their second year of life, in comparison to GSK Biologicals' licensed MMR vaccine(Priorix) given according to a two-dose schedule and one dose of GSK Biologicals'licensed Varicella vaccine (Varilrix). The safety of the study vaccines following eachvaccination was also assessed in the study. In addition, the study is also evaluating thepersistence of antibodies against measles, mumps, rubella and varicella as well as theoccurrence of varicella breakthrough cases within three years after vaccination. Thislong- term follow-up is currently ongoing and will be presented in a separate annexreport.

The active phase of the study was initiated on 16 July 2003 and concluded on 09 January2004. The immunogenicity and safety of the study vaccines within 43 days of follow-upafter each vaccination was presented in the clinical study report issued on 28 April 2004.

ELISA (Enzyme-Linked Immunosorbent Assay) was used to determine mumpsimmunogenicity. The observed mumps seroconversion (SC) rates by ELISA were 91.4%,85.7% and 92.9% 43 days after the first dose for the three MeMuRu-OKA lots. In orderto evaluate the functional aspects of the immune response induced by the vaccines, GSKBiologicals generated mumps immunogenicity data by neutralization assay.

Re-testing of serum samples by mumps neutralisation assay was carried out at twodifferent periods (i.e. a random subset was assayed in 2004 while the remaining sampleswere assayed in 2005). The results are presented in this annex report.

2. STUDY DESIGN AND METHODOLOGY

Refer to 208136 MeMuRu-OKA 038 Main Report.

3. LABORATORY ASSAY

The neutralisation assay is an in-house method developed at GSK Biologicals based uponthe method previously described by Sato et. al. (1978). The cut-off of the assay formumps antibody is 1/28 dilution.

All subjects with sufficient volume of serum at pre-, post-dose I and post-dose II wereconsidered to evaluate mumps neutralising antibodies. The mumps neutralisation testingwas performed at two different periods:

1. 33% of samples randomly selected from each of the three MeMuRu-OKA groupsand 100% of samples from the control Priorix+Varilrix group were assayed in2004 (random subset).

2. The remaining samples from the three MeMuRu-OKA groups (i.e., 67%) wereassayed in 2005 (non-random subset).



4. STATISTICAL CONSIDERATIONS

4.1. Study cohorts

Statistical analyses presented in this annex report were performed on the cohort definedfor the anlysis in the main report, i.e. Total vaccinated cohort and ATP immunogenicitycohort. The primary analysis on immunogenicity for this report was based on the Totalvaccinated cohort.

Total Vaccinated Cohort (Total cohort)The Total Vaccinated Cohort included all vaccinated subjects for whom data wereavailable. For the total analysis of safety, this included all vaccinated subjects with atleast one vaccine administration documented. For the total cohort analysis ofimmunogenicity, this included vaccinated subjects for whom data concerningimmunogenicity were available.

ATP cohort for analysis of immunogenicityThe protocol-defined cohort for analysis of immunogenicity included subjects eligible inthe protocol-defined cohort for safety (defined in the Part I Main Report of the study208136 MeMuRu-OKA 038) and:

• with blood samples available for pre and post dose 1 or post dose 2 time points;

• who complied with all protocol procedures (e.g., the time schedule for post-vaccination blood sampling were between Day 35 and Day 77 after the pre-vaccination blood sampling/ previous dose);

• who were seronegative for measles, mumps, rubella and varicella antibodies atbaseline by ELISA/IFA (initially seropositive for these antigens were excludedfrom the ATP immunogenicity cohort);

• whose post-vaccination serology data were available for at least one of thevaccine antigens and were taken within 35-77 days after vaccination;

• who did not received any medication forbidden by the protocol;

• with no underlying medical condition forbidden by the protocol.The mumps immunogenicity results are presented respectively for subjects who wereincluded in the random subset (sera tested in 2004) and for subjects who were includedin the non-random subset (sera tested in 2005).

Analysis of mumps immunogenicity:

All analyses were descriptive.

For each group (subjects with pre-vaccination serological status available), mumpsimmunogenicity after each vaccination was evaluated in terms of GMTs andseroconversion/seropositivity rates (PRNT) with their 95% confidence intervals (CIs).The distribution of mumps antibody titres in initially seronegative subjects was displayedusing reverse cumulative curves (RCCs) after each dose.



5. RESULTS

Table 1 presents the number of subjects enrolled in the study and the number of subjectsincluded in the neutralization analyses.

Table 1 Number of subjects enrolled into the study as well as the number ofsubjects excluded from the neutralisation analyses with reasons forexclusion

Title Total Percent MMRV_1 MMRV_2 MMRV_3 MMRV MMR_VNumber of vaccines prepared 840 210 210 210 630 210

Subjects or vaccine number not allocated(code 1010 )

346 85 88 86 259 87

Total enrolled cohort 494 - 125 122 124 371 123

Total Vaccinated Cohort 494 100 125 122 124 371 123

Number of subjects with post-dose 1 (PDI) orpost-dose 2 (PDII) neutralisation results

486 98.4 123 120 121 364 122

Number of subjects with PDI or PDII but noresult at pre-vaccination

11 2.2 2 2 4 8 3

Random subsetNumber of subjects in the random subset2004

246 49.8 41 41 41 123 123

Number of subjects with PDI or PDIIneutralisation results

243 49.2 41 40 40 121 122


7 1.4 2 . 2 4 3

Non-random subsetNumber of subjects not in random subset 248 50.2 84 81 83 248 .Number of subjects with PDI or PDIIneutralisation results

243 49.2 82 80 81 243 .


4 0.8 . 2 2 4 .

MMRV_1 : MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 : MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 : MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)MMRV : MeMuRu-OKA pooled lotsMMR_V : GR2**#1 MJR vaccine(MJR622A44) mix Diluent for MJR(03A10/585) sep Varicella vaccine(VA271A43) mix Dil. forVaricella(02E07/511)#2 MJR vaccine(MJR622A44)Percent = percentage of subjects relative to the Total Vaccinated Cohort.Individual subjects data can be found in Appendix table IA

From the 494 subjects included in the Total vaccinated cohort, 246 were included in therandom subset (123 subjects in the pooled MeMuRu-OKA groups and all 123 subjects inthe Priorix+Varilrix group) and 248 were not included in the random subset (all from thepooled MeMuRu-OKA groups).



5.1. Mumps immune response by neutralisation assay

5.1.1. Random subset

See definition of random subset in Section 3 and Section 4 of the annex report.

Table 2 presents the serological status before vaccination for subjects in the Totalvaccinated cohort who were included in the random subset.

Supplement 1 presents the pre-vaccination serological status for subjects in the ATPimmunogenicity cohort who were included in the random subset.

Table 2 Pre-vaccination status (PRE) for mumps by neutralisation assay(Total Vaccinated Cohort, subjects included in random subset)

MMRV_1N=125

MMRV_2N=122

MMRV_3N=124

MMRVN=371

MMR_VN=123

TotalN=494

n % n % n % n % n % n %S- 35 89.7 38 92.7 35 89.7 108 90.8 105 87.5 213 89.1S+ 4 10.3 3 7.3 4 10.3 11 9.2 15 12.5 26 10.9Unknown 2 . 0 . 2 . 4 . 3 . 7 .

MMRV_1 = MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 = MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 = MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)MMRV : MeMuRu-OKA pooled lotsMMR_V = #1 MJR vaccine(MJR622A44) mix Diluent for MJR(03A10/585) sep Varicella vaccine(VA271A43) mix Dil. for Varicella(02E07/511)#2MJR vaccine(MJR622A44) mix Diluent(03A10/585) MJR + VaricellaS- = seronegative subjects (titre < 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccinationS+ = seropositive subjects (titre ≥ 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccinationN = number of subjects regardless of whether there is a result (sum of S-, S+ and Unknown).n = number of subjects with the considered pre-vaccination status.% = n / (seronegative + seropositive).Data source = Appendix table IIIA

For subjects in the Total vaccinated cohort who were included in the random subset, 15subjects (12.5%) in MeMuRu-OKA pooled groups and 15 subjects (12.5%) in the controlgroup (corresponds to MMRV and MMR_V in Table 2, respectively) were seropositivefor mumps neutralising antibodies before study vaccination.

Table 3 presents the mumps seroconversion rates and geometric mean tires as assessed byneutralisation assay for initially seronegative subjects in the Total vaccinated cohort whowere included in the random subset.

Similarly, the immunogenicity results for all subjects (including initiallyseronegative/seropositive and overall) are presented in Supplement 2 for the Totalvaccinated cohort and Supplement 4 for the ATP immunogenicity cohort.



Table 3 Seroconversion rates and geometric mean titres (GMT) for ANTI-MUMPS (PRNT) antibody titres (Total vaccinated cohort, initiallyseronegative subjects included in random subset)

Group Timing N ≥≥≥≥28 1/DIL GMT95% CI Value 95% CI

n % LL UL LL ULMMRV_1 PI(D42) 35 34 97.1 85.1 99.9 153.7 104.1 227.0

PII(D84) 34 34 100 89.7 100 398.9 289.0 550.6MMRV_2 PI(D42) 36 33 91.7 77.5 98.2 197.0 123.9 313.2

PII(D84) 36 36 100 90.3 100 351.1 239.9 513.8MMRV_3 PI(D42) 34 34 100 89.7 100 135.9 93.0 198.6

PII(D84) 34 34 100 89.7 100 357.5 244.6 522.6MMRV PI(D42) 105 101 96.2 90.5 99.0 160.8 127.4 203.1

PII(D84) 104 104 100 96.5 100 368.3 300.7 451.0MMR_V PI(D42) 102 101 99.0 94.7 100 195.9 159.3 240.9

PII(D84) 105 104 99.0 94.8 100 316.0 258.0 387.1MMRV_1 : MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 : MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 : MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)MMRV : MeMuRu-OKA pooled lotsMMR_V : GR2**#1 MJR vaccine(MJR622A44) mix Diluent for MJR(03A10/585) sep Varicella vaccine(VA271A43) mix Dil. forVaricella(02E07/511)#2 MJR vaccine(MJR622A44)N = number of subjects with available results at pre-vaccinationn/% = number/percentage of subjects with titre within the specified range95% CI = 95% confidence interval; LL = Lower Limit; UL = Upper LimitPI(D42)=POST-VACCINATION BLOOD SAMPLE AT DAY 42PII(D84) =POST-VACCINATION BLOOD SAMPLE AT DAY 84Individual subject data can be found in Appendix table IIIA

After the first dose (day 42), the observed mumps seroconversion rate by neutralisationassay was 97.1%, 91.7% and 100% for subjects in Group MeMuRu-OKA LotMJRV159A48, Lot MJRV160A48 and Lot MJRV163A48, respectively (the overallseroconversion rate was 96.2%).

After the second dose (day 84), all subjects seroconverted to mumps antibodies in theMeMuRu-OKA groups.

For subjects in the Total vaccinated cohort who were included in the random subset, thedistribution of mumps antibody titres is presented in Supplement 4 and the reversecumulative curves for mumps antibodies are presented in Supplement 5 (after the firstdose) and Supplement 6 (after the second dose).

For subjects in ATP immunogenicity cohort who were included in the random subset, thedistribution of mumps antibodies is presented in Supplement 7 and reverse cumulativecurves are presented in Supplement 8 (after the first dose) and Supplement 9 (after thesecond dose).



5.1.2. Non-random subset

See definition of non-random subset in Section 3 and Section 4 of the annex report.

Table 4 presents the serological status before vaccination for subjects in the Totalvaccinated cohort who were included in the non-random subset.

Supplement 10 presents the serological status before vaccination for subjects in the ATPimmunogenicity cohort who were included in the non-random subset.

Table 4 Pre-vaccination status (PRE) for mumps by neutralisation assay(Total Vaccinated Cohort, subjects included in non-random subset;tested in 2005)

MMRV_1N=84

MMRV_2N=81

MMRV_3N=83

MMRVN=248

TotalN=248

n % n % n % n % n %S- 81 96.4 74 93.7 81 100 236 96.7 236 96.7S+ 3 3.6 5 6.3 0 0.0 8 3.3 8 3.3Unknown 0 . 2 . 2 . 4 . 4 .

MMRV_1 = MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 = MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 = MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)MMRV : MeMuRu-OKA pooled lotsS- = seronegative subjects (titre < 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccinationS+ = seropositive subjects (titre ≥ 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccinationN = number of subjects regardless of whether there is a result (sum of S-, S+ and Unknown).n = number of subjects with the considered pre-vaccination status.% = n / (seronegative + seropositive).Data source = Appendix table IIIA

For subjects in the Total vaccinated cohort who were included in the non-random subset,8 subjects (3.3%; all from the MeMuRu-OKA groups) were seropositive for mumpsantibodies before vaccination.

Table 5 presents the mumps seroconversion rates and geometric mean tires as assessed byneutralisation assay for initially seronegative subjects in the Total vaccinated cohort whowere included in the non-random subset.

Similarly, the immunogenicity results for all subjects in non-random subset (includinginitially seronegative/seropositive and overall) are presented in Supplement 11 for theTotal vaccinated cohort and Supplement 12 for the ATP immunogenicity cohort.



Table 5 Seroconversion rates and GMTs for ANTI-MUMPS (PRNT) antibodiesby pre-vaccination status (Total Vaccinated Cohort, initiallyseronegative subjects included in non-random subset; tested in2005)

≥≥≥≥ 28 1/DIL GMT95% CI 95% CIGroup Timing N

n % LL UL value LL ULMMRV_1 PI(W6) 77 70 90.9 82.2 96.3 97.9 72.3 132.6

PII(W12) 77 77 100 95.3 100 165.9 128.1 214.9MMRV_2 PI(W6) 71 63 88.7 79.0 95.0 85.5 63.5 115.1

PII(W12) 72 67 93.1 84.5 97.7 145.7 109.8 193.4MMRV_3 PI(W6) 79 77 97.5 91.2 99.7 101.3 77.5 132.3

PII(W12) 78 75 96.2 89.2 99.2 147.9 114.2 191.7MMRV PI(W6) 227 210 92.5 88.3 95.6 94.9 80.5 111.9

PII(W12) 227 219 96.5 93.2 98.5 153.1 131.5 178.1MMRV_1 = MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 = MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 = MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)MMRV : MeMuRu-OKA pooled lotsS- = seronegative subjects (antibody titre < 28 1/DIL) prior to vaccinationS+ = seropositive subjects (antibody titre ≥ 28 1/DIL) prior to vaccinationGMT = geometric mean antibody titre calculated on all subjectsN = number of subjects with pre-vaccination results availablen/% = number/percentage of subjects with titre within the specified range95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper LimitPI(D42)=POST-VACCINATION BLOOD SAMPLE AT DAY 42PII(D84) =POST-VACCINATION BLOOD SAMPLE AT DAY 84Data source = Appendix table IIIA

After the first dose (day 42), the observed mumps seroconversion rate by neutralisationassay was 90.9%, 88.7% and 97.5% for subjects in Group MeMuRu-OKA LotMJRV159A48, Lot MJRV160A48 and Lot MJRV163A48, respectively (i.e., an overallpost-dose 1 seroconversion rate of 92.5%). After the second dose (day 84), the observedmumps seroconversion rate was 100%, 93.1% and 96.2% for Group MeMuRu-OKA LotMJRV159A48, Lot MJRV160A48 and Lot MJRV163A4, respectively (i.e., an overallpost-dose 2 seroconversion rate of 96.5%).

For subjects in the Total vaccinated cohort who were included in the non-random subset,the distribution of mumps antibody titres is presented in Supplement 13 and the reversecumulative curves for mumps antibodies are presented in Supplement 14 (after the firstdose) and Supplement 15 (after the second dose).

For subjects in ATP immunogenicity cohort who were included in the non-randomsubset, the distribution of mumps antibodies is presented in Supplement 16 and reversecumulative curves are presented in Supplement 17 (after the first dose) and Supplement18 (after the second dose).



6. SUPPLEMENTS

6.1. Random subset

Supplement 1 Pre-vaccination status (PRE) for mumps by neutralisationassay (ATP cohort for immunogenicity, subjects included in randomsubset)

MMRV_1N=35

MMRV_2N=33

MMRV_3N=29

MMRVN=

MMR_VN=108

TotalN=205

n % n % n % n % n % n %S- 30 88.2 30 90.9 26 92.9 86 90.5 94 88.7 180 89.6S+ 4 11.8 3 9.1 2 7.1 9 9.5 12 11.3 21 10.4Unknown 1 . 0 . 1 . 2 . 2 . 4 .

MMRV_1 = MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 = MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 = MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)MMRV : MeMuRu-OKA pooled lotsMMR_V = #1 MJR vaccine(MJR622A44) mix Diluent for MJR(03A10/585) sep Varicella vaccine(VA271A43) mix Dil. for Varicella(02E07/511)#2MJR vaccine(MJR622A44) mix Diluent(03A10/585) MJR + VaricellaS- = seronegative subjects (titre < 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccinationS+ = seropositive subjects (titre ≥ 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccinationN = number of subjects regardless of whether there is a result (sum of S-, S+ and Unknown).n = number of subjects with the considered pre-vaccination status.% = n / (seronegative + seropositive).Data source = Appendix table IIIA



Supplement 2 Seroconversion rates and geometric mean titres (GMTs) forANTI-MUMPS (PRNT) antibody titres (Total vaccinated cohort,subjects included in random subset)

Group Pre-vaccstatus Timing N ≥≥≥≥ 28 1/DIL GMT

95% CI Value 95% CIn % LL UL LL UL

MMRV_1 S- PI(D42) 35 34 97.1 85.1 99.9 153.7 104.1 227.0PII(D84) 34 34 100 89.7 100 398.9 289.0 550.6

S+ PI(D42) 4 4 100 39.8 100 263.1 49.6 1395.2PII(D84) 4 4 100 39.8 100 415.8 118.6 1457.9

Total PI(D42) 39 38 97.4 86.5 99.9 162.4 112.8 234.0PII(D84) 38 38 100 90.7 100 400.7 298.0 538.7

MMRV_2 S- PI(D42) 36 33 91.7 77.5 98.2 197.0 123.9 313.2PII(D84) 36 36 100 90.3 100 351.1 239.9 513.8

S+ PI(D42) 3 3 100 29.2 100 254.5 108.1 599.3PII(D84) 3 3 100 29.2 100 300.2 14.5 6197.1

Total PI(D42) 39 36 92.3 79.1 98.4 200.9 131.0 308.2PII(D84) 39 39 100 91.0 100 346.9 241.6 498.2

MMRV_3 S- PI(D42) 34 34 100 89.7 100 135.9 93.0 198.6PII(D84) 34 34 100 89.7 100 357.5 244.6 522.6

S+ PI(D42) 3 3 100 29.2 100 275.3 20.4 3724.1PII(D84) 3 3 100 29.2 100 632.6 140.7 2844.3

Total PI(D42) 37 37 100 90.5 100 143.9 100.2 206.8PII(D84) 37 37 100 90.5 100 374.5 262.7 533.8

MMRV S- PI(D42) 105 101 96.2 90.5 99.0 160.8 127.4 203.1PII(D84) 104 104 100 96.5 100 368.3 300.7 451.0

S+ PI(D42) 10 10 100 69.2 100 264.1 149.1 467.6PII(D84) 10 10 100 69.2 100 427.7 233.9 782.0

Total PI(D42) 115 111 96.5 91.3 99.0 167.9 135.0 208.9PII(D84) 114 114 100 96.8 100 373.1 308.6 451.2

MMR_V S- PI(D42) 102 101 99.0 94.7 100 195.9 159.3 240.9PII(D84) 105 104 99.0 94.8 100 316.0 258.0 387.1

S+ PI(D42) 14 13 92.9 66.1 99.8 258.2 117.0 569.9PII(D84) 14 14 100 76.8 100 360.2 163.5 793.2

Total PI(D42) 116 114 98.3 93.9 99.8 202.5 165.6 247.6PII(D84) 119 118 99.2 95.4 100 320.9 263.6 390.7

MMRV_1 : MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 : MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 : MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)MMRV : MeMuRu-OKA pooled lotsMMR_V : GR2**#1 MJR vaccine(MJR622A44) mix Diluent for MJR(03A10/585) sep Varicella vaccine(VA271A43) mix Dil. forVaricella(02E07/511)#2 MJR vaccine(MJR622A44)S- = titre < 28 1/DIL at PRES+ = titre ≥ 28 1/DIL at PREN = number of subjects with available results at pre-vaccinationn/% = number/percentage of subjects with titre within the specified range95% CI = 95% confidence interval; LL = Lower Limit; UL = Upper LimitPI(D42)=POST-VACCINATION BLOOD SAMPLE AT DAY 42PII(D84) =POST-VACCINATION BLOOD SAMPLE AT DAY 84PRE = PRE-VACCINATION BLOOD SAMPLE AT DAY 0Individual subject data can be found in Appendix table IIIA



Supplement 3 Seroconversion rates and geometric mean titres (GMT) forANTI-MUMPS (PRNT) antibody titres (ATP cohort forimmunogenicity, subjects included in random subset)

≥≥≥≥ 28 1/DIL GMT95% CI 95% CI

Group Pre-vaccstatus

Timing N n % LL UL value LL UL

MMRV_1 S- PI(W6) 30 29 96.7 82.8 99.9 144.0 95.4 217.3PII(W12) 29 29 100 88.1 100 401.5 281.6 572.5

S+ PI(W6) 4 4 100 39.8 100 263.1 49.6 1395.2PII(W12) 4 4 100 39.8 100 415.8 118.6 1457.9

Total PI(W6) 34 33 97.1 84.7 99.9 154.5 105.3 226.8PII(W12) 33 33 100 89.4 100 403.2 292.5 555.9

MMRV_2 S- PI(W6) 29 26 89.7 72.6 97.8 197.3 110.7 351.4PII(W12) 29 29 100 88.1 100 349.3 220.3 553.7

S+ PI(W6) 3 3 100 29.2 100 254.5 108.1 599.3PII(W12) 3 3 100 29.2 100 300.2 14.5 6197.1

Total PI(W6) 32 29 90.6 75.0 98.0 202.0 119.9 340.5PII(W12) 32 32 100 89.1 100 344.3 224.0 529.4

MMRV_3 S- PI(W6) 26 26 100 86.8 100 141.2 90.5 220.3PII(W12) 26 26 100 86.8 100 377.7 234.5 608.3

S+ PI(W6) 2 2 100 15.8 100 156.2 1.4 17025.8PII(W12) 1 1 100 2.5 100 461.0 - -

Total PI(W6) 28 28 100 87.7 100 142.2 94.1 214.9PII(W12) 27 27 100 87.2 100 380.5 240.7 601.5

MMRV S- PI(W6) 85 81 95.3 88.4 98.7 159.3 121.6 208.8PII(W12) 84 84 100 95.7 100 375.5 295.7 476.8

S+ PI(W6) 9 9 100 66.4 100 231.7 132.7 404.7PII(W12) 8 8 100 63.1 100 372.8 183.0 759.3

Total PI(W6) 94 90 95.7 89.5 98.8 165.2 128.7 211.9PII(W12) 92 92 100 96.1 100 375.2 300.2 469.0

MMR_V S- PI(W6) 91 90 98.9 94.0 100 183.2 146.8 228.8PII(W12) 94 94 100 96.2 100 317.7 256.7 393.4

S+ PI(W6) 12 11 91.7 61.5 99.8 204.0 87.0 477.9PII(W12) 12 12 100 73.5 100 332.0 133.2 827.8

Total PI(W6) 103 101 98.1 93.2 99.8 185.5 149.8 229.8PII(W12) 106 106 100 96.6 100 319.3 259.1 393.6

MMRV_1 : MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 : MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 : MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)MMRV : MeMuRu-OKA pooled lotsMMR_V : GR2**#1 MJR vaccine(MJR622A44) mix Diluent for MJR(03A10/585) sep Varicella vaccine(VA271A43) mix Dil. forVaricella(02E07/511)#2 MJR vaccine(MJR622A44)S- = titre < 28 1/DIL at PRES+ = titre ≥ 28 1/DIL at PREN = number of subjects with available results at pre-vaccinationn/% = number/percentage of subjects with titre within the specified range95% CI = 95% confidence interval; LL = Lower Limit; UL = Upper LimitPI(D42)=POST-VACCINATION BLOOD SAMPLE AT DAY 42PII(D84) =POST-VACCINATION BLOOD SAMPLE AT DAY 84PRE = PRE-VACCINATION BLOOD SAMPLE AT DAY 0Individual subject data can be found in Appendix table IIIA



Supplement 4 Distribution of ANTI-MUMPS (PRNT) antibody titres by pre-vaccination status (Total Vaccinated Cohort, subjects included inrandom subset)

<28 1/DIL ≥≥≥≥28 1/DIL ≥≥≥≥56 1/DIL ≥≥≥≥112 1/DIL ≥≥≥≥224 1/DIL ≥≥≥≥448 1/DIL ≥≥≥≥896 1/DILGroup Pre-

vaccstatus

Timing N n % n % n % n % n % n % n %

MMRV_1 S- PI(D42) 35 1 2.9 34 97.1 28 80 21 60 16 45.7 7 20 1 2.9PII(D84) 34 0 0 34 100 33 97.1 31 91.2 26 76.5 15 44.1 4 11.8

S+ PI(D42) 4 0 0 4 100 4 100 3 75 2 50 1 25 1 25PII(D84) 4 0 0 4 100 4 100 4 100 3 75 1 25 1 25

MMRV_2 S- PI(D42) 36 3 8.3 33 91.7 30 83.3 26 72.2 16 44.4 9 25 5 13.9PII(D84) 36 0 0 36 100 33 91.7 33 91.7 26 72.2 14 38.9 7 19.4

S+ PI(D42) 3 0 0 3 100 3 100 3 100 2 66.7 0 0 0 0PII(D84) 3 0 0 3 100 3 100 2 66.7 2 66.7 1 33.3 0 0

MMRV_3 S- PI(D42) 34 0 0 34 100 26 76.5 21 61.8 13 38.2 4 11.8 1 2.9PII(D84) 34 0 0 34 100 33 97.1 31 91.2 24 70.6 13 38.2 7 20.6

S+ PI(D42) 3 0 0 3 100 3 100 2 66.7 2 66.7 1 33.3 0 0PII(D84) 3 0 0 3 100 3 100 3 100 3 100 2 66.7 1 33.3

MMRV S- PI(D42) 105 4 3.8 101 96.2 84 80 68 64.8 45 42.9 20 19 7 6.7PII(D84) 104 0 0 104 100 99 95.2 95 91.3 76 73.1 42 40.4 18 17.3

S+ PI(D42) 10 0 0 10 100 10 100 8 80 6 60 2 20 1 10PII(D84) 10 0 0 10 100 10 100 9 90 8 80 4 40 2 20

MMR_V S- PI(D42) 102 1 1 101 99 89 87.3 78 76.5 48 47.1 21 20.6 8 7.8PII(D84) 105 1 1 104 99 98 93.3 97 92.4 69 65.7 37 35.2 12 11.4

S+ PI(D42) 14 1 7.1 13 92.9 12 85.7 11 78.6 8 57.1 6 42.9 3 21.4PII(D84) 14 0 0 14 100 12 85.7 11 78.6 11 78.6 8 57.1 2 14.3

MMRV_1 = MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 = MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 = MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)MMRV : MeMuRu-OKA pooled lotsMMR_V = #1 MJR vaccine(MJR622A44) mix Diluent for MJR(03A10/585) sep Varicella vaccine(VA271A43) mix Dil. for Varicella(02E07/511)#2 MJRvaccine(MJR622A44) mix Diluent(03A10/585) MJR + VaricellaN = number of subjects with available resultsn/% = number/percentage of subjects with titre within the specified rangePI(D42)=POST-VACCINATION BLOOD SAMPLE AT DAY 42PII(D84) =POST-VACCINATION BLOOD SAMPLE AT DAY 84S- = seronegative subjects (antibody titre < 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccinationS+ = seropositive subjects (antibody titre ≥ 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccinationData source = Appendix table IIIA



Supplement 5 Reverse Cumulative Curve of anti-Mumps antibody titres postdose 1 in intially seronegative subjects (Total vaccinated cohort,subjects included in random subset)

Source: Appendix Table III.aMMRV_1 : MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 : MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 : MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)Group MMR_V = Priorix+ Varilrix

Source: Appendix Table III.aGroup MMRV = Pooled MeMuRu-OKA lotsGroup MMR_V = Priorix+ Varilrix



Supplement 6 Reverse Cumulative Curve of anti-Mumps antibody titres postdose 2 in intially seronegative subjects (Total vaccinated cohort,subjects included in random subset)





Supplement 7 Distribution of ANTI-MUMPS (PRNT) antibody titre by pre-vaccination status (ATP cohort for immunogenicity, subjectsincluded in random subset)

<28 1/DIL ≥≥≥≥28 1/DIL ≥≥≥≥56 1/DIL ≥≥≥≥112 1/DIL ≥≥≥≥224 1/DIL ≥≥≥≥448 1/DIL ≥≥≥≥896 1/DILGroup Pre-

vaccstatus

Timing N n % n % n % n % n % n % n %

MMRV_1 S- PI(D42) 30 1 3.3 29 96.7 24 80 18 60 13 43.3 4 13.3 1 3.3PII(D84) 29 0 0 29 100 28 96.6 27 93.1 22 75.9 13 44.8 3 10.3

S+ PI(D42) 4 0 0 4 100 4 100 3 75 2 50 1 25 1 25PII(D84) 4 0 0 4 100 4 100 4 100 3 75 1 25 1 25

MMRV_2 S- PI(D42) 29 3 10.3 26 89.7 23 79.3 20 69 13 44.8 9 31 5 17.2PII(D84) 29 0 0 29 100 26 89.7 26 89.7 20 69 13 44.8 6 20.7

S+ PI(D42) 3 0 0 3 100 3 100 3 100 2 66.7 0 0 0 0PII(D84) 3 0 0 3 100 3 100 2 66.7 2 66.7 1 33.3 0 0

MMRV_3 S- PI(D42) 26 0 0 26 100 20 76.9 17 65.4 11 42.3 3 11.5 1 3.8PII(D84) 26 0 0 26 100 25 96.2 23 88.5 19 73.1 12 46.2 6 23.1

S+ PI(D42) 2 0 0 2 100 2 100 1 50 1 50 0 0 0 0PII(D84) 1 0 0 1 100 1 100 1 100 1 100 1 100 0 0

MMRV S- PI(D42) 85 4 4.7 81 95.3 67 78.8 55 64.7 37 43.5 16 18.8 7 8.2PII(D84) 84 0 0 84 100 79 94 76 90.5 61 72.6 38 45.2 15 17.9

S+ PI(D42) 9 0 0 9 100 9 100 7 77.8 5 55.6 1 11.1 1 11.1PII(D84) 8 0 0 8 100 8 100 7 87.5 6 75 3 37.5 1 12.5

MMR_V S- PI(D42) 91 1 1.1 90 98.9 78 85.7 68 74.7 40 44 16 17.6 7 7.7PII(D84) 94 0 0 94 100 88 93.6 87 92.6 60 63.8 33 35.1 11 11.7

S+ PI(D42) 12 1 8.3 11 91.7 10 83.3 9 75 6 50 4 33.3 1 8.3PII(D84) 12 0 0 12 100 10 83.3 9 75 9 75 7 58.3 1 8.3

MMRV_1 = MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 = MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 = MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)MMRV : MeMuRu-OKA pooled lotsMMR_V = #1 MJR vaccine(MJR622A44) mix Diluent for MJR(03A10/585) sep Varicella vaccine(VA271A43) mix Dil. for Varicella(02E07/511)#2 MJRvaccine(MJR622A44) mix Diluent(03A10/585) MJR + VaricellaN = number of subjects with available resultsn/% = number/percentage of subjects with titre within the specified rangePI(D42)=POST-VACCINATION BLOOD SAMPLE AT DAY 42PII(D84) =POST-VACCINATION BLOOD SAMPLE AT DAY 84S- = seronegative subjects (antibody titre < 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccinationS+ = seropositive subjects (antibody titre ≥ 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccination

Data source = Appendix table IIIA



Supplement 8 Reverse Cumulative Curve of anti-Mumps antibody titres postdose 1 in intially seronegative subjects (ATP cohort forimmunogenicity, subjects included in random subset)





Supplement 9 Reverse Cumulative Curve of anti-Mumps antibody titres postdose 2 in intially seronegative subjects (ATP cohort forimmunogenicity, subjects included in random subset)





6.2. Non-random subset

Supplement 10 Pre-vaccination status (PRE) for mumps by neutralisationassay (ATP cohort for immunogenicity, subjects included in non-random subset; tested in 2005)

MMRV_1N=73

MMRV_2N=70

MMRV_3N=71

MMRVN=214

n % n % n % n %S- 73 100 66 95.7 71 100 210 98.6S+ 0 0.0 3 4.3 0 0.0 3 1.4Unknown 0 . 1 . 0 . 1 .MMRV_1 = MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 = MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 = MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)MMRV : MeMuRu-OKA pooled lotsS- = seronegative subjects (titre < 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccinationS+ = seropositive subjects (titre ≥ 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccinationN = number of subjects regardless of whether there is a result (sum of S-, S+ and Unknown).n = number of subjects with the considered pre-vaccination status.% = n / (seronegative + seropositive).Data source = Appendix table IIIA



Supplement 11 Seroconversion rates and GMTs for ANTI-MUMPS (PRNT)antibodies by pre-vaccination status (Total Vaccinated Cohort,subjects included in non-random subset; tested in 2005)

≥≥≥≥28 1/DIL GMT95% CI 95% CI



MMRV_1 S- PI(W6) 77 70 90.9 82.2 96.3 97.9 72.3 132.6PII(W12) 77 77 100 95.3 100 165.9 128.1 214.9

S+ PI(W6) 3 3 100 29.2 100 184.5 43.6 779.6PII(W12) 3 3 100 29.2 100 193.3 25.9 1444.4

Total PI(W6) 80 73 91.3 82.8 96.4 100.3 74.8 134.5PII(W12) 80 80 100 95.5 100 166.8 129.9 214.4

MMRV_2 S- PI(W6) 71 63 88.7 79.0 95.0 85.5 63.5 115.1PII(W12) 72 67 93.1 84.5 97.7 145.7 109.8 193.4

S+ PI(W6) 5 5 100 47.8 100 148.3 25.8 852.4PII(W12) 5 5 100 47.8 100 114.7 21.9 601.6

Total PI(W6) 76 68 89.5 80.3 95.3 88.6 66.4 118.3PII(W12) 77 72 93.5 85.5 97.9 143.4 109.1 188.6

MMRV_3 S- PI(W6) 79 77 97.5 91.2 99.7 101.3 77.5 132.3PII(W12) 78 75 96.2 89.2 99.2 147.9 114.2 191.7

Total PI(W6) 79 77 97.5 91.2 99.7 101.3 77.5 132.3PII(W12) 78 75 96.2 89.2 99.2 147.9 114.2 191.7

MMRV S- PI(W6) 227 210 92.5 88.3 95.6 94.9 80.5 111.9PII(W12) 227 219 96.5 93.2 98.5 153.1 131.5 178.1

S+ PI(W6) 8 8 100 63.1 100 160.9 63.4 408.7PII(W12) 8 8 100 63.1 100 139.5 54.2 359.0

Total PI(W6) 235 218 92.8 88.7 95.7 96.7 82.3 113.6PII(W12) 235 227 96.6 93.4 98.5 152.6 131.5 177.0

MMRV_1 = MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 = MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 = MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)MMRV : MeMuRu-OKA pooled lotsS- = seronegative subjects (antibody titre < 28 1/DIL) prior to vaccinationS+ = seropositive subjects (antibody titre ≥ 28 1/DIL) prior to vaccinationGMT = geometric mean antibody titre calculated on all subjectsN = number of subjects with pre-vaccination results availablen/% = number/percentage of subjects with titre within the specified range95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper LimitPI(D42)=POST-VACCINATION BLOOD SAMPLE AT DAY 42PII(D84) =POST-VACCINATION BLOOD SAMPLE AT DAY 84Data source = Appendix table IIIA



Supplement 12 Seroconversion rates and GMTs for ANTI-MUMPS (PRNT)antibodies by pre-vaccination status (ATP cohort forimmunogenicity, subjects included in non-random subset; tested in2005)

≥ 28 1/DIL GMT95% CI 95% CI



MMRV_1 S- PI(W6) 71 64 90.1 80.7 95.9 95.4 69.2 131.5PII(W12) 72 72 100 95.0 100 163.2 124.2 214.5

Total PI(W6) 71 64 90.1 80.7 95.9 95.4 69.2 131.5PII(W12) 72 72 100 95.0 100 163.2 124.2 214.5

MMRV_2 S- PI(W6) 64 57 89.1 78.8 95.5 83.9 61.5 114.5PII(W12) 65 61 93.8 85.0 98.3 148.2 110.2 199.2

S+ PI(W6) 3 3 100 29.2 100 57.7 12.1 275.1PII(W12) 3 3 100 29.2 100 50.9 3.9 664.6

Total PI(W6) 67 60 89.6 79.7 95.7 82.5 61.2 111.2PII(W12) 68 64 94.1 85.6 98.4 141.3 105.7 189.1

MMRV_3 S- PI(W6) 71 69 97.2 90.2 99.7 97.4 73.3 129.4PII(W12) 71 68 95.8 88.1 99.1 133.9 103.9 172.7

Total PI(W6) 71 69 97.2 90.2 99.7 97.4 73.3 129.4PII(W12) 71 68 95.8 88.1 99.1 133.9 103.9 172.7

MMRV S- PI(W6) 206 190 92.2 87.7 95.5 92.3 77.6 109.8PII(W12) 208 201 96.6 93.2 98.6 148.0 126.7 173.0

S+ PI(W6) 3 3 100 29.2 100 57.7 12.1 275.1PII(W12) 3 3 100 29.2 100 50.9 3.9 664.6

Total PI(W6) 209 193 92.3 87.9 95.6 91.7 77.2 108.9PII(W12) 211 204 96.7 93.3 98.7 145.8 124.8 170.3

MMRV_1 = MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 = MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 = MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)MMRV : MeMuRu-OKA pooled lotsS- = seronegative subjects (antibody titre < 28 1/DIL) prior to vaccinationS+ = seropositive subjects (antibody titre ≥ 28 1/DIL) prior to vaccinationGMT = geometric mean antibody titre calculated on all subjectsN = number of subjects with pre-vaccination results availablen/% = number/percentage of subjects with titre within the specified range95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper LimitPI(D42)=POST-VACCINATION BLOOD SAMPLE AT DAY 42PII(D84) =POST-VACCINATION BLOOD SAMPLE AT DAY 84Data source = Appendix table IIIA



Supplement 13 Distribution of ANTI-MUMPS (PRNT) antibody titre by pre-vaccination (Total Vaccinated Cohort, subjects included in non-random subset; tested in 2005)

<28 1/DIL ≥≥≥≥28 1/DIL ≥≥≥≥56 1/DIL ≥≥≥≥112 1/DIL ≥≥≥≥224 1/DIL ≥≥≥≥448 1/DIL ≥≥≥≥896 1/DILGroup Pre-vacc

statusTiming N n % n % n % n % n % n % n %

MMRV_1 S- PI(D42) 77 7 9.1 70 90.9 47 61.0 34 44.2 24 31.2 11 14.3 6 7.8PII(D84) 77 0 0.0 77 100 63 81.8 53 68.8 29 37.7 12 15.6 6 7.8

S+ PI(D42) 3 0 0.0 3 100 3 100 3 100 1 33.3 0 0.0 0 0.0PII(D84) 3 0 0.0 3 100 3 100 2 66.7 1 33.3 0 0.0 0 0.0

MMRV_2 S- PI(D42) 71 8 11.3 63 88.7 42 59.2 32 45.1 18 25.4 6 8.5 2 2.8PII(D84) 72 5 6.9 67 93.1 56 77.8 46 63.9 29 40.3 11 15.3 3 4.2

S+ PI(D42) 5 0 0.0 5 100 4 80.0 2 40.0 2 40.0 1 20.0 1 20.0PII(D84) 5 0 0.0 5 100 3 60.0 3 60.0 2 40.0 0 0.0 0 0.0

MMRV_3 S- PI(D42) 79 2 2.5 77 97.5 49 62.0 42 53.2 23 29.1 8 10.1 3 3.8PII(D84) 78 3 3.8 75 96.2 63 80.8 48 61.5 33 42.3 13 16.7 2 2.6

MMRV S- PI(D42) 227 17 7.5 210 92.5 138 60.8 108 47.6 65 28.6 25 11.0 11 4.8PII(D84) 227 8 3.5 219 96.5 182 80.2 147 64.8 91 40.1 36 15.9 11 4.8

S+ PI(D42) 8 0 0.0 8 100 7 87.5 5 62.5 3 37.5 1 12.5 1 12.5PII(D84) 8 0 0.0 8 100 6 75.0 5 62.5 3 37.5 0 0.0 0 0.0

MMRV_1 = MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 = MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 = MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)MMRV : MeMuRu-OKA pooled lotsN = number of subjects with available resultsn/% = number/percentage of subjects with titre within the specified rangePI(D42)=POST-VACCINATION BLOOD SAMPLE AT DAY 42PII(D84) =POST-VACCINATION BLOOD SAMPLE AT DAY 84S- = seronegative subjects (antibody titre < 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccinationS+ = seropositive subjects (antibody titre ≥ 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccinationData source = Appendix table IIIA



Supplement 14 Reverse Cumulative Curve of anti-Mumps antibody titres postdose 1 in intially seronegative subjects (Total Vaccinated Cohort,subjects included in non-random subset; tested in 2005)

Source: Appendix Table III.aMMRV_1 : MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 : MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 : MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)

Source: Appendix Table III.aGroup MMRV = Pooled MeMuRu-OKA lots



Supplement 15 Reverse Cumulative Curve of anti-Mumps antibody titres postdose 2 in intially seronegative subjects (Total Vaccinated Cohort,subjects included in non-random subset; tested in 2005)





Supplement 16 Distribution of ANTI-MUMPS (PRNT) antibody titre by pre-vaccination status (ATP cohort for immunogenicity, subjectsincluded in non-random subset; tested in 2005)

<28 1/DIL ≥28 1/DIL ≥56 1/DIL ≥112 1/DIL ≥224 1/DIL ≥448 1/DIL ≥896 1/DILGroup Pre-vacc

statusTiming N n % n % n % n % n % n % n %

MMRV_1 S- PI(D42) 71 7 9.9 64 90.1 42 59.2 31 43.7 23 32.4 10 14.1 5 7.0PII(D84) 72 0 0.0 72 100 58 80.6 49 68.1 27 37.5 11 15.3 6 8.3

MMRV_2 S- PI(D42) 64 7 10.9 57 89.1 37 57.8 30 46.9 16 25.0 5 7.8 1 1.6PII(D84) 65 4 6.2 61 93.8 51 78.5 41 63.1 27 41.5 10 15.4 3 4.6

S+ PI(D42) 3 0 0.0 3 100 2 66.7 0 0.0 0 0.0 0 0.0 0 0.0PII(D84) 3 0 0.0 3 100 1 33.3 1 33.3 0 0.0 0 0.0 0 0.0

MMRV_3 S- PI(D42) 71 2 2.8 69 97.2 43 60.6 36 50.7 19 26.8 7 9.9 3 4.2PII(D84) 71 3 4.2 68 95.8 57 80.3 42 59.2 28 39.4 9 12.7 1 1.4

MMRV S- PI(D42) 206 16 7.8 190 92.2 122 59.2 97 47.1 58 28.2 22 10.7 9 4.4PII(D84) 208 7 3.4 201 96.6 166 79.8 132 63.5 82 39.4 30 14.4 10 4.8

S+ PI(D42) 3 0 0.0 3 100 2 66.7 0 0.0 0 0.0 0 0.0 0 0.0PII(D84) 3 0 0.0 3 100 1 33.3 1 33.3 0 0.0 0 0.0 0 0.0

MMRV_1 = MJRV vaccine(MJRV159A48) mix Diluent(03A10/585) (Lot A)MMRV_2 = MJRV vaccine(MJRV160A48) mix Diluent(03A10/585) (Lot B)MMRV_3 = MJRV vaccine(MJRV163A48) mix Diluent(03A10/585) (Lot C)MMRV : MeMuRu-OKA pooled lotsN = number of subjects with available resultsn/% = number/percentage of subjects with titre within the specified rangePI(D42)=POST-VACCINATION BLOOD SAMPLE AT DAY 42PII(D84) =POST-VACCINATION BLOOD SAMPLE AT DAY 84S- = seronegative subjects (antibody titre < 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccinationS+ = seropositive subjects (antibody titre ≥ 28 1/DIL for ANTI-MUMPS (PRNT)) prior to vaccinationData source = Appendix table IIIA



Supplement 17 Reverse Cumulative Curve of anti-Mumps antibody titres postdose 1 in intially seronegative subjects status (ATP cohort forimmunogenicity, subjects included in non-random subset; tested in2005)





Supplement 18 Reverse Cumulative Curve of anti-Mumps antibody titres postdose 2 in intially seronegative subjects status (ATP cohort forimmunogenicity, subjects included in non-random subset; tested in2005)





7. REFERENCES

Sato H, Albrecht P, Hicks JT, Meyer BC, and Ennis FA. Sensitive Neutralisation Test forVirus Antibody. Archives of Virology (1978); 58: 301-311.

GlaxoSmithKline Biologicals Clinical Report 208136/038 (MeMuRu-OKA-038) PartI Main Report. A phase III, randomized, controlled study to evaluate theimmunogenicity and safety of three production lots of GlaxoSmithKline Biologicals’combined measles-mumps-rubella-varicella (MeMuRu-OKA) candidate vaccine given ona two-dose schedule to healthy children in their second year of life, as compared toseparate administration of GlaxoSmithKline Biologicals’ measles-mumps-rubella vaccine(Priorix®) and varicella vaccine (Varilrix®).



8. STUDY REPORT AUTHORS/ CONTRIBUTING AUTHORS

Scientific Writer:

Statistician:

Central Study Coordinator:

Clinical Development Manager: MD

Regulatory Affairs Manager:

N + 1 of CDM:



9. APPENDICES

List of Appendices available for the annex report

Clintrial Eligibility Code Not applicable.

Notes To Individual Listings

APPENDIX 1: INDIVIDUAL LISTINGSAppendix table IA - Individual subject data : sub-randomisationAppendix table IIIA - Individual subject data : IMMUNOGENICITY

Notes To Individual ListingsThe following abbreviations are common throughout the Appendix tables:

Sub. No. : subject numberElig. : eligibilityE : eliminated from reactogenicity and immunogenicity analysesI : eliminated from immunogenicity analysisCtr. : Study centreAbbreviations which are unique to a particular appendix are presented below.

Appendix table IIIAcut : Cut-off of the laboratory assayAP : Absence of parallelismBS ND : Blood sampling not doneIR : Invalid resultQNS : Quantity of serum not sufficientBlank : Blood sample not available or test not requested

Appendix 1Individual Listings

This section contained data from each individual patient, rather than in aggregate. They have

been excluded to protect patient privacy. Anonymized data from each patient may be made

available subject to an approved research proposal. For further information please see the

Patient Level Data section of the GSK Clinical Study Register.

This section contained Principal Investigator’s Curriculum Vitae and has been excluded to

protect Principal Investigator privacy.

in february 2013, glaxosmithkline (gsk) announced a … · 2018-11-04 · 28 april 2004...

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