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Clinical Study Report

Combined Cumulative Irritation Potential and Repeat Insult Patch Test of LEO 90100 Aerosol Foam

A phase 1 study evaluating the skin irritation potential and sensitisation potential of LEO 90100 aerosol foam and the aerosol foam vehicle after repeated applications to the

skin of healthy subjects

A single-centre, prospective, randomised, investigator-blinded, vehicle- and negative-controlled clinical study, with intra-individual comparison of treatments

LEO Pharma A/S LP0053-66Clinical Development and Safety 18-Jun-2014

EudraCT Number: 2012-004264-21

00449562

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Clinical Study Report Statement

Approval Statement, Sponsor

The following persons have approved this clinical study report on behalf of LEO Pharma A/S

using electronic signatures:

Biostatistics

Medical Department

Approval Statement, Investigator

The coordinating investigator approves the clinical study report by manually signing the

Coordinating Investigator Clinical Study Report Approval Form, which is a separate

document adjoined to this report.

The following person has approved this clinical study report:

, MD

International co-ordinating investigator

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Compliance with Good Clinical Practice

This clinical study report is designed to comply with the standards issued by the International

Conference on Harmonisation (ICH) (E3 Structure and Content of Clinical Study Reports and

clarified in the ICH E3 Q&A document 07-Jun-2012; E6 Good Clinical Practice; E9

Statistical Principles for Clinical Trials and M4 Common Technical Document) (1,2,3,4,5).

Public Registration of the Clinical Trial

The trial was registered on Clinicaltrials.gov on 27-Aug-2013, NTC01935869.

Synopsis

The synopsis of this clinical study report exists as a separately approved document.

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Table of Contents

Clinical Study Report Statement ................................................................................................ 2

Compliance with Good Clinical Practice ................................................................................... 3

Synopsis ..................................................................................................................................... 3

Table of Contents ....................................................................................................................... 4

List of Tables (In-Text)............................................................................................................... 8

List of Figures (In-Text) ............................................................................................................. 9

List of Appendices.................................................................................................................... 10

List of Abbreviations and Definition of Terms ........................................................................ 12

1 Ethics ................................................................................................................................... 14

1.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB) .................. 14

1.2 Ethical Conduct of the Trial ............................................................................................ 14

1.3 Subject Information and Informed Consent .................................................................... 14

2 Investigators and Trial Administrative Structure................................................................. 16

3 Introduction ......................................................................................................................... 18

3.1 Psoriasis Vulgaris ............................................................................................................ 18

3.2 Investigational Product.................................................................................................... 18

3.3 Trial Rationale ................................................................................................................. 19

4 Trial Objectives ................................................................................................................... 20

5 Investigational Plan ............................................................................................................. 21

5.1 Overall Trial Design ........................................................................................................ 21

5.1.1 Overview of the Trial .................................................................................................. 21

5.1.2 Trial Phases.................................................................................................................. 22

5.1.2.1 Screening Phase, Day -42 to Day -1........................................................................ 22

5.1.2.2 Induction Phase, Day 1 to Day 21 ........................................................................... 22

5.1.2.3 Rest Phase, Day 22 to Day 35 ................................................................................. 24

5.1.2.4 Challenge Phase, Day 36 to Day 40 (Day 41, if applicable) ................................... 24

5.1.2.5 Re-Challenge Phase, if applicable ........................................................................... 25

5.1.2.6 Follow-up Visit, if applicable .................................................................................. 25

5.2 Discussion of Trial Design, Including the Choice of Control Groups ............................ 25

5.3 Selection of Trial Population........................................................................................... 26

5.3.1 Inclusion Criteria ......................................................................................................... 26

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5.3.2 Exclusion Criteria........................................................................................................ 27

5.3.3 Removal of Subjects from Therapy or Assessment..................................................... 28

5.4 Treatments ....................................................................................................................... 28

5.4.1 Treatments Administered............................................................................................. 28

5.4.2 Investigational Products .............................................................................................. 29

5.4.3 Method of Assigning Subjects to Treatment Groups................................................... 32

5.4.4 Selection and Timing of Dose for each Subject .......................................................... 33

5.4.5 Blinding ....................................................................................................................... 34

5.4.6 Prior and Concomitant Therapy .................................................................................. 34

5.4.7 Treatment Compliance ................................................................................................ 35

5.5 Assessments..................................................................................................................... 35

5.5.1 Frequency and Timing of Measurements .................................................................... 35

5.5.2 Baseline Characteristics and Demographics Assessed ................................................ 38

5.5.3 Clinical Assessments ................................................................................................... 39

5.5.3.1 Skin Test Site Assessments ...................................................................................... 39

5.5.3.2 Imaging Assessments............................................................................................... 40

5.5.4 Safety Measurements Assessed ................................................................................... 41

5.5.4.1 Adverse Events ........................................................................................................ 41

5.5.4.2 Reporting of Adverse Events ................................................................................... 42

5.5.4.3 Other Events to be Reported.................................................................................... 44

5.5.4.4 Serious Adverse Events ........................................................................................... 45

5.5.5 Appropriateness of Measurements .............................................................................. 45

5.6 Endpoints/Response Criteria ........................................................................................... 46

5.6.1 Efficacy Evaluation ..................................................................................................... 46

5.6.2 Safety Evaluation ........................................................................................................ 46

5.6.2.1 Primary Response Criteria....................................................................................... 46

5.6.2.2 Secondary Response criteria.................................................................................... 46

5.6.2.3 Evaluation of (Serious) Adverse Events .................................................................. 47

5.7 Data Quality and Assurance ............................................................................................ 47

5.8 Changes to the Conduct of the Trial ................................................................................ 48

6 Statistical Methods .............................................................................................................. 49

6.1 Determination of Sample Size......................................................................................... 49

6.2 Statistical and Analytical Plan......................................................................................... 49

6.2.1 Summary ..................................................................................................................... 49

6.2.2 General principles........................................................................................................ 49

6.2.3 Subject qualification for analysis ................................................................................ 50

6.2.4 Reasons for Leaving the Trial ..................................................................................... 50

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6.2.5 Demographics and Baseline Characteristics ............................................................... 51

6.2.6 Treatment Compliance and Extent of Exposure.......................................................... 51

6.2.7 Analysis of Efficacy .................................................................................................... 51

6.2.8 Analysis of Safety ....................................................................................................... 51

6.2.8.1 Skin Irritation Potential............................................................................................ 51

6.2.8.2 Skin Sensitisation Potential ..................................................................................... 52

6.2.8.3 Adverse Events ........................................................................................................ 53

6.3 Changes to the Statistical Analysis Plan.......................................................................... 53

6.4 Software and Dictionaries ............................................................................................... 54

7 Trial Population ................................................................................................................... 55

7.1 Disposition of Subjects.................................................................................................... 55

7.2 Protocol Deviations ......................................................................................................... 57

7.3 Trial Analysis Sets ........................................................................................................... 57

7.3.1 Skin Irritation Analysis Set.......................................................................................... 58

7.3.2 Skin Sensitisation Analysis Set ................................................................................... 58

7.3.3 Safety Analysis Set ...................................................................................................... 58

7.4 Demographic and other Baseline Characteristics............................................................ 59

7.4.1 Demographic Data....................................................................................................... 59

7.4.2 Medical history and Use of Concomitant Medication................................................. 61

8 Exposure and Treatment Compliance.................................................................................. 62

9 Efficacy Evaluation ............................................................................................................. 63

10 Safety Evaluation................................................................................................................. 64

10.1 Skin Irritation Potential ................................................................................................... 64

10.2 Skin Sensitisation Potential ............................................................................................. 67

10.3 Adverse Events................................................................................................................ 69

10.3.1 Brief Summary of Adverse Events .............................................................................. 70

10.3.2 Incidence of Adverse Events ....................................................................................... 70

10.3.3 Adverse Events by Intensity........................................................................................ 73

10.3.4 Adverse Drug Reactions and Adverse Events on the Application Areas .................... 74

10.3.5 Adverse Events Leading to Withdrawal ...................................................................... 76

10.4 Deaths, other Serious Adverse Events, and other Significant Adverse Events ............... 76

10.4.1 Narratives of Serious Adverse Events ......................................................................... 76

10.5 Pregnancies...................................................................................................................... 76

10.6 Safety Conclusions .......................................................................................................... 77

11 Discussion and Overall Conclusions ................................................................................... 79

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11.1 Discussion ....................................................................................................................... 79

11.2 Overall Conclusions ........................................................................................................ 80

12 References ........................................................................................................................... 81

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List of Tables (In-Text)

Table 1: Identity of LEO 90100 ..................................................................................... 30

Table 2: Identity of Aerosol Foam Vehicle..................................................................... 31

Table 3: Identity of White Petrolatum............................................................................ 32

Table 4: Schedule of Trial Procedures............................................................................ 36

Table 5: Fitzpatrick Skin Type ....................................................................................... 38

Table 6: Age: Skin Sensitisation Analysis Set ............................................................... 60

Table 7: Sex and Skin Type: Skin Sensitisation Analysis Set ........................................ 60

Table 8: Ethnic Origin and Race: Skin Sensitisation Analysis Set ................................ 60

Table 9: Baseline Skin Assessment of Dermal Response by Treatment Group: Skin Sensitisation Analysis Set................................................................................. 61

Table 10: Maximal Dermal Response Category During the Induction Phase (Day 2-22): Skin Irritation Analysis Set .............................................................................. 64

Table 11: Maximal Dermal Response During the Induction Phase (Day 2-22): Skin Irritation Analysis Set....................................................................................... 65

Table 12: Mean Cumulative Irritation Index (MCII) During the Induction Phase: Skin Irritation Analysis Set....................................................................................... 66

Table 13: Maximal Dermal Response Category During Challenge Phase: Skin Sensitisation Analysis Set................................................................................. 68

Table 14: Dermal Response Category During Challenge Phase by Time Point: Skin Sensitisation Analysis Set................................................................................. 69

Table 15: Overall Summary of Adverse Events: Safety Analysis Set.............................. 70

Table 16: Treatment-Emergent Adverse Events by MedDRA Primary System Organ Class: Safety Analysis Set ................................................................................ 71

Table 17: Treatment-Emergent Adverse Events by MedDRA Primary SOC and Preferred Term: Safety Analysis Set ................................................................................ 72

Table 18: Treatment-Emergent Adverse Drug Reactions by MedDRA Primary System Organ Class and Preferred Term: Safety Analysis Set ..................................... 75

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List of Figures (In-Text)

Figure 1: Trial Design ...................................................................................................... 22

Figure 2: Example of Allocation of Test Sites ................................................................. 33

Figure 3: Disposition of Subjects..................................................................................... 56

Figure 4: Trial Analysis Sets............................................................................................ 59

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List of Appendices

Trial Information

Appendix No.

Appendix Title Status

1.1 Clinical Study Protocol and Amendments Enclosed

1.2 Sample CRF Enclosed

1.3 List of IEC or IRBs and Representative Written Information for the Subjects and Sample Consent Form

Enclosed

1.4 List of Investigators and CV for International Coordinating Investigator

Enclosed

1.5 Signatures of International Coordinating Investigator Enclosed

1.6 Listing of Subjects receiving Investigational Product from Specific Batches

NA

1.7 Randomisation Scheme and Codes Enclosed

1.8 Audit Certificates NA

1.9 Documentation of Statistical Methods Enclosed

1.10 Documentation of Laboratory Standardisation Methods and Quality Assurance Procedures

NA

1.11 Publications based on the Trial NA

1.12 Important Publications Referenced in the Clinical Study Report

Available upon request

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Listings

Appendix No Appendix Title Status

2.1 Discontinued Subjects Enclosed

2.2 Protocol Deviations Enclosed

2.3 Trial Analysis Sets Enclosed

2.4 Demographic Data Enclosed

2.5 Compliance and/or Investigational Product Concentration Data

Enclosed

2.6 Efficacy (or other as appropriate) Data NA

2.7 Safety Data Enclosed

2.8 Listing of Laboratory Values by Subject Enclosed

Case Report Forms

Appendix No Appendix Title Status

3.1 CRFs for Deaths, other SAEs, and Withdrawals due to AEs

Available upon request

3.2 Other CRFs Submitted NA

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List of Abbreviations and Definition of Terms

LIST OF ABBREVIATIONS

ADR Adverse drug reaction

AE Adverse event

ANOVA Analysis of variance

BMI Body mass index

CI Confidence interval

CRF Case report form

CRO Contract research organisation

EU European Union

FDA Food and Drug Administration

FU Follow-up

GCP Good Clinical Practice

ICH International Conference on Harmonisation

ICTM International clinical trial manager

IEC Independent ethics committee

IR Irritant reaction

IRB Institutional review board

LOCF Last observation carried forward

MCII Mean Cumulative Irritation Index

MedDRA Medical Dictionary for Regulatory Activities

NLCRA National lead clinical research associate

NT Not tested

SAE Serious adverse event

SAPU Statistical analysis plan update

SD Standard deviation

SmPC Summary of product characteristics

SOC System Organ Class

SOP Standard Operating Procedure

SUSAR Suspected unexpected serious adverse reaction

UV Ultraviolet

DEFINITION OF TERMS

Terms defined by ICH Guidelines are not mentioned here.

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Assessment

A (cluster of) characteristic(s) measured and/or recorded for a subject.

Concomitant Medication

Any medication used by a subject during the clinical trial apart from the trial medication.

DAIVOBET®/DOVOBET®/TACLONEX® Ointment

Referred to as Daivobet® ointment.

Enrolled Subject

A subject for who informed consent has been obtained and who has been registered in a

clinical trial.

International Clinical Trial Manager (ICTM)

The qualified person appointed by LEO to be the main international sponsor representative

responsible for all aspects of a clinical trial as outlined in Global Clinical Operations Standard

Operational Procedures (SOPs).

LEO

LEO (no suffix): refers to the corporate organisation of LEO Pharma A/S.

Monitor

A person appointed by LEO to carry out monitoring of a clinical trial.

National Lead Clinical Research Associate (NLCRA)

The person appointed to be the national sponsor representative responsible for all aspects of a

clinical trial within a country as outlined in Global Clinical Operations SOPs.

Randomisation Code List

A list of (sequential) numbers to each of which a treatment is allocated (assigned). Treatment

may be revealed as a code letter (e.g. A, B, …) or by directly revealing the specific treatment

(investigational product).

Response Criterion

An assessment or a transformation of the assessment(s) described on a subject level, for

which a statistical analysis is performed, i.e. a p-value or a confidence interval is stated, or for

which tabulation serves as important supportive evidence of efficacy/safety.

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1 Ethics

1.1 Independent Ethics Committee (IEC) or Institutional Review Board

(IRB)

The clinical study protocol received favourable opinion from the relevant Independent Ethics

Committee (IEC).

The appropriate regulatory authority approved the clinical trial, as required.

All details of the IEC consulted are given in Appendix 1.1.

1.2 Ethical Conduct of the Trial

The clinical trial was conducted to conform to the principles of the Declaration of Helsinki as

adopted by the 18th World Medical Assembly, June 1964, and subsequent amendments.

The clinical trial was conducted in compliance with the clinical study protocol, Good Clinical

Practice (GCP), and the applicable regulatory requirements.

All subjects received written and verbal information concerning the clinical trial as specified

in Section 1.3.

Subjects were asked to consent that their personal data were recorded, collected, processed

and could be transferred to EU and non-EU countries in accordance with any national

legislation regulating privacy and data protection.

All information containing personal data was to be handled in accordance with the general

terms of the authorisation granted by the Danish Data Protection Agency to LEO Pharma A/S

(hereafter referred to as LEO), as appended to the clinical study protocol, in accordance with

the EU Data protection Directive (95/46/EC) as well as any national data protection

legislation.

1.3 Subject Information and Informed Consent

All subjects received written and verbal information concerning the clinical trial. This

information emphasised that participation in the clinical trial was voluntary and that the

subject could withdraw from the clinical trial at any time and for any reason. All subjects

were given an opportunity to ask questions and were given sufficient time to consider all

relevant issues before consenting.

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The subject’s signed and dated informed consent to participate in the clinical trial was

obtained prior to any trial-related activities being carried out. A representative subject

information sheet and informed consent form is provided in Appendix 1.3.

The investigator signed a clinical trial agreement before the clinical trial was initiated to

confirm the above.

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2 Investigators and Trial Administrative Structure

LEO Phan na A/S was the sponsor of the clinical trial and the pruiicipating LEO affiliate was

authorised by the sponsor to act on behalf of the sponsor.

Role

Intemational coordinating investigator:

Head of Medical Department:

Head of Biostatistics:

Ttial statistician:

Intemational clinical trial manager (ICTM)/National Lead CRA (NLCRA):

Sponsor 's Medical Expett s:

Name, title, affiliation

--, MSc, ~ma Denmark. Tel. :

MD.---Ph~quee 1' Archet 06202 Nice Cedex 3,

e-mail:

Biostatistics and Data Management, DK-2750 Ballemp,

, Fax: email:

, MSc,- Biostatistics and Data ~aboratoires LEO),

c auCIIon. 78960 Voisins-le-Bretonneux, France, Tel. : e-mail:

LP0053-66

Contract Research Organisations (CROs)

Pharmacovigilance scientist:

Medical writer:

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C3i Europe Inc, Sofia Business Park, Mladost 4, Building 7, Floor 1; Sofia, Bulgaria 1766. The CRO was responsible for help desk services to Remote Data Capture users at the investigational site and for any emergency unblinding.

The CRO was responsible for the manufacture of the aerosol foam (filled bulk) investigational products

The CRO was responsible for secondary packaging, labelling final QP release and distribution of the investigational products as well as reconciliation and destruction of returned investigational products.

, Medical Department, Ballemp,

The cmTiculum vitae of the international coordinating investigator and a list of other persons

whose participation materially affected the conduct of the trial are included in Appendix 1.4.

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3 Introduction

3.1 Psoriasis Vulgaris

Psoriasis is one of the most common chronic skin diseases affecting approximately 1–3% of

the population (6,7,8). The major manifestation of psoriasis vulgaris (also known as plaque

psoriasis) is chronic inflammation of the skin, characterised by sharply demarcated, scaling,

and erythematous plaques that may be painful and often severely pruritic. In order to reduce

the risk of systemic toxicity, topical therapy is the regimen of choice for subjects with less

extensive disease which comprises two thirds of all subjects with psoriasis (9). The most

commonly used topical treatments are corticosteroids and vitamin D analogues which can be

used alone or in combination. However, application of topical therapies can be cumbersome,

messy and time-consuming, which can have a negative impact on adherence to the prescribed

treatment regimen and ultimately result in poor control of the disease. Thus, there is an unmet

need for development of topical psoriasis treatments that, in addition to being highly

efficacious, are also convenient and easy to use, which could reduce the burden of daily

treatment and improve adherence to therapy.

3.2 Investigational Product

LEO 90100 is an aerosol formulation of calcipotriol 50 mcg/g (as hydrate) and betamethasone

0.5 mg/g (as dipropionate) currently under development for the topical treatment of psoriasis

vulgaris. LEO 90100 is contained in an aluminium can with dimethyl ether and butane

propellants. At administration, the majority of propellants (butane and dimethyl ether)

evaporate quickly leaving a foam with propellant residues on the skin. Apart from the

propellants, no new excipients have been added to LEO 90100 as compared to the marketed

formulation of the investigational product, DAIVOBET®/DOVOBET®/TACLONEX®

ointment (hereafter referred to as Daivobet® ointment).

LEO 90100 has been developed with the purpose of improving the convenience and ease of

use of the product for patients with psoriasis vulgaris. It may be a more cosmetically accept-

able alternative to Daivobet® ointment, which contains the same active ingredients in the

same concentration.

The efficacy and safety of LEO 90100 were evaluated in two phase 2 trials and one phase 3

trial including a total of 1,104 subjects with psoriasis vulgaris whereof 564 subjects received

LEO 90100 (10,11,12). LEO 90100 applied once daily for 4 weeks was shown to be more

effective than either of its individual components (betamethasone dipropionate and

calcipotriol) formulated in the same vehicle, Daivobet® ointment, and the vehicle alone.

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Overall, LEO 90100 appeared to be well tolerated with a safety profile comparable to that of

Daivobet® ointment.

In the present trial, the skin irritation and sensitisation potential of LEO 90100 was compared

with the foam vehicle and a negative control. The foam vehicle was included to determine if

any possible irritation or sensitisation reaction could be induced by the drug substance or by

the vehicle formulation. White petrolatum was used as negative control, as this product is

considered to be one of the most inert of all topical agents and well-known for its low-

sensitising and low-irritating properties (13).

3.3 Trial Rationale

Assessment of skin irritation and sensitisation potential is required by regulatory authorities

for new topical drugs. As LEO 90100 is a new formulation containing dimethyl ether and

butane as propellants, there is a need to confirm the dermal safety of this formulation.

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4 Trial Objectives

The primary objective of the trial was to determine the skin irritation potential and

sensitisation potential of LEO 90100 aerosol foam and the aerosol foam vehicle after repeated

applications on the skin of healthy subjects.

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5 Investigational Plan

5.1 Overall Trial Design

The clinical study protocol is enclosed in Appendix 1.1 and the unique pages of the case

report form (CRF) are presented in Appendix 1.2.

5.1.1 Overview of the Trial

Trial LP0053-66 was a single-centre, prospective, randomised, investigator-blinded, vehicle-

and negative-controlled phase 1 trial with intra-individual comparison of treatments.

In total, 200 healthy subjects who fulfilled all eligibility criteria were planned to be

randomised to receive repeated topical applications of each of the following products:

LEO 90100 aerosol foam (LEO 90100)

Aerosol foam vehicle

Vaseline officinale Cooper (white petrolatum; negative control)

The trial consisted of 4 phases: a screening phase (up to 6 weeks), an induction phase

(3 weeks), a rest phase (2 weeks), and a challenge phase (5 or 6 days). A re-challenge phase

and/or a follow-up phase were performed, if required.

Each subject received 15 applications of each investigational product during the induction

phase (21 days) and one application of each investigational product during the challenge

phase. The duration of trial participation for each subject was up to 12 weeks, including a

screening phase and a rest-phase where subjects were not treated.

In case re-challenge was needed, additional 3 weeks’ trial participation was required.

The trial design is presented in Figure 1.

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Figure 1: Trial Design

5.1.2 Trial Phases

5.1.2.1 Screening Phase, Day -42 to Day -1

The screening phase took place within 6 weeks before the start of the induction phase

(Day 1).

Before any trial related procedure, the subjects received the necessary written and verbal

information and instructions including informed consent form (written informed consent) and

the written subject information sheet. Each subject received a unique CRF number and

eligibility was determined by clinical examination and confirmation of in- and exclusion

criteria.

During the screening phase general data such as demographics, vital signs (blood pressure and

heart rate), physical examination, height and weight, relevant medical history, concomitant

medication, and concurrent diagnoses were recorded. All women of childbearing potential had

to take a urine pregnancy test.

5.1.2.2 Induction Phase, Day 1 to Day 21

Each subject received 15 applications of each investigational product during the induction

phase (21 days), distributed as five applications per week (every day except weekends) of

each product on the 3 selected test sites under semi-occlusive conditions (patches) on the

subject’s middle back. All subjects received the investigational products according to the

randomisation list. Each investigational product was applied on the same test site throughout

the induction phase.

Day 1

The start of the induction phase was defined as Day 1 (baseline). A re-check of all in- and

exclusion criteria was performed in subjects who were suitable based on examinations

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performed at the screening visit. Concomitant medication and adverse events (AEs) were

reported. Vital signs were evaluated and all women of childbearing potential had to take a

urine pregnancy test. If all eligibility criteria were met, the subject continued in the trial and

received a unique randomisation number.

After randomisation, skin test sites on the subject’s middle back were identified and a baseline

assessment of the skin test site was performed prior to the first application (score 0, no

reaction). Subsequently, each investigational product was applied on each of the test sites by

gently rubbing of the products into the skin followed by covering of test sites by semi-

occlusive patches.

Day 2 to Day 21

The rest of the induction phase took place from Day 2 to Day 21 of the trial. The following

procedures were performed at each visit:

Test patches applied on a Monday to Thursday were removed after 24 hours and those applied

on a Friday were removed after 72 hours. Skin reactions (score 0 to score 4) were assessed for

each test site approximately 30 minutes after removal of the patch and any products left on the

skin test site. Concomitant medication and AEs were reported. New applications of the

investigational products on the test sites and gently rubbing of the products into the skin were

performed, followed by covering of test sites by semi-occlusive patches.

If a subject missed one visit in the induction phase, one replacement application was to be

performed during the rest phase (Section 5.1.2.3). Subjects who missed additional visits were

to be withdrawn from the trial.

It was allowed to change application site if an unacceptable reaction was observed (score 3 or

4, or symptomatic intolerance irritation). In this case, the test site was to be relocated to

another skin area beside the original test site. The application was continued at the relocated

site to ensure the maximum had been done to achieve the intended induction phase of 21

days. This procedure could be repeated two times. If the skin reaction was rated as 3 or 4, or if

the subject experienced symptomatic intolerance irritation on the third relocated site (original

test site + second relocated test site), product applications were to be discontinued until the

challenge phase. The subject would not necessarily be withdrawn. The new test site would be

clinically scored in consistency with the trial procedures at the planned days using the same

dermal response score. However, for the analysis, the highest score observed prior to

discontinuation of the original test site, was to be carried forward for all remaining

observations in the skin irritation analysis.

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5.1.2.3 Rest Phase, Day 22 to Day 35

After completion of the induction phase, the subjects continued in a 2-week period without

any applications or assessments. However, if a subject had missed a single visit in the

induction phase, one replacement application was to be performed during the rest phase.

On Day 22, the patches and any product left on the skin test sites were removed after the last

application in the induction phase. Concomitant medication and AEs were reported. Skin

reactions (score 0 to score 4) were assessed for each test site approximately 30 minutes after

removal of the patch and any products left on the skin test site.

5.1.2.4 Challenge Phase, Day 36 to Day 40 (Day 41, if applicable)

In the challenge phase, the sensitisation potential of each investigational product was tested

on a treatment-naive skin test site on the subject’s upper back.

On Day 36, concomitant medication and AEs were reported. New skin test sites on the

subject’s upper back were identified according to the randomisation code list and the baseline

assessment of the skin test sites prior to the first applications. Subsequently, each

investigational product was applied on each of the test sites by gently rubbing of the products

into the skin followed by covering of test sites by semi-occlusive patches.

On Day 38, patches and any products left on the skin test sites were removed 48 hours after

application. Concomitant medication and AEs were reported. Skin reactions (score - to score

+++) were assessed for each test site approximately 30 minutes after removal of the patches

and any products left on the skin test site.

On Day 39, concomitant medication and AEs were reported. Skin reactions (score - to score

+++) were assessed for each test site approximately 24 hours after removal of the patches.

On Day 40, concomitant medication and AEs were reported and all women of childbearing

potential had to take a urine pregnancy test. Skin reactions (score - to score +++) were

assessed for each test site approximately 48 hours after removal of the patches. On each test

site, the investigator’s assessed whether a possible sensitisation reaction

(negative/equivocal/positive) had occurred, taking into account all skin assessments

performed during the challenge phase. Any positive or equivocal reaction was to be

photographed. If the sensitisation reaction was assessed equivocal, an additional visit could be

arranged at the investigator’s discretion on Day 41.

On Day 41 (if applicable), concomitant medication and AEs were reported. Skin reactions

(score - to score +++) were assessed for each test site approximately 72 hours after removal of

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the patches. On each test site, the investigator assessed whether a possible sensitisation

reaction (negative/equivocal/positive) had occurred, taking into account all skin assessments

performed during the challenge phase. Any positive or equivocal reaction was to be

photographed.

5.1.2.5 Re-Challenge Phase, if applicable

Any subject with a sensitisation reaction assessed as equivocal was re-challenged once after

approximately 2-week rest period using a new naive test site, under the same conditions as for

Day 36 in the challenge phase (Section 5.1.2.4).

5.1.2.6 Follow-up Visit, if applicable

The investigator had to follow up for outcome on all non-serious AEs classified as

possibly/probably related to the investigational product or not assessable for 2 weeks after the

subject’s final visit or until final outcome was determined, whichever came first.

SAEs were to be followed indefinitely until a final outcome has been established, i.e. the

follow-up could continue beyond the end of the clinical trial.

5.2 Discussion of Trial Design, Including the Choice of Control Groups

Trial Design

Trial LP0053-66 was a single-centre, prospective, randomised, investigator-blinded, vehicle-

and negative-controlled phase 1 trial with intra-individual comparison of treatments in healthy

subjects. The trial was conducted to provide complementary data on the skin irritation

potential and sensitisation potential of LEO 90100. The trial combined the trial designs of two

commonly accepted tests: the 21-day cumulative irritation test to evaluate the potential of a

topical product to induce skin irritation after repeated exposure to the skin (14,15), and the

human repeated insult patch test to determine the allergic contact dermatitis potential of

topically applied products (16).

Subjects

Healthy subjects, rather than patients with skin disease, were enrolled in this trial to eliminate

the possible complication of distinguishing between signs and symptoms associated with a

skin disease and those caused by a possible irritation and sensitisation reaction.

Endpoints

The endpoints considered in this clinical trial reflect the combination of the two well-

established methods of assessing the irritation potential and sensitisation potential of topical

products (see above). This approach is in accordance with recommendations from the Food

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and Drug Administration (FDA) (Guidance for Industry. Acne Vulgaris: Developing Drugs for

Treatment. U.S. Department of Health and Human Services Food and Drug Administration

Center for Drug Evaluation and Research (CDER), September 2005). See Section 5.5.5 and

Section 6.1 for further details.

Dosage

Subjects in the present trial received approximately 122 mg × 16 times of each aerosol foam

investigational product corresponding to 50 mg per dose (on 4 cm2 skin area) after

evaporation of the propellants. The total dose applied is thus below the amount of calcipotriol

and steroids typically used by psoriasis patients. The aerosol foam vehicle was included to

determine if any irritation or sensitisation reaction was induced by the drug substance or by

the vehicle formulation. White petrolatum was used as negative control, as this product is

considered to be one of the most inert of all topical agents and well-known for its low-

sensitising and low-irritating properties (13).

5.3 Selection of Trial Population

5.3.1 Inclusion Criteria

To be included in the trial, subjects had to fulfil all of the following criteria:

1. Following verbal and written information about the trial, subjects had to provide signed

and dated informed consent before any trial related activities were carried out.

2. Healthy male or female subjects, 18 to 65 years of age inclusive at Screening.

3. Female subjects of childbearing potential had to be willing to use an effective method

of contraception for at least 1 month before the trial start and for the duration of the

trial participation (e.g., oral contraceptive pill, intrauterine device, contraceptive

patches, implantable contraception, condoms) or females of non-childbearing potential

(i.e. post-menopausal (absence of menstrual bleeding for 1 years), hysterectomy,

bilateral ovariectomy or tubal section/ligation).

4. Subjects had to be in good health, as determined by medical history, physical

examination and vital signs.

5. Subjects affiliated to a social security system.

6. Female subjects of childbearing potential with a negative urine pregnancy test (at the

Screening Visit and Day 1).

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5.3.2 Exclusion Criteria

Any of the following was regarded as a criterion for exclusion from the trial:

1. Female subjects who were pregnant, of childbearing potential and who wish to become

pregnant during the trial, or who were breast feeding.

2. Subjects with any systemic or cutaneous disorder that could interfere with the

evaluation of the test site reactions (e.g. atopic dermatitis, contact eczema, psoriasis).

3. Subjects with scars, moles or other abnormal pigmentation of the skin or skin type that

could, in any way, confound interpretation of the trial results (skin type V and VI on

the Fitzpatrick scale).

4. Subjects with any of the following conditions on the test area: viral (e.g. herpes or

varicella) lesions of the skin, fungal or bacterial skin infections, parasitic infections,

acne vulgaris, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, ulcers

and wounds.

5. Subjects who had been exposed to excessive or chronic ultraviolet (UV) radiation (i.e.

sunbathing, solarium) prior to randomisation or who could foresee an intensive UV

exposure during trial participation.

6. Subjects with known sensitivity or allergy to any component(s) of the investigational

products.

7. Subjects who had received any topical or systemic corticosteroids (except for

nasal/inhaled corticosteroids) or immune-suppressors within 3 weeks prior to

randomisation.

8. Subjects who had received systemic or topical analgesics, antihistamines or non-

steroidal anti-inflammatory drugs within 3 days prior to randomisation.

9. Subjects who had participated in any other interventional clinical trial within 1 month

prior to randomisation.

10. Subjects, who in the opinion of the investigator, were unlikely to comply with the

clinical study protocol (e.g. alcoholism, drug dependency, or psychotic state).

11. Subjects who were in an exclusion period in the National Biomedical Research

Register of the French Ministry of Health at randomisation.

12. Subject under guardianship, hospitalised in a public or private institution, for a reason

other than the research or subject deprived of freedom.

13. Subjects previously randomised in this trial.

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5.3.3 Removal of Subjects from Therapy or Assessment

Subjects could withdraw for any of the following reasons:

1. Unacceptable AEs: any AE that the investigator or the subject considered unacceptable.

2. Exclusion criteria: any exclusion criteria which emerged/became apparent during the

subject’s participation in the clinical trial.

3. Voluntary withdrawal: subjects were free to withdraw from the clinical trial at any time

and for any reason.

4. Other reasons: other reasons than stated above which required the subject to (be) with-

draw(n) had to be specified.

Subjects who were discovered, after enrolment/randomisation, not to have fulfilled all

in-/exclusion criteria at time of enrolment, were to be withdrawn from treatment unless the

investigator, based on clinical and ethical evaluation, found withdrawal inappropriate. Such

deviation(s) from the clinical study protocol had to be reported to LEO (and IEC) and

recorded in the clinical study report.

Reason(s) for withdrawal were to be recorded in the CRF.

Subjects withdrawn were not to be substituted.

5.4 Treatments

5.4.1 Treatments Administered

No investigational products were dispensed to the subjects. All applications were performed

by designated trial personnel at the trial site.

LEO 90100 aerosol foam and the aerosol foam vehicle were applied (sprayed) directly to each

subject’s back using a template with a 2×2 cm square stamped out. A total of 122 mg of the

aerosol foam product was applied per dose, corresponding to 50 mg per dose after

evaporation of the propellants and each investigational product was gently massaged into the

skin test site of 4 cm2 using a gloved finger.

The negative control, white petrolatum (50 mcl), was applied on the skin test sites delimitated

by a 2×2 cm template using a calibrated Eppendorf combitip® and gently massaged into the

skin using a gloved finger.

Gloves were changed between each product application to avoid contamination.

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The 3 test sites were covered by semi-occlusive patches consisting of a thin 2×2 cm piece of

non-woven compress maintained on the skin surface with a 5×5 cm piece of kind removal,

breathable, hypoallergenic medical tape with silicone adhesive, standard roll (Micropore

Silicone 3M tape). The patch was semi-occlusive to allow the propellants in the aerosol foam

to evaporate after application.

The distance between the patches was at least 2 cm. The skin test areas were to be clean, i.e.

free excessive sebum and product (after start of dosing) before (re)-application of the

products.

The evaluators and (sub)investigators performing the skin test site assessments were not

allowed to perform the applications and the removal of the semi-occlusive patches. Likewise,

the site personnel performing the applications for a group of subjects were the only persons at

the trial site who had access to the randomisation code list for this group of subjects.

The site staff weighed each aerosol foam can before and after daily use. A can was only used

for one day, and the weights for pre-use and after-use was recorded on a paper log at the trial

site together with information about number of sprayings.

On Day 1, a subject instruction sheet was handed to the subject. On this sheet, the subject was

instructed:

Not to remove the patch without the trial (sub)investigator’s permission.

To refrain from wetting the skin test sites during the induction phase and challenge phases,

i.e., bath and showers on the back were not permitted.

To avoid swimming, sauna visits and vigorous exercise leading to excessive sweating

(except during the rest phase).

To avoid sunlight, UV light exposure (e.g., solarium).

Not to use any topical products, including emollients on the skin test areas (back).

Not to use systemic products, that could interfere with the skin assessments during trial

participation. Inhaled/nasal corticosteroids were allowed.

Not to take any products without informing the (sub)investigator first. Paracetamol was

allowed, but the (sub)investigator was to be informed at the next visit.

To avoid donating blood.

5.4.2 Investigational Products

The identity of investigational products is presented in Table 1 to Table 3.

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Table 1: Identity of LEO 90100

Name investigational product

F01mulation

Active ingredient name/concenu·ation

Excipients

Manufacturer 's name of ointment bulk

Manufacturer 's name of filled bulk (aerosol foam)

Ce1tifier 's name of filled bulk (aerosol foam)

Supplier 's name

Manufacturer 's name of secondaty packaging and labelling

Ce1tifier 's name of seconda1y packaging and labelling

Lot number/expiry date

LEO 90100 aerosol foam

Aerosol foam

Calcipou·iol50 mcg/g (as hydrate) and betamethasone 0.5 mg/g (as dipropionate)

Paraffm, white soft; paraffin, liquid; PPG-11 steruyl ether, all-rae-a-tocopherol, dimethyl ether, butane

LEO Phruma, 285 Cashel Road, Dublin 12, Ireland

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Table 2: Identity of Aerosol Foam Vehicle

Name investigational product Aerosol foam vehicle

F01mulation Aerosol foam

Active ingredient name/concenu·ation Not applicable

Excipients Paraffin, white soft; paraffin, liquid; PPG-11 steruyl ether, all-rae-a-tocopherol, dimethyl ether, butane

Manufacturer 's name of ointment bulk LEO Laboratories Ltd., 285 Cashel Road, Dublin

~----------------------------4 Manufacturer 's name of filled bulk (aerosol foam)

Ce1tifier 's name of filled bulk (aerosol foam)

Supplier 's name

Manufacturer 's name of seconda1y packaging and labelling

Certifier 's name of secondruy packaging and labelling

Lot number/expi1y date

12, h eland

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Table 3: Identity of White Petrolatum

Name investigational product

F01mulation

Active ingredient name/concenu·ation

Excipients

Manufacturer's name of marketed product

Certifier 's name of marketed product

Supplier's name

Manufacturer's name of seconda1y packaging and labelling

Certifier 's name of secondruy packaging and labelling

Lot number/expi1y date

Vaseline officinale Cooper

Ointment

Not applicable

Peu·olatum 100%

or Cooperation Phrum aceutique Francaise 2 m e de la Saussaie, 77310 Saint F ru·geau Ponthieny, France

Cooperation Phrumaceutique Franc;aise Place Lucien-Auvert, F-77020 Melun Cedex, France

12110078D/April2018

5.4.3 Method of Assigning Subjects to Treatment Groups

For subjects who had been found to comply with all the protocol's inclusion and exclusion

criteria, the location of the test sites with LEO 90100 aerosol foam and the aerosol foam

vehicle, as well as the location of white peu·olatum (negative conu·ol) was pre-planned

according to a computer generated randomisation schedule. The Randomisation Schedule was

generated by LEO.

A subject was to be assigned the next (ascending) randomisation code number available at the

u·ial site.

LEO 90100 aerosol foam and the aerosol foam vehicle were coded as A or B and white

peu·olatum was coded C.

Each of the investigational products was applied on a test site on the subject's back according

to the randomisation code list and refen ed to as Z1, Z2, and Z3. Different skin test sites were

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used during the induction phase (middle back) and the challenge phase (upper back)

(Figure 2).

The site personnel performing the assessments were not allowed to perform the application

and the removal of the semi-occlusive patches. Likewise, the site personnel performing the

applications were the only persons at site having access to the randomisation code list.

The following figure shows an example of allocation of test sites on the subject’s back.

Figure 2: Example of Allocation of Test Sites

5.4.4 Selection and Timing of Dose for each Subject

Each subject received 15 applications of each investigational product during the 21-day

induction phase, distributed as 5 applications per week (every day except weekends) and one

application of each investigational product during the challenge phase.

The procedure of product applications and the doses applied are further detailed in Sections

5.4.1 and 5.4.3.

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5.4.5 Blinding

The trial was performed as an investigator-blinded trial as the (sub)investigator was both

blinded to the identity of the 3 investigational products and the location of the 3 skin test sites.

The site personnel applying products and removing the semi-occlusive patches were blinded

to the identity of the two aerosol foam investigational products (coded A or B on the label).

The access to the randomisation code list was limited to the site personnel applying the

investigational products. For the same subject, the site personnel applying the products were

not allowed to perform any assessments of the skin test sites.

The packaging and labelling of the aerosol foam investigational products contained no

evidence of their identity. Furthermore, it was considered not possible to differentiate between

the 2 different aerosol foams (LEO 90100 and the aerosol foam vehicle) solely by sensory

evaluation.

No effects of the investigational products were expected that would reveal the identity of the

individual treatment allocations.

Emergency un-blinding of individual subject treatment could be achieved by contacting C3i

Helpdesk responsible for un-blinding. An emergency un-blinding request could be made by

the (sub)investigators, other health care professionals, or authorised LEO personnel.

If code break was considered necessary for other safety concerns, for example due to signals

of alerting adverse drug reactions, un-blinding could be performed by Global

Pharmacovigilance at LEO, and the reason for un-blinding had to be documented.

Treatment codes were not broken for the planned analyses of data until all decisions on the

evaluability of the data from each individual subject had been made and documented.

5.4.6 Prior and Concomitant Therapy

Treatments requiring washout prior to randomisation

Any topical or systemic corticosteroids (except nasal/inhaled corticosteroids), immuno-

suppressors within 3 weeks prior to randomisation

Systemic or topical analgesics, antihistamines or non-steroidal anti-inflammatory drugs

within 3 days prior to randomisation

Use of non-marketed/other investigational products 1 months prior to randomisation was

not permitted

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Exposure to excessive or chronic UV radiation (i.e. sunbathing, solarium) prior to the

randomisation and during the trial

During the trial

During Day 1 until trial completion, subjects were not allowed to use any medication which

could interfere with the trial results, including the treatments requiring washout listed above.

Also, no topical products, including emollients, were allowed to be applied on the skin test

sites (middle and upper back) besides the investigational product.

Nasal/inhaled corticosteroids were allowed during the trial.

Use of concomitant treatment was to be recorded in the subject’s medical record and the CRF

(treatment/drug name, dose, indication and dates of start and stop).

5.4.7 Treatment Compliance

No investigational product was dispensed to the subjects. The investigational products were

applied by designated trial personnel at the trial site to ensure treatment compliance.

5.5 Assessments

5.5.1 Frequency and Timing of Measurements

The schedule of all trial procedures for all trial visits is presented in Table 4.

.

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Table 4: Schedule of Trial Procedures

Induction phase (Week 1-3, Day 1- Day 21) Rest period

Challenge phase (Week 6) (Week 4-5)8

Scree FU

Procedures ning Day

visit1 Day Day Day Day

DayS, 6-7, Day Day Day Day Day Day Day (Dax visit5

1, 8, 2, 9, 3, 10, 4, 11, 12, 19 13-14, 22 22-358 36 37 38 39 40 41) I

15 16 17 18 20-21

Inf01med Consenr X

Relevant Medical Hist01y X

Physical examination X

Height and weight X

Vital signs X X

Demographics X

Inclusion/exclusion X X

Criteria

Urine pregnancy tesf X X X

Conctu1·ent diagnoses X

Concomitant X X X X X X X (X) X X X X X X

Medications

Randomisation x4 Baseline Assessment of skin test sites prior to x7 x7 product application

Product application m1der semi -occlusive X X X X X (X) X conditions6

Patch Removal x9 X X X X X (X) X

Test Site Assess-ment10 X X X X X X (X) X X X X

Evaluation of X X

sensitisation potential

Adverse Events X X X X X X (X) X X X X X X

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1. Screening visit was performed within 6 weeks prior to Day 1 in the induction phase.

2. Informed consent was to be signed by the subject and (sub)investigator before any trial related activities were carried out. The subjects were to have enough

time to decide whether or not they would like to participate in the trial.

3. For female of childbearing potential only. A urine pregnancy test was performed at the last visit, but could be earlier than Day 40, in case of premature

withdrawal or later in case of re-challenge.

4. Randomisation on Day 1, Week 1. If the subject was not randomised, the End of Trial Form was to be completed.

5. Follow-up (FU) visit/contact: only applicable if a non-serious adverse event classified as possibly or probably related to the investigational product or not

assessable in relation to the investigational product was present at the subject’s last visit. This follow-up was to be performed 14 ± 2 days after the subject’s

last visit or until final outcome of the adverse event was determined, whichever comes first.

6. Each product was applied on the skin and covered by a semi-occlusive patch. The distance between the patches was at least 2 cm. During the induction

phase, 15 products applications (5 weekly over 3 weeks) were performed on designated sites on the middle of the back. During challenge phase, 1 product

application was performed on designated sites on the upper part of the back.

7. First application in the induction phase (Day1) and the single application in the challenge phase (Day 36) were made on healthy skin.

8. If a subject missed a visit, a replacement application was performed during the rest phase and skin test sites assessed (score 0 to score 4).

9. Except Day 1, Week 1.

10. Scorings were performed 30 minutes after each patch removal in the induction phase and on Day 38 in the challenge phase. Furthermore scoring was

performed 24 and 48 hours after patch removal during challenge phase. During the induction phase, if an unacceptable reaction was observed (score 3 or 4,

or symptomatic intolerance irritation), the investigator was allowed to relocate.

11. On Day 40 (48 hours after patch removal), if the sensitisation reaction evaluation were equivocal, a facultative assessment could be performed at the

investigator's discretion on Day 41 (72 hours after patch removal).

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5.5.2 Baseline Characteristics and Demographics Assessed

Subject’s eligibility for the clinical trial was checked according to the inclusion and exclusion

criteria at Screening and at the Day 1 visit.

Subject’s demographic details (date of birth, gender, race, and ethnic origin) were recorded at

the Screening Visit. The subject reported their ethnicity (Hispanic or Latino, not Hispanic or

Latino) and race (American Indian or Alaska Native; Asian; Black or African America; Native

Hawaiian or Other Pacific Islander; White or Caucasian; Other).

Skin type was assessed by the (sub)investigator and recorded according to the classification in

Table 5 (17).

Table 5: Fitzpatrick Skin Type

Skin Type Skin Colour

(unexposed skin)

History (to first 30 to 45 minutes of sun exposure after a

winter season of no sun exposure)

I White Always burns easily; never tans

II White Always burns easily; tans minimally

III White Burns moderately; tans gradually (light brown)

IV White Burns minimally; always tans well (moderate brown)

V (exclude) Brown Rarely burns; tans profusely (dark brown)

VI (exclude) Black Never burns; deeply pigmented

At the Screening Visit, an abbreviated physical examination was performed and included the

following: general appearance, regional lymph nodes, and dermatologic examination of the

skin in general. The subject’s height was measured without shoes and the weight was

determined with indoor clothing and without shoes.

Relevant medical history and concurrent diagnosis were recorded at the Screening Visit.

Concomitant medications were recorded at all trial visits.

Vital signs (blood pressure and heart rate in supine position) were recorded at the Screening

Visit and Day 1.

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For females of childbearing potential a urine pregnancy test was performed at the Screening

Visit plus the Day 1 and Day 40 visits.

A urine pregnancy test was performed at the last visit (planned on Day 40), but could be

earlier in case of premature withdrawal or later in case of re-challenge.

5.5.3 Clinical Assessments

5.5.3.1 Skin Test Site Assessments

All skin reactions at the applications sites were examined and scored. The scoring was

conducted by a qualified evaluator, under the supervision of the (sub)investigator (certified

dermatologist). Ideally, all assessments for a subject were to be performed by the same

evaluator.

Induction Phase

In the induction phase, the dermal response at each test site was assessed using the scale

below (18):

0 No response

0.5 Questionable or faint, indistinct erythema

1 Well-defined erythema

2 Erythema with slight to moderate oedema

3 Vesicles (small blisters) or papules (small circumscribed elevations)

4 Bullous (large blisters), spreading or other severe reaction

The dermal response was scored 30 minutes after removal of each semi-occlusive patch and if

applicable, gently removal of excess product on the skin.

Challenge Phase

In the challenge phase, the dermal response at each test site was assessed using the scale

below based on the International Contact Dermatitis Research Group’s recommendations

(19):

- No reaction

?+ Doubtful reaction (faint erythema only)

+ Weak positive reaction (erythema, infiltration, possibly papules)

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++ Strong positive reaction (erythema, infiltration, papules, vesicles)

+++ Extreme positive reaction (intense erythema and infiltration and coalescing

vesicles or bullae)

IR Irritant reaction

NT Not tested

The dermal response was scored 30 minutes, 24, and 48 hours (potentially at 72 hours at the

investigator’s discretion) after removal of each semi-occlusive patch and if applicable, gently

removal of excess product on the skin.

Throughout trial conduct, all other skin reactions than the ones assessed according to the

dermal response scales above, were to be reported as AEs.

Assessment of Sensitisation Reaction

At the last dermal response score, 48 hours after removal of the patch in the challenge phase

(Day 40), the (sub)investigator (certified dermatologist) gave her/his opinion concerning a

possible sensitisation reaction of each test site taking into account all skin assessments

performed during the challenge phase, using the following scale:

0: Negative

1: Equivocal

2: Positive

The investigator was to provide a narrative description of each positive sensitisation reaction.

If a sensitisation reaction evaluation was equivocal, a facultative assessment could be

performed at the investigator’s discretion at 72 hours after patch removal.

A re-challenge test, conducted in the same manner, was to be performed for all equivocal

reactions.

5.5.3.2 Imaging Assessments

Any positive or equivocal sensitisation reaction as well as any unexpected and/or severe skin

reaction was photographed to provide visual documentation. The photographs could also be

used by LEO for publication in scientific and medical journals.

Each photo was identified with LEO trial number, CRF number, date of birth, date of visit,

and test site number (Z1, Z2 or Z3).

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5.5.4 Safety Measurements Assessed

5.5.4.1 Adverse Events

An AE is defined as:

‘Any untoward medical occurrence in a patient or clinical investigation subject administered

a pharmaceutical product and which does not necessarily have a causal relationship with this

treatment. An AE can therefore be any unfavourable and unintended sign (including an

abnormal laboratory finding), symptom, or disease temporally associated with the use of a

medicinal (investigational) product, whether or not related to the medicinal (investigational)

product’ (ICH Harmonized Tripartite Guideline for Good Clinical Practice, E6 (R1)).

A serious adverse event (SAE) is any untoward medical occurrence that

Results in death

Is life-threatening

Requires inpatient hospitalisation or prolongation of existing hospitalisation

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

or

Other medically important conditions*)

*) Events that may not be immediately life-threatening or result in death or hospitalisation but

may jeopardise the subject or may require intervention to prevent one of the other outcomes

listed in the definition above. Examples of such events are allergic broncospasm, blood

dyscrasias and convulsions.

Global Pharmacovigilance, LEO, was responsible for the assessment of headquarter

expectedness according to LEO procedures. The relevant reference document for this clinical

trial was the Investigator’s Brochure "LEO 90100 in psoriasis vulgaris", Edition 3 and

subsequent updates, and the French summary of product characteristics (SmPC) for white

petrolatum (see Appendix 1.1).

At all visits, the subject was asked a non-leading question by the investigator: “How have you

felt since I saw you last?” No specific symptoms were to be asked for.

If there were no AEs to record, no further questions were asked and “NO” was to be stated. In

case there were one or more AEs to record, “YES” was to be stated and the investigator

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recorded the event term, intensity, duration, suspected causal relationship to the

investigational product, and outcome.

The investigator also observed the subject for any changes not reported by the subject and

recorded these changes.

Only medically qualified personnel assessed AEs.

5.5.4.2 Reporting of Adverse Events

Events reported by the subject or observed by the (sub)investigator and that fell into any of

the above definitions were to be recorded on the AE page of the CRF and described in the

following manner:

The nature of the event was described in precise English medical terminology (i.e. not

necessarily the exact words used by the subject). Whenever possible, a specific diagnosis was

to be stated (e.g. allergic contact dermatitis).

For cutaneous AEs the location had to be part of the AE description and was described using

the following terminology:

Application area (≤2 cm from the border of test site treated with investigational product

or

Distant (>2 cm from skin application area)

If the AE was described on application area(s), the application area number(s) had to be

specified (i.e., Z1, Z2, Z3).

The intensity of the event was described in terms of mild, moderate, or severe according to the

investigator’s clinical judgment.

Mild: The AE does not interfere in a significant manner with the subject’s normal

functioning level and requires no medical intervention

Moderate: The AE interferes with the subject’s normal functioning level and may or may

not require medical intervention

Severe: The AE produces significant impairment of the subject’s functioning or requires

medical intervention

The duration of the event was reported as the start date and stop date of the event.

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The causal relation of the event to the use of the investigational product was described in

terms of probable, possible, not related or not assessable according to the following:

Probably related

Follows a reasonable temporal sequence from administration of the investigational

product

Could not be reasonably explained by the subject’s clinical state, environmental or toxic

factors or other therapies administered to the subject

Follows a known pattern of response to the investigational product

Disappears or decreases on cessation or reduction in dose of the investigational product

Reappears or worsens upon re-challenge

Possibly related

Follows a reasonable temporal sequence from administration of the investigational

product

Could also be reasonably explained by the subject’s clinical state, environmental or toxic


Follows a known pattern of response to the investigational product

Not related

Does not follow a reasonable temporal sequence from administration of the

investigational product

Is better explained by other factors like the subject’s clinical state, environmental or toxic


Does not follow a known pattern of response to the investigational product

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Not assessable

The AE cannot yet be judged otherwise because present information is insufficient or

contradictory. A final assessment (i.e. probably, possibly or not related) shall be made as

more information becomes available, at the latest when the subject has completed the trial.

The outcome of the event was classified and handled as follows:

Recovered/resolved The event has stopped. The stop date of the event must be recorded.

Recovering/resolving The subject is clearly recovering from an event. The event is, however, not yet completely resolved. Follow-up on the event is required until final outcome is established.

Not recovered/not resolved Event is still ongoing.

Follow-up on the event is required until final outcome is established.

Recovered with sequelae The event has reached a state where no further changes are expected and the residual symptoms are assumed to persist. An example is hemiparesis after stroke.

The stop date of the event must be recorded.

Fatal The subject has died as a consequence of the event. Date of death is recorded as stop date for the adverse event.

Unknown Unknown to investigator, e.g. subject lost to follow-up.

Once a subject had completed the clinical trial, the investigator followed up for outcome on

all non-serious AEs classified as possibly/probably related to the investigational product or

not assessable for 2 weeks, or until final outcome was determined, whichever came first.

5.5.4.3 Other Events to be Reported

Pregnancy

Pregnancy which occurred during the clinical trial was to be reported to LEO within 24 hours

of first knowledge using the (paper) LEO Pregnancy Follow-Up form Part I supplied by LEO.

Follow-up on pregnancy outcome was to be reported on the LEO Pregnancy Follow-Up form

Part II. All pregnancies were to be followed up until delivery or termination.

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Overdose

Any overdose defined as any higher dose than prescribed for the individual subject was to be

reported on the AE form of the CRF book. Adverse events originating in the overdose were to

be documented on a separate line.

5.5.4.4 Serious Adverse Events

Any SAE, related or unrelated to the investigational product or any trial procedure after

signature of the Informed Consent Form must be reported to LEO Pharma A/S on the (paper)

Serious Adverse Event Form – Clinical Trial within 24 hours

Note: Planned hospitalisation or planned prolonged hospitalisation does not fulfil the criteria

for being an SAE. The elective nature of the event must be clearly documented in the

subject’s medical record.

SAEs were to be reported on the AE form of the CRF book. Additionally reports were to be

made using the paper Serious Adverse Event Form – Clinical Trial, supplied by LEO. Apart

from the assessment of the intensity, causal relationship to the investigational product(s)

and/or trial procedures, the action taken and the outcome to date, this report had to contain a

comprehensive narrative description of the course of the event.

All other relevant reports of diagnostic procedures, hospital records, autopsy reports etc. had

to be included, as applicable, or upon request from Global Pharmacovigilance.

The IEC(s), regulatory authorities, and concerned investigators were to be notified of SAEs

according to current regulation and local requirements.

All suspected, unexpected serious adverse reactions (SUSARs) were subject to expedited

reporting to regulatory authorities. Global Pharmacovigilance was to un-blind such cases prior

to reporting. Investigators were to remain blinded.

SAEs were to be followed indefinitely until a final outcome had been established, i.e. the

follow-up could continue beyond the end of the clinical trial.

5.5.5 Appropriateness of Measurements

Assessment of the skin irritation and sensitisation potential is required by regulatory

authorities for new topical drugs. The current trial combines the trial designs of two

commonly accepted tests: the 21-day cumulative irritation test, which evaluates the potential

of a topical product to induce skin irritation after repeated exposure to the skin (14,15) and the

human repeated insult patch test to determine the allergic contact dermatitis potential of

LP0053-66 18-Jun-2014 of 121

topically applied products (16). The combination and design of the 2 tests are in accordance

with recommendations from the FDA (Guidance for Industry. Acne Vulgaris: Developing

Drugs for Treatment. U.S. Department of Health and Human Services Food and Drug

Administration CDER, September 2005). The schedule for application and rest periods is

dictated by the type of reaction (delayed hypersensitivity, type IV immune response) which

mediates the allergic reaction. The induction phase is followed by a rest phase to allow an

eventual allergic reaction to take place during the challenge phase.

The irritative and sensitisation potential of the investigational products were evaluated by use

of standardised visual assessment scales (18,19).

5.6 Endpoints/Response Criteria

5.6.1 Efficacy Evaluation

Not applicable.

5.6.2 Safety Evaluation

5.6.2.1 Primary Response Criteria

The primary response criteria were:

Skin irritation potential:

Mean Cumulative Irritation Index (MCII) and maximal dermal response during the

induction phase (Day 2-22) were considered as co-primary endpoints for skin irritation

potential assessments

Skin sensitisation potential:

Number of subjects with positive sensitisation according to investigator’s assessment of

sensitisation at the end of the challenge phase

Note: The induction phase took place from Day 1 to Day 21 and the patch after the last

application was removed on Day 22. Thus the final test site assessment pertaining to the

induction phase was made on Day 22.

5.6.2.2 Secondary Response criteria

The secondary response criterion was:

Dermal response by visit during induction and challenge phase and maximal dermal

response during the challenge phase

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5.6.2.3 Evaluation of (Serious) Adverse Events

Any AE reported

Any adverse drug reaction (ADR) reported

The reason for withdrawal from the trial

5.7 Data Quality and Assurance

LEO has implemented a system of quality assurance, including all the elements described in

this report. Within this system company Standard Operating Procedures (SOPs) are

implemented to ensure that clinical trials are conducted in compliance with regulatory

requirements and Good Clinical Practice (GCP). Quality control is applied to each stage of

data handling to ensure that data are accurate, reliable and processed correctly.

Trial sites, facilities, and all data (including sources) and documentation were available for

GCP audit by LEO or inspection by competent authorities.

No audits were conducted in this trial.

Training of Site Staff

LEO held a site initiation visit just prior to the start of the trial to familiarise the investigator

and other trial site personnel with the trial protocol, procedures, and GCP, if required.

Trial Monitoring

LEO, as sponsor of this clinical trial, was responsible to the authorities for assuring the proper

conduct of the trial with regard to protocol adherence and validity of the data recorded on the

CRFs. The company, therefore, assigned persons to monitor this clinical trial. It was their

duty to serve as the principal link between (sub)investigators and LEO and advise the

investigators on the collection and maintenance of complete, legible, well organised, and

easily retrievable data for the clinical trial. In addition, they were to explain to the

investigators any aspect of the (conduct of the) trial, including interpretation of the protocol,

and purpose of collection of the specified data and reporting responsibilities.

Case Report Forms

In this clinical trial, data were collected by means of remote data capture. The investigator, or

staff authorised by the investigator, were to enter subject data into an electronic CRF designed

by LEO. A uniquely numbered CRF book was used for each subject enrolled. Data recorded

in the electronic CRFs were accessible to site staff through a secure internet connection

immediately after entry of data had taken place. The CRFs were to be maintained in an up-to-

date condition at all times by the investigator.

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Data Handling

Subject data were to be entered into the electronic CRF by authorised site staff in a timely

manner. Data were to be entered by site staff and systematic data validation was performed

through the discrepancy management system within the data collection software. Queries for

discrepant data were generated either automatically by the system upon entry or generated

manually by the monitor or the trial data manager. All queries, whether generated by the

system or by a user, would be in an electronic format. This systematic validation was made to

ensure that a clean and consistent database was provided prior to the statistical analysis being

performed.

5.8 Changes to the Conduct of the Trial

There were no amendments to the protocol for this trial.

Protocol deviations are addressed in Sections 7.2 and 7.3.

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6 Statistical Methods

6.1 Determination of Sample Size

The principles for establishing the skin irritation potential and sensitisation potential of topical

drug products are addressed in the FDA draft guidances for skin irritation and skin

sensitisation tests using Rivastigmine (Draft guidance for Rivastigmine. U.S. Department of

Health and Human Services FDA; recommended Feb-2010; revised Jun-2010, Nov-2010, and

Nov-2013: page 1-16) and Diclofenac Epolamine (Draft guidance for Diclofenac Epolamine.

U.S. Department of Health and Human Services FDA; recommended Mar-2012: page 1-21).

Trials to provide information regarding cumulative skin irritation should include at least 30

evaluable subjects and skin sensitisation at least 200 evaluable subjects.

The sample size in the present trial was based on the FDA recommendations above. Thus, a

total of 220 subjects were planned to be enrolled to obtain 200 evaluable subjects to establish

the skin irritation potential and skin sensitisation potential of LEO 90100.

Withdrawn subjects were not to be replaced.

6.2 Statistical and Analytical Plan

6.2.1 Summary

Overall, the statistical analyses were performed as outlined in the clinical study protocol

(Appendix 1.1). The applied statistical analyses are further detailed in the statistical analysis

plan update (SAPU) (Appendix 1.9), and relevant information therefrom is included in the

following sections.

The SAPU was finalised before unblinding of the trial, but after blind review of data.

6.2.2 General principles

All significance tests were two-sided and all confidence intervals were presented with 95%

degree of confidence.

Summary statistics included n, mean, standard deviation (SD), minimum, median, and

maximum for continuous parameters. Categorical and ordinal scale parameters were

summarised with frequencies and percentages.

Subjects were allowed one missed visit during the induction phase of the trial. If a subject

missed a visit, a replacement application was to be performed during the rest phase (Section

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5.1.2.3). Subjects who missed additional visits were to be withdrawn from analyses and

described separately.

For subjects with relocation of test patch because of unacceptable irritation in the induction

phase, the highest score observed prior to discontinuation of the first test site was to be carried

forward for all remaining observations in the skin irritation analysis. This occurred for 2

subjects on Day 15 and Day 17, respectively, and the maximal irritation scores (0.5 for both

subjects) were carried forward from these visits. Details are provided in the SAPU in

Appendix 1.9.

All the analyses specified in the protocol were reviewed in relation to the blinded data

actually obtained and the SAPU was finalised before breaking the randomisation code.

6.2.3 Subject qualification for analysis

All enrolled subjects, defined as having signed the informed consent form and with a CRF

number assigned, were accounted for.

Three analysis sets were considered:

A skin irritation analysis set, defined as all randomised subjects who received trial

medication, provided data on dermal response during the induction phase, and did not

present other protocol violations requiring exclusion (decided and documented before

breaking the randomisation code).

A skin sensitisation analysis set, defined as all randomised subjects who received trial

medication, reached challenge phase, were assessed for skin sensitisation, and did not

present other protocol violations requiring exclusion (decided and documented before

breaking the randomisation code).

A safety analysis set, defined as all randomised subjects who had received at least one

application of investigational product and for whom the presence or confirmed absence of

AEs was available. The number of subjects excluded from these analyses sets and the

reason for exclusion were to be described.

The decisions regarding inclusion/exclusion of subjects and/or subject data from the trial

populations were documented in the SAPU before breaking the randomisation code.

6.2.4 Reasons for Leaving the Trial

The reasons for leaving the trial were presented for all randomised subjects and were also

presented by last visit.

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6.2.5 Demographics and Baseline Characteristics

Descriptive statistics of demographics and other baseline characteristics recorded at the

Screening Visit were summarised for the skin sensitisation analysis set.

Concomitant medications, including baseline concomitant medications were listed.

The outcome of physical examinations at baseline was normal for all subjects and no table or

listing of physical examination was made.

6.2.6 Treatment Compliance and Extent of Exposure

Treatment compliance was listed by subject.

6.2.7 Analysis of Efficacy

Not applicable.

6.2.8 Analysis of Safety

6.2.8.1 Skin Irritation Potential

The skin irritation potential analysis was performed on the skin irritation analysis set.

Based on the visual scorings during the induction phase (dermal response), a Cumulative

Irritancy Index (CII) for each subject was calculated for each product:

CII = Sum of clinical scores across readings (Day 2-22)/number of readings

The Mean Cumulative Irritancy Index (MCII) was calculated for each treatment group by

averaging individual CIIs across subjects. MCII and its 95% confidence interval (CI) were

tabulated per treatment group. MCII of aerosol foam investigational products were compared

with the negative control using a two-way analysis of variance (ANOVA) having subjects and

treatments as factors. Treatment differences were tested as contrasts and 95% CI of

differences between aerosol foam investigational products and the negative control were

calculated.

The MCII was initially tested for normality for each treatment group separately. In case of

significant deviation to the normal assumption, a non-parametric Wilcoxon signed rank test

was added to test robustness of comparisons.

MCII was not considered as the unique primary endpoint for skin irritation potential because,

the same mean cumulative score could be reached with a small number of high scores

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(e.g., ≥3) as with a larger number of low scores (e.g., 1, which is of less clinical significance).

Thus, it could be difficult to determine the clinical meaningfulness of a given cumulative

score, or a given difference between products with regard to mean cumulative scores. The co-

primary endpoint, evaluation of maximal dermal response during induction phase, was

therefore added to aid the interpretation of the skin irritation potential.

Maximal dermal response (analysed as a quantitative parameter) observed during the

induction phase was analysed as described above for MCII.

A frequency table presenting the count and frequency of subjects by category of dermal

response (0 to 4) observed during the induction phase was provided by treatment group.


response (0 to 4) observed during the induction phase was provided by visit and treatment

group using a last observation carried forward (LOCF) approach, as detailed in Section 6.2.2

for subjects with relocation of test patch because of unacceptable irritation.


response (0 to 4) observed during induction phase for subjects who did not complete the

induction phase and were excluded from the skin irritation analysis set was provided by visit

and treatment group.

6.2.8.2 Skin Sensitisation Potential

The skin sensitisation potential was analysed for the skin sensitisation analysis set.

All sensitisation assessments were negative. Consequently, no table by category of

sensitisation was produced and none of the sensitisation tests specified in the protocol were

performed.

The count and frequency of subjects by category of dermal response (-, ?+, +, ++, +++, IR)

observed during the challenge phase was tabulated by time and treatment group.

The count and frequency of subjects by category of maximum dermal response (-, ?+, +, ++,

+++) observed during the challenge phase excluding IR category was tabulated by treatment

group.

No subjects experienced a score of 1+ or more at 48 or 72 hours after patch removal in the

challenge phase. Consequently, tables showing the actual scores for each subject with a score

of 1+ or more at each evaluation time and narratives planned in the protocol were not

prepared.

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6.2.8.3 Adverse Events

The analysis of AEs was based on the safety analysis set for treatment-emergent AEs.

Adverse events were coded during the course of the trial in accordance with the current

version of the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. The AEs

were presented by preferred terms and primary system organ class (SOC).

An overall summary table of AEs was made presenting the number of subjects with any AEs,

ADRs, AEs on the application area, SAEs, and AEs leading to withdrawal from the trial. The

tabulation was made for the overall safety analysis set, i.e. independently of the treatment

group.

The number of subjects experiencing any type of AE (according to MedDRA Preferred Term

within primary SOC) was tabulated for all subjects included in safety analysis set

independently of the treatment group and regardless of the number of times each AE was

reported by each subject. Similar tabulations presenting the causal relationship of AEs and

intensity of AEs were made.

Adverse events where the investigator had not excluded a causal relationship to trial

medication (i.e. not described relationship as “not related”, adverse drug reactions) were

tabulated by investigational product. Similar tabulations presenting the causal relationship of

ADRs and intensity of ADRs were made. If there were several recordings of causal

relationship and intensity for the same event, causal relationship was taken from the last

report of the event and intensity was taken as the worst ever recording.

Listings presenting AEs, AEs localised on application areas, and severe AEs were made.

6.3 Changes to the Statistical Analysis Plan

For all treatments, a significant deviation from normality was observed for the parameters

MCII and the maximal dermal response during the induction phase (primary response

criterion) and a non-parametric Wilcoxon signed rank test was therefore added to test the

robustness of the treatment comparisons (Section 6.2.8.1).

All other statistical analyses were performed as described in the clinical study protocol

(Appendix 1.1) and in the SAPU (Appendix 1.9).

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6.4 Software and Dictionaries

SAS® version 9.3 was used to create listings, tables, figures, and statistical analyses.

MedDRA version 15.1 was used for coding of AEs and medical history.

WHO-DD version 2012Q3 was used for coding concomitant medication.

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7 Trial Population

7.1 Disposition of Subjects

In total, 224 subjects were enrolled into the trial (i.e. informed consent signed and CRF

number assigned). The first subject was enrolled on 02-Sep-2013 and the last subject

completed the trial (inclusive follow-up) on 06-Dec-2013.

All 224 subjects were screened among whom 3 were screening failures, 2 subjects withdrew

consent to participate in the trial before randomisation, and 1 subject did not fulfil inclusion

and/or exclusion criteria on Day 1 and was withdrawn before randomisation (Appendix 2.1).

The remaining 218 subjects were randomised (Appendix 2.1).

In total, 4 of the randomised subjects withdrew from the trial and 214 (98%) subjects

completed the trial. The reasons for withdrawal were: 1 subject was lost to follow-up after

Day 1, 1 subject withdrew from the trial on Day 16 for voluntary reasons, 1 subject withdrew

from the trial on Day 16 due to initiation of prednisolone treatment (Section 7.2), and 1

subject experienced an SAE (rectal haemorrhage) on Day 3 (Appendix 2.1). The SAE was

evaluated as not related to investigational product by the investigator and is described in

Section 10.4.

The number of subjects who attended each visit is shown in Figure 3.

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Figure 3: Disposition of Subjects

Saeenirg visit

1-------'s~-... 3 Sawning fa ihr&S (CRFs •••••• 2 voluntsry (CRF~. - )

ViSit Day 1

ViSit Day2

Visit Day3 CRF -

._ 1 SAE (CRF- )

ViSit Day4

ViSit DayS

Visit DayS

ViSit Day9 CRF -

Visit Day 10 and ViSit Day 11

Visit Day 12

ViSit Day1S

Visit Day 16

---.- 1Exdusion ail (CR F - )

ViSit Day 36,38 and 39

AE folo.v-~ visil'

Visit Day40 2 I

1) Qlly for subjeas who mised s vis il in indudion ph sse

2) only applicable it ongoing .AD R at the subjects last visit No slbjeas needed to sttend oplionsl V isit Osy " 1 0' s re-chsnenge visil

Cr o ss- reference : Eo T Figu re 1- 2.

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7.2 Protocol Deviations

Inclusion and Exclusion Criteria

All randomised subjects fulfilled all inclusion and exclusion criteria.

Procedure Compliance Deviations

Procedure compliance deviations were identified for the following 14 subjects:

4 subjects did not complete the trial and missed more than 1 induction visit (Section 7.1).

The data related to these subjects were excluded from the skin irritation analysis set and

skin sensitisation analysis set (Sections 7.3.1 and 7.3.2) as pre-specified in the SAPU

(Appendix 1.9).

1 subject initiated treatment with Chondrofult® (chondroitin sulphate) for treatment of

arthralgia prior to trial enrolment and continued treatment during the entire duration of the

trial. The data related to this subject were excluded from the skin irritation analysis set and

skin sensitisation analysis set (Sections 7.3.1 and 7.3.2).

2 subjects were treated with a systemic anti-inflammatory drug (Nurofen®, ibuprofen and

Spifen®, ibuprofen) on one occasion during the trial. Since the drug had only been taken

once it was unlikely that the treatment would affect the outcome of the trial. The data

related to these subjects were therefore not excluded from any analysis sets.

1 subject had challenge visits performed 1 week later than the protocol scheduled visits.

The delay would unlikely affect delayed sensitisation and the data related to this subject

were therefore not excluded from any analysis sets.

6 subjects missed a single visit during the induction phase, but completed the Day 23 Visit

which was planned for subjects who missed a visit during the induction phase. The data

related to these subjects were therefore not excluded from any analysis sets.

Protocol deviations are listed in Appendix 2.2 and are also detailed in the SAPU (Appendix

1.9).

7.3 Trial Analysis Sets

The analysis sets were determined based on the criteria defined in Section 6.2.3, according to

the clinical study protocol (Appendix 1.1), and the SAPU (Appendix 1.9). All decisions on the

inclusion and exclusion of subjects from analyses were made while the data were still blinded.

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7.3.1 Skin Irritation Analysis Set

The skin irritation analysis set was defined as all randomised subjects who received trial

medication, provided data on dermal response during the induction phase, and did not present

other protocol violations requiring exclusion.

Four subjects did not complete the trial and missed more than 1 induction visit for the reasons

described in Section 7.1. Since subjects were only allowed one missed visit during the

induction phase (see Section 6.2.2), these 4 subjects were excluded from the skin irritation

analysis set.

One subject initiated treatment Chondrofult® (chondroitin sulphate) for treatment of arthralgia

prior to trial enrolment and continued treatment during the entire duration of the trial. Since a

potential anti-inflammatory effect on the skin could not be excluded, the subject was excluded

from the skin irritation analysis set.

The skin irritation analysis set thus comprised 213 subjects.

7.3.2 Skin Sensitisation Analysis Set

The skin sensitisation analysis set was defined as all randomised subjects who received trial

medication, reached challenge phase, were assessed for skin sensitisation, and did not present

other protocol violations requiring exclusion.

The skin sensitisation analysis set was identical to the skin irritation analysis set and thus

comprised 213 subjects.

7.3.3 Safety Analysis Set

The safety analysis set was defined as all randomised subjects who received at least one

application with investigational product and for whom the presence or confirmed absence of

AEs was available.

Among the 218 randomised subjects, one subject was lost to follow-up after first application

and did not provide post-randomisation data (Section 7.1). The subject was excluded from the

safety analysis set.

The safety analysis set thus comprised 217 subjects.

Individual data on subjects and observations excluded from the analysis sets are listed in

Appendix 2.3 Listing 3-1 and the reasons for exclusions from analysis sets are presented in

Appendix 2.3 Listing 3-2.

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The number of subjects in the trials analysis sets is presented in Figure 4.

Figure 4: Trial Analysis Sets

Cross-reference: EoT Figure 1-1.

7.4 Demographic and other Baseline Characteristics

7.4.1 Demographic Data

Demographic data (age, sex, skin type, ethnicity, and race) are summarised for the skin

sensitisation analysis set (identical to the skin irritation analysis set) in Table 6, Table 7, and

Table 8. The results for the baseline skin assessment of dermal response are presented by

treatment group in Table 9.

Overall, baseline demographics and subject characteristics for the 213 subjects were in line

with the targeted trial population. All subjects were above 18 years of age and below 66 years

of age (range: 19-65 years), and no subjects had skin type V or VI (exclusion criterion No. 3).

The outcome of physical examinations at baseline was normal for all subjects and all subjects

had baseline skin assessments of dermal response evaluated as ‘no response’. All subjects

were white.

There were no clinically relevant observations with regard to vital signs at baseline

(EoT Table 1-5). The height, weight, and body mass index (BMI) are summarised in EoT

Table 1-4. Individual subject demographics and other baseline data are included in Appendix

2.4.

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Table 6: Age: Skin Sensitisation Analysis Set

Age (Years)

Skin SensitisationAnalysis Set

(n=213)

Mean 43.5 SD 12.5 Median 44.0 Minimum 19 Maximum 65 Number 213

03FEB14:17:57:54 LP0053-66 age 1 1.doc

Cross-reference: EoT Table 1-1.

Table 7: Sex and Skin Type: Skin Sensitisation Analysis Set


(n=213)

Sex and Skin typeNumber of subjects %

SexMale 54 25.4 Female 159 74.6 Total 213 100.0

Skin typeII 33 15.5 III 178 83.6 IV 2 0.9 Total 213 100.0

03FEB14:17:52:24 LP0053-66 SexST 1 2.doc


Table 8: Ethnic Origin and Race: Skin Sensitisation Analysis Set


(n=213)

Ethnicity and RaceNumber of subjects %

EthnicityNot Hispanic or Latino 213 100.0 Total 213 100.0

RaceWhite 213 100.0 Total 213 100.0

04FEB14:14:44:31 LP0053-66 ethnrace_1_3.doc


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Table 9: Baseline Skin Assessment of Dermal Response by Treatment Group: Skin Sensitisation Analysis Set

LEO90100(n=213)

Aerosol foam vehicle(n=213)

White petrolatum(n=213)

Dermal ResponseNumber of subjects %

Number of subjects %


No Response 213 100.0 213 100.0 213 100.0 Total 213 100.0 213 100.0 213 100.0

03FEB14:17:52:02 LP0053-66 DRbas_1_7.doc


7.4.2 Medical history and Use of Concomitant Medication

A full list of medical history is given in Appendix 2.4 (Listing 4-3). The use of concomitant

medication during the trial is summarised in Appendix 2.4 (Listing 4-5). No medical history

contradicted the eligibility requirements (Appendix 2.4).

One subject initiated treatment with Chondrofult® (chondroitin sulphate) for treatment of

arthralgia prior to trial enrolment and continued treatment during the entire duration of the

trial. The data related to this subject were excluded from the skin irritation analysis set and

skin sensitisation analysis set (Sections 7.3.1 and 7.3.2).

Two subjects received a systemic anti-inflammatory drug (ibuprofen) on one occasion during

the trial. Since the drug had only been taken once it was unlikely that the treatment would

affect the outcome of the trial and the data related to these subjects were therefore not

excluded from any analysis sets.

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8 Exposure and Treatment Compliance

No products were dispensed to subjects. The products were applied by designated trial

personnel at the trial centre to ensure compliance (Section 5.4.1).

All 218 randomised subjects received at least one application of investigational product.

Deviations to the planned treatment exposure were identified for 4 subjects who were

withdrawn before trial completion (see Sections 7.2 and 7.3.1 for details). In addition,

6 subjects missed a single application, but completed the Day 23 Visit (which was planned for

subjects who missed a visit during the induction phase) and these subjects were therefore

exposed as planned. Hence, 214 subjects received the planned 15 topical applications of each

of the 3 investigational products during the induction phase and 1 application during the

challenge phase according to the protocol (Appendix 2.5).

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9 Efficacy Evaluation

Not applicable.

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10 Safety Evaluation

10.1 Skin Irritation Potential

Maximal Dermal Response During the Induction Phase

The maximal dermal response during the induction phase is presented by category in

Table 10. During the induction phase, the majority of subjects had a maximum dermal

response score of 0 (‘no response’) or 0.5 (‘questionable or faint, indistinct erythema’),

reported for 168 (78.9%) subjects after application of LEO 90100 and 209 (98.1%) subjects

after application of both the aerosol foam vehicle and the negative control (Table 10).

A maximum dermal response score of 1 (‘well-defined erythema’) was reported for 42

(19.7%) subjects after application of LEO 90100 and for 4 (1.9%) after application of both the

aerosol foam vehicle and the negative control.

The highest reported dermal response score was 2 (‘erythema with slight to moderate

oedema’), reported in 3 (1.4%) subjects after application of LEO 90100.

Table 10: Maximal Dermal Response Category During the Induction Phase (Day 2-22): Skin Irritation Analysis Set

LEO90100(n=213)



Maximal dermalresponse




No Response 76 35.7 148 69.5 161 75.6 Questionable or faint, indistinct erythema

92 43.2 61 28.6 48 22.5

Well-defined erythema 42 19.7 4 1.9 4 1.9 Erythema with slight to moderate edema

3 1.4 0 0.0 0 0.0

Total 213 100.0 213 100.0 213 100.0

05FEB14:11:41:26 LP0053-66 MAXIIc_3_3.doc


The mean maximal dermal response during the induction phase was 0.44 for LEO 90100,

0.16 for the aerosol foam vehicle, and 0.13 for the negative control (white petrolatum) (Table

11). There was a statistically significant difference between LEO 90100 and the negative

control (95% CI 0.25 to 0.37; p<0.001). The maximal dermal response for the aerosol foam

vehicle was similar to the negative control.

A significant deviation from normality was observed for this parameter in all treatment

groups, and a non-parametric Wilcoxon signed rank test was therefore added to test

robustness of treatment comparisons (Section 6.2.8.1). The Wilcoxon signed rank test

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confirmed the statistically significant difference between LEO90100 and the negative control

and the absence of statistically significant difference between the aerosol foam vehicle and the

negative control.

Table 11: Maximal Dermal Response During the Induction Phase (Day 2-22): Skin Irritation Analysis Set


LEO90100(n=213)

Aerosol foamvehicle(n=213)


Maximum scoreMean 0.44 0.16 0.13 SD 0.41 0.25 0.24 Median 0.50 0.00 0.00 Minimum 0.00 0.00 0.00 Maximum 2.00 1.00 1.00 Number 213 213 213

Lower 95% confidence limit (mean)

0.39 0.13 0.10

Upper 95% confidence limit (mean)

0.50 0.20 0.16

Comparisons1

Difference2 0.31 0.03 95% CI2 0.25 to 0.37 -0.02 to 0.09 P-value2 <0.001 0.28 P-value3 <0.001 0.11

04FEB14:16:22:53 LP0053-66 MAXII 3 2.doc

1) Comparisons versus White petrolatum2) ANOVA with treatment and subject as factors3) Wilcoxon paired signed rank test


Mean Cumulative Irritation Index (MCII)

In the induction phase, the dermal response at each test site was assessed using a 0 to 4-point

scale as described in Section 5.5.3.1. A Cumulative Irritancy Index (CII) for each subject was

calculated for each product as the sum of clinical scores across readings (Day 2-22)/number

of readings and the Mean Cumulative Irritancy Index (MCII) was calculated for each

treatment group by averaging individual CIIs across subjects (Section 6.2.8.1).

The MCII during the induction phase was low for all treatments; 0.102 for LEO 90100, 0.019

for the aerosol foam vehicle, and 0.018 for the negative control (white petrolatum) (Table 12).

There was a statistically significant difference between LEO 90100 and the negative control

(95% CI 0.069 to 0.101; p<0.001). The MCII for the aerosol foam vehicle was similar to the

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negative control. As for the maximal dermal response, a significant deviation from normality

in all treatment groups was observed for MCII, with more than 50% null values for MCII, and

a non-parametric Wilcoxon signed rank test was therefore added to test robustness of

treatment comparisons (Section 6.2.8.1). The Wilcoxon signed rank test confirmed the

statistically significant difference between LEO 90100 and the negative control and the

absence of statistically significant difference between the aerosol foam vehicle and the

negative control (Table 12).

Table 12: Mean Cumulative Irritation Index (MCII) During the Induction Phase: Skin Irritation Analysis Set

MCIILEO90100(n=213)



MCIIMean 0.102 0.019 0.018 SD 0.137 0.042 0.043 Median 0.031 0.000 0.000 Minimum 0.000 0.000 0.000 Maximum 0.781 0.344 0.313 Number 213 213 213


0.084 0.013 0.012


0.121 0.025 0.024

Comparisons1


05FEB14:11:46:44 LP0053-66 MCII 3 1.doc



Dermal Response by Visit During the Induction Phase

The dermal response categories are presented by visit during the induction phase in EoT Table

3-4 for the skin irritation analysis set.

At all visits and for all treatments, the most frequently reported dermal response score was 0

(‘no response’). Between Day 2 and Day 22, the incidence of this score ranged from 152

(71.4%) subjects to 210 (98.6%) subjects after application of LEO 90100, from 196 (92.5%)

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subjects to 211 (99.1%) subjects after application of the aerosol foam vehicle, and from 195

(92.0%) to 211 (99.1%) subjects for the negative control. The frequencies fluctuated across

visits with no distribution pattern observed.

Between Day 2 and Day 22, a dermal response score of 0.5 (‘questionable or faint, indistinct

erythema’) ranged from 3 (1.4%) subjects to 46 (21.6%) subjects after application of

LEO 90100 from 2 (0.9%) subjects to 14 (6.6%) subjects after application of the aerosol foam

vehicle, and from 2 (0.9%) to 10 (4.7%) subjects for the negative control. The frequencies

fluctuated across visits with no distribution pattern observed.

Between Day 2 and Day 22, a dermal response score of 1 (‘well-defined erythema’) ranged

from 0 subjects to 14 (6.6%) subjects after application of LEO 90100, from 0 subjects to 2

(0.9%) subjects after application of both the aerosol foam vehicle and the negative control,

with no apparent distribution pattern across visits.

The dermal response score of 2 (‘erythema with slight to moderate oedema’) observed in the

LEO 90100 group was reported on Day 8 in 2 (0.9%) subjects and in 1 (0.5%) subject at all

visits between Day 15 and Day 22 (EoT Table 3-4).

10.2 Skin Sensitisation Potential

Maximal Dermal Response During the Challenge Phase

During the challenge phase (Day 36 to Day 40), the majority of subjects had a maximum

dermal response score of ‘no reaction’, reported for 159 (74.6%) subjects after application of

LEO 90100, 211 (99.1%) subjects after application of the aerosol foam vehicle, and 209

(98.1%) subjects after application of the negative control (Table 13).

A maximum dermal response score of ‘doubtful reaction (faint erythema only)’, was reported

for 52 (24.4%) subjects after application of LEO 90100, for 2 (0.9%) after application of the

aerosol foam vehicle, and for 4 (1.9%) subjects after application of the negative control.

The highest reported dermal response score was ‘weak positive reaction (erythema

infiltration, possibly papules)’, reported in 2 (0.9%) subjects after application of LEO 90100.

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Table 13: Maximal Dermal Response Category During Challenge Phase: Skin Sensitisation Analysis Set

LEO90100(n=213)







No reaction 159 74.6 211 99.1 209 98.1 Doubtful reaction 52 24.4 2 0.9 4 1.9 Weak positive reaction

2 0.9 0 0.0 0 0.0

Total 213 100.0 213 100.0 213 100.0

05FEB14:11:47:38 LP0053-66 MAXICc 3 6.doc


Dermal Response by Visit During the Challenge Phase

The dermal response categories are presented by time-point during the challenge phase in

Table 14 for the skin sensitisation analysis set.

During the challenge phase, the majority of those reactions evaluated as either ‘doubtful

reactions’ or ‘weak positive reactions’ were observed on Day 38 for all treatment groups, and

the frequency of these reactions decreased successively during the challenge phase. On Day

40, 6 (2.8%) subjects in the LEO 90100 group had a ‘doubtful reaction’ whilst all other

subjects, including the aerosol foam vehicle- and the negative control groups, had ‘no

reaction’.

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Table 14: Dermal Response Category During Challenge Phase by Time Point: Skin Sensitisation Analysis Set

LEO90100(n=213)



VisitDermal response




Visit Day 36No reaction 213 100.0 213 100.0 213 100.0 Total 213 100.0 213 100.0 213 100.0

Visit Day 38No reaction 170 79.8 211 99.1 209 98.1 Doubtful reaction 41 19.2 2 0.9 4 1.9 Weak positive

reaction 2 0.9 0 0.0 0 0.0

Total 213 100.0 213 100.0 213 100.0

Visit Day 39No reaction 185 86.9 213 100.0 212 99.5 Doubtful reaction 28 13.1 0 0.0 1 0.5 Total 213 100.0 213 100.0 213 100.0


05FEB14:11:42:07 LP0053-66 DRCvis 3 7.doc


Evaluation of Sensitisation Reaction at the End of the Challenge Phase

At the end of the challenge phase (Day 40), the (sub)investigator evaluated each test site for

possible sensitisation reactions using a 3-point scale as described in Section 5.5.3.1.

In the opinion of the investigator there were no signs/symptoms that would be suggestive of

an equivocal/positive sensitisation reaction. Therefore, all subjects were concluded to have

‘negative’ response. As there in the opinion of the investigator were no equivocal reactions,

none of the subjects were re-challenged.

10.3 Adverse Events

This section gives an overview of all treatment emergent AEs (i.e., those that started after the

first application of the trial medication, or started before this and worsened in intensity after).

Throughout this section treatment-emergent AEs will be denoted as AEs. The summary of the

overall frequency of AEs is done on the preferred term level, which means that multiple

occurrences of AEs on a particular preferred term level in the same subject count as one

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occurrence. For a given preferred term, severity is recorded as the worst severity experienced

and relationship is recorded from the last available assessment.

10.3.1 Brief Summary of Adverse Events

In total, 116 AEs were reported during the trial (Table 15). There were no deaths in the trial.

One SAE was reported and led to withdrawal from the trial (see Section 10.4.1). The SAE

was assessed as having no relation to investigational product by the investigator. No other

AEs led to discontinuation from treatment or trial. The vast majority of the AEs were mild or

moderate and only 3 AEs were rated as severe, see Section 10.3.3. In total, 22 (10.1%)

subjects experienced ADRs. The ADRs were identical to the AEs occurring on the application

areas (see Section 10.3.4).

Table 15: Overall Summary of Adverse Events: Safety Analysis Set

Safety Aalysis Set(n=217)

Adverse event categoryNumberof AEs1

Number of subjects (%)

All adverse events 116 86 (39.6) Severe adverse events 3 3 ( 1.4) Adverse drug reactions 30 22 (10.1) AEs leading to withdrawal from trial 1 1 ( 0.5) AEs on treatment site 30 22 (10.1) SAEs 1 1 ( 0.5)

20MAR14:11:52:48 LP0053-66 aeall 3 8.doc

1) Different adverse events within the same preferred term and system organ class and involving the same subject have been counted as one.


10.3.2 Incidence of Adverse Events

The incidence of AEs is presented by MedDRA SOC in Table 16 and by MedDRA SOC and

preferred term in Table 17.

The overall incidence of AEs was 86 (39.6%) subjects reporting 116 AEs. AEs were most

frequently reported in the SOCs ‘Infections and infestations’, and ‘Nervous system disorders’.

In these 2 SOCs, nasopharyngitis and folliculitis were both reported by 20 (9.2%) subjects

and ‘headache’ was reported by 27 subjects (12.4%) (Table 17). The remaining individual

AEs in the 2 SOCs were reported by 1 to 3 subjects.

Individual AE data are listed in Appendix 2.7.

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Table 16: Treatment-Emergent Adverse Events by MedDRA Primary System Organ Class: Safety Analysis Set

Safety analysis set(n=217)

System Organ Class1 Number of subjects %

Infections and infestations 42 19.4Nervous system disorders 30 13.8Skin and subcutaneous tissue disorders

11 5.1

Musculoskeletal and connective tissuedisorders

9 4.1

Gastrointestinal disorders 5 2.3Respiratory, thoracic and mediastinaldisorders

5 2.3

Reproductive system and breast disorders

3 1.4

Injury, poisoning and proceduralcomplications

2 0.9

General disorders and administration siteconditions

1 0.5

Neoplasms benign, malignant and unspecified(incl cysts and polyps)

1 0.5

Psychiatric disorders 1 0.5 Total number of adverse events2 116 Total number of subjects 86 39.6

07FEB14:10:23:09 LP0053-66 aesoc 3 9.doc

1) Classification according to MedDRA version 15.1.2) Different adverse events within the same preferred term and system

organ class and involving the same subject have been counted as one. A single subject could appear in multiple classes.


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Table 17: Treatment-Emergent Adverse Events by MedDRA Primary SOC and Preferred Term: Safety Analysis Set


System Organ Class (SOC)Preferred Term1 Number of subjects %

Infections and infestationsNasopharyngitis 20 9.2Folliculitis 20 9.2Influenza 3 1.4Gastroenteritis 1 0.5Oral herpes 1 0.5Pharyngitis 1 0.5SOC total 42 19.4

Nervous system disordersHeadache 27 12.4Neuralgia 2 0.9Migraine 1 0.5Sciatica 1 0.5VIIth nerve paralysis 1 0.5SOC total 30 13.8

Skin and subcutaneous tissue disordersPruritus 8 3.7Urticaria 1 0.5Prurigo 1 0.5Skin irritation 1 0.5SOC total 11 5.1

Musculoskeletal and connective tissuedisordersMyalgia 4 1.8Back pain 3 1.4Arthralgia 2 0.9SOC total 9 4.1

Gastrointestinal disordersToothache 2 0.9Gastritis 1 0.5Gastrooesophageal reflux disease 1 0.5Rectal haemorrhage 1 0.5SOC total 5 2.3

Respiratory, thoracic and mediastinaldisordersAsthma 1 0.5Oropharyngeal pain 2 0.9Rhinitis allergic 2 0.9

07FEB14:10:25:58 LP0053-66 aept 3 10.doc Continued...

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Table 17: Treatment-Emergent Adverse Events by MedDRA Primary SOC and Preferred Term: Safety Analysis Set (Continued)




Respiratory, thoracic and mediastinaldisordersSOC total 5 2.3

Reproductive system and breast disordersDysmenorrhoea 3 1.4SOC total 3 1.4

Injury, poisoning and proceduralcomplicationsFoot fracture 1 0.5Ligament sprain 1 0.5SOC total 2 0.9

General disorders and administration siteconditionsPyrexia 1 0.5SOC total 1 0.5

Neoplasms benign, malignant and unspecified(incl cysts and polyps)Mycosis fungoides 1 0.5SOC total 1 0.5

Psychiatric disordersAnxiety 1 0.5SOC total 1 0.5

Total number of adverse events2 116

Total number of subjects 86 39.6

07FEB14:10:25:58 LP0053-66 aept 3 10.doc




10.3.3 Adverse Events by Intensity

All AEs were assessed for intensity (mild, moderate, or severe). A summary of AEs by

MedDRA primary SOC and preferred term with information on maximum intensity is given

in EoT Table 3-12.

The vast majority of the AEs were mild or moderate and only 3 AEs were rated as severe. The

events were single occurrences of ‘folliculitis’, ‘headache’, and ‘rectal haemorrhage’.

The event ‘rectal haemorrhage’was also an SAE, see Section 10.4.1.

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10.3.4 Adverse Drug Reactions and Adverse Events on the Application

Areas

All AEs were to be assessed for causal relationship to the investigational product, as judged

by the investigator. Adverse drug reactions (defined as AEs for which the investigator had not

described the causal relationship to trial medication as ‘not related’) are presented by

MedDRA primary system organ class and preferred term in Table 18.

AEs on the application areas were those AEs judged by the investigator as located within 2

cm from the border of test site treated with investigational product (Section 5.5.4.2). In this

clinical trial, all AEs localised on the application areas were evaluated by the investigator as

having a possible or probable relation to treatment, and all ADRs were localised on the

application areas. Hence, ADRs and AEs localised on the application areas were identical.

Adverse events localised on the application areas are listed in Appendix 2.7 Listing 7-2.

In total, 31 AEs were localised on the application areas and consisted of 20 events of

folliculitis, 8 events of pruritus, 2 events of urticaria, and 1 event of skin irritation (Table 18).

All events were non-serious and the majority of events (29 of 31) were reported after

application of LEO 90100. The 2 other events (urticaria and skin irritation) were reported

after application of the aerosol foam vehicle. The reported outcomes for AEs on the

application areas were ‘recovered’ for 28 events (LEO 90100: 26 events; aerosol foam

vehicle: 2 events) and ‘recovering’ for 3 events after application of LEO 90100. The vast

majority of AEs on the application areas were mild (19 events) or moderate (11 events) in

intensity. One AE was evaluated as severe and concerned folliculitis after application of

LEO 90100. The reported outcome was ‘recovered’ after 23 days (Appendix 2.7 Listing 7-2).

Note: One subject experienced an urticaria event on 2 application areas (LEO 90100 and

aerosol foam vehicle). The total number of AEs localised on application areas were therefore

counted as 30 in Table 15 (which is an overall tabulation of AEs irrespective of treatment) and

as 31 in Table 18 (which presents AEs by investigational product).

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Table 18: Treatment-Emergent Adverse Drug Reactions by MedDRA Primary System Organ Class and Preferred Term: Safety Analysis Set

LEO90100(n=217)



System Organ Class (SOC)Preferred Term1




Infections and infestationsFolliculitis 20 9.2 0 0.0 0 0.0SOC total 20 9.2 0 0.0 0 0.0

Skin and subcutaneous tissue disordersPruritus 8 3.7 0 0.0 0 0.0Urticaria 1 0.5 1 0.5 0 0.0Skin irritation 0 0.0 1 0.5 0 0.0SOC total 9 4.1 2 0.9 0 0.0

Total number of drug reactions2 29 2

Total number of subjects 21 9.7 2 0.9 0 0.0

07FEB14:10:52:24 LP0053-66 Adrpt_3_13.doc

1) Classification according to MedDRA version 15.1.2) Different adverse drug reactions within the same preferred term and system organ class and involving the same

subject have been counted as one. A single subject could appear in multiple classes.


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10.3.5 Adverse Events Leading to Withdrawal

One AE led to withdrawal from the trial. The event was serious and assessed as having no

relation to investigational product by the investigator. The AE is further described in Section

10.4.1.

10.4 Deaths, other Serious Adverse Events, and other Significant Adverse

Events

10.4.1 Narratives of Serious Adverse Events

There were no deaths in the trial. One SAE was reported. A narrative is given below.

Subject number:

SAE: Rectal haemorrhage/severe

This case concerns a treated with investigational products from

to . The patient did not receive concomitant medications. On

the subject was attacked The subject suffered from crania trauma,

abdominal and thoracic trauma, and perineal trauma. On the subject presented at

the trial centre with a periocular haematoma and a cut on the wrist. On the

subject was hospitalised due to proctorrhagia. The subject underwent a proctoscopy,

sigmoidoscopy, and colposcopy, which showed intensive necrosis with ulceration, probably

due to the trauma. The patient was withdrawn from the trial due to the SAE. The subject

recovered with sequalae from the event. Causality per investigator: not related. Causality per

sponsor: not related.

10.5 Pregnancies

No pregnancies occurred during the trial (Appendix 2.8 Listing 8-2).

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10.6 Safety Conclusions

Skin Irritation Potential

During the induction phase (Day 1 to 21), the majority of subjects had a maximum dermal

response score of 0 (‘no response’) or 0.5 (‘questionable or faint, indistinct erythema’),

reported for 168 (78.9%) subjects after application of LEO 90100 and 209 (98.1%)

subjects after application of both the aerosol foam vehicle and the negative control. A

maximum dermal response score of 1 (‘well-defined erythema’) was reported for 42

(19.7%) subjects after application of LEO 90100 and for 4 (1.9%) after application of both

the aerosol foam vehicle and the negative control.

The highest reported dermal response score was 2 (‘erythema with slight to moderate

oedema’), reported in 3 (1.4%) subjects after application of LEO 90100.

The mean maximal dermal response during the induction phase (co-primary endpoint)

was 0.44 for LEO 90100, 0.16 for the aerosol foam vehicle, and 0.13 for the negative

control (white petrolatum).There was a statistically significant difference between

LEO 90100 and the negative control (95% CI 0.25 to 0.37; p<0.001). The maximal dermal

response for the aerosol foam vehicle was similar to the negative control.

The MCII during the induction phase (co-primary endpoint) was low for all treatments;

0.102 for LEO 90100, 0.019 for the aerosol foam vehicle, and 0.018 for the negative

control (white petrolatum). There was a statistically significant difference between LEO

90100 and the negative control (95% CI 0.069 to 0.101; p<0.001). The MCII for the

aerosol foam vehicle was similar to the negative control.

Skin Sensitisation Potential

During the challenge phase (Day 36 to Day 40), the majority of subjects had a maximum

dermal response score of ‘no reaction’. A maximum dermal response score of ‘doubtful

reaction (faint erythema only)’, was reported for 52 (24.4%) subjects after application of

LEO 90100, for 2 (0.9%) after application of the aerosol foam vehicle, and for 4 (1.9%)

subjects after application of the negative control. The highest reported dermal response

score was ‘weak positive reaction (erythema infiltration, possibly papules)’, reported in 2

(0.9%) subjects after application of LEO 90100.

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During the challenge phase, the majority of those reactions evaluated as either ‘doubtful

reactions’ or ‘weak positive reactions’ were observed on Day 38 (start of challenge phase)

for all treatment groups, and the frequency of these reactions decreased successively

during the challenge phase. On Day 40, 6 (2.8%) subjects in the LEO 90100 group had a

‘doubtful reaction’ whilst all other subjects, including the aerosol foam vehicle- and the

negative control groups, had ‘no reaction’.

Taking into account the dermal response evaluations performed in the challenge phase, the

investigator concluded that there was no indication of a sensitisation reaction for any

subject.

Adverse Events

In total, 116 AEs were reported. There were no deaths in the trial. One SAE was reported

and led to withdrawal from the trial. The SAE was assessed as having no relation to

investigational product. No other AEs led to discontinuation from treatment or trial. The

vast majority of the AEs were mild or moderate and only 3 AEs were rated as severe.

The overall incidence of AEs was 86 (39.6%) subjects reporting 116 AEs. The most

frequently reported AEs were nasopharyngitis and folliculitis, both reported by 20 (9.2%)

subjects and headache, reported by 27 subjects (12.4%).

In total, 31 AEs were localised on the application areas and consisted of 20 events of

folliculitis, 8 events of pruritus, 2 events of urticaria, and 1 event of skin irritation. All

events were non-serious and the majority of events (29 of 31) were reported after

application of LEO 90100. The 2 other events (urticaria and skin irritation) were reported

after application of the aerosol foam vehicle. The vast majority of AEs on the application

areas were mild (19 events) or moderate (11 events) in intensity. One AE was evaluated as

severe and concerned folliculitis reported after application of LEO 90100. The reported

outcome was ‘recovered’.

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11 Discussion and Overall Conclusions

11.1 Discussion

The objective of this trial was to provide complementary data on the skin irritation potential

and sensitisation potential of LEO 90100 after repeated topical applications on the skin of

healthy subjects. The trial combined the trial designs of two commonly accepted tests: the 21-

day cumulative irritation test to evaluate the potential of a topical product to induce skin

irritation after repeated exposure to the skin (14,15), and the human repeat insult patch test to

determine the allergic contact dermatitis potential of topically applied products (16).

The skin irritation potential was estimated from MCII and the maximal dermal response

during an induction phase over 21 days on a scale from 0 to 4. The MCII during the induction

phase was 0.102 for LEO 90100, 0.019 for aerosol foam vehicle, and 0.018 for the negative

control (white petrolatum). The mean maximal dermal response during the induction phase

was 0.44 for LEO 90100, 0.16 for aerosol foam vehicle, and 0.13 for the negative control

(white petrolatum). Although there was a statistically significantly difference between

LEO 90100 and the negative control for the above parameters, the skin irritation potential of

LEO 90100 was low. The aerosol foam vehicle generated the same minimal response as the

negative control; thus it appears that the vehicle itself does not have any irritation potential.

The slightly higher scores for LEO 90100 compared with the vehicle and the negative control

are most likely attributable to the presence of calcipotriol, which is known to cause local

irritation is some subjects. However, the potential irritant effects of calcipotriol would be

expected to be minimised by the presence of the corticosteroid, resulting in a limited potential

for irritancy, which was actually observed in the present trial.

In the challenge phase, the dermal response at each test site was assessed based on the

International Contact Dermatitis Research Group’s recommendations (19). The highest

reported dermal response score reported in this trial was a ‘weak positive reaction (erythema

infiltration, possibly papules)’, reported in 2 (0.9%) subjects after application of LEO 90100.

At the last dermal response score, 48 hours after removal of the patch in the challenge phase

(Day 40), the investigator (certified dermatologist) gave her/his opinion concerning a possible

sensitisation reaction of each test site taking into account all skin assessments performed

during the challenge phase. The presence of a sensitisation reaction was evaluated using a 3-

point scale (0: negative; 1: equivocal; 2: positive).

The positive reaction would be the clinical diagnosis of contact dermatitis (eczematous

reaction) made by the investigator. This takes into account the severity of typical

signs/symptoms indicative of sensitisation reactions, e.g. erythema,, infiltration, papules,

vesicles, bullae, spreading of the skin reaction beyond the application area, crumbling of the

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lesion border, intensive associated pruritus which does not fade despite product removal,

kinetics of the reaction (i.e. the reaction continues to spread or increase after removal of the

patch), or if a pruritus reaction does not decrease after removal of the patch. In the opinion of

the investigator there were no positive or equivocal sensitisation reactions for any subject,

neither for LEO 90100, aerosol foam vehicle, nor for the negative control.

The results in the present trial are in line with findings from previously conducted trials of

similar designs that investigated the skin irritation potential and skin sensitisation potential of

Daivobet® ointment versus ointment vehicle (20,21). In these trials, the vast majority of

subjects had maximum dermal response scores of either ‘no erythema’ or ‘barely perceptible

erythema’/‘equivocal erythema’ during the induction phase after application of Daivobet®

ointment and no test sites had scores higher than 1 (‘slight erythema with or without

oedema’). No sensitisation reactions were reported.

The overall incidence of AEs was 86 (39.6%) subjects reporting 116 AEs. AEs were most

frequently reported in the SOCs ‘Infections and infestations’, and ‘Nervous system disorders’.

One SAE was reported, led to withdrawal from the trial, and was assessed by the investigator

as having no relation to investigational product. The vast majority of the AEs were mild or

moderate and only 3 AEs were rated as severe.

In total, 31 ADRs were reported and consisted of 20 events of folliculitis, 8 events of pruritus,

2 events of urticaria, and 1 event of skin irritation. All ADRs were non-serious, were localised

on application areas, and the majority of events (29 of 31) were reported after application of

LEO 90100. Folliculitis was reported on 9.2% of test sites treated with LEO 90100. This is

not an unexpected finding as an incidence of 19% was observed in a previous trial of similar

design investigating the skin irritation potential of Daivobet® ointment and is most likely due

to the applied trial methods with use of corticosteroid products under (semi)occlusive

conditions (21). This is supported by the lower incidence of folliculitis in the LEO 90100

phase 2 and phase 3 trials, which were conducted under standard clinical use of LEO 90100.

In these trials, there was only 1 event of folliculitis reported out of 564 subjects treated with

LEO 90100 (12,22,23).

11.2 Overall Conclusions

LEO 90100 had a low skin irritation potential in healthy subjects. The aerosol foam

vehicle alone was shown to be non- irritant.

LEO 90100 as well as the aerosol foam vehicle alone showed no skin sensitisation

potential in healthy subjects.

There were no unexpected AEs.

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12 References

1. ICH E3. Structure and Content of Clinical Study Reports. November 1995

2. ICH E3 (R1). ICH E3 Guideline: Structure and Content of Clinical Study Reports

Questions and Answers. July 2012

3. ICH E6 (R1). Guideline for Good Clinical Practice. June 1996

4. ICH E9. Statistical Principles for Clinical Trials. February 1998

5. M4E(R1). The Common Technical Document for the Registration of Pharmaceuticals

for Human Use Efficacy. September 2002

6. Menter A, Gottlieb A, Feldman SR, van Voorhees AS, Leonardi CL, Gordon KB et al.

Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 1.

Overview of psoriasis and guidelines of care for the treatment of psoriasis with

biologics. J Am Acad Dermatol. 2008;58(5):826-50.

7. National Center for Health Statistics. Current estimates from the National Health Inter-

view Survey: United States, 1996, Vital Health Stat. 1999;10(200):81-6.

8. Farber EM, Nall L. Epidemiology: Natural history and genetics. In: Roenigk HHJ,

Maibach HI, editors. Psoriasis. New York: Marcel Dekker, 1998:107-57.

9. Gottlieb AB. Psoriasis. Dis Manag Clin Outcomes. 1998;1(6):195-202.

10. Douglas WS, Poulin Y, Decroix J, Ortonne JP, Mrowietz U, Gulliver W et al. A new

calcipotriol/betamethasone formulation with rapid onset of action was superior to

monotherapy with BDP or calcipotriol in psoriasis vulgaris. Acta Derm Venereol.

2002;82(2):131-5.

11. Guenther L, van de Kerkhof PC, Snellman E, Kragballe K, Chu AC, Tegner E et al.

Efficacy and safety of a new combination of calcipotriol and betamethasone

dipropionate (one or twice daily) compared to calcipotriol (twice daily) in the treatment

of psoriasis vulgaris: a randomized, double-blind, vehicle-controlled clinical trial. Br J

Dermatol. 2002;147(2):316-23.

12. Clinical Study Report. LEO 90100 Compared to Vehicle in Subjects with Psoriasis

Vulgaris. A phase 3 trial comparing once daily treatment with LEO 90100 calcipotriol

50 mcg/g plus betamethasone 0.5 mg/g (as dipropionate) with vehicle in subjects with

psoriasis vulgaris. A multi-centre, prospective, randomised, double-blinded, 2-arm,

parallel group, 4-week trial in subjects with psoriasis vulgaris; 26-Feb-2014. LEO

Study No. LP0053-1001.

LP0053-66 18-Jun-2014 of 121

13. Rietschel RL, Joseph FF. Fisher's Contact Dermatitis, 5th ed. Lippincott Williams &

Wilkins, Philadelphia, 2001;114-116.

14. Phillips L, Steinberg M, Maibach HI, Akers WA. A comparison of rabbit and human

skin responses to certain irritants. Toxicol Appl Pharmacol. 21:369-92,1972.

15. Berger RS, Bowman JP. A reappraisal of the 21-day cumulative irritation test in man. J

Toxicol – Ot & Ocular Toxicol. 1982;1(2);109-115.

16. Marzulli FN, Maibach. The use of graded concentrations in studying skin sensitizers:

Experimental contact sensitization in man. Food Cosmet. Toxicol. 1974;12(2):219-227.

17. Fitzpatrick TB: Soleil et peau. J Med Esthet. 1975;2:330-34.

18. National Academy of Sciences. Dermal and eye toxicity tests. Principles and

Procedures for Evaluating the Toxicity of Household Substances: Washington DC,

National Academy of Sciences, National Research Council. 1977;pp. 23-59.

19. Wilkinson DS, Fregert S, Magnusson B et el. Terminology of contact dermatitis. Acta

Derm Venereol. 1970;50:287-292.

20. Clinical Study Report. Repeat insult patch test with Daivobet/Dovobet ointment. A

study on the sensitisation potential of Daivobet/Dovobet ointment and the ointment

vehicle when applied on healthy skin in 200 healthy subjects; 24-Oct-2003. LEO Study

No. MCB 0202 FR.

21. Clinical Study Report. 21- day cumulative irritation test. Assessment of the local skin

tolerability, after repeated application of Daivobet/Dovobet ointment (calcipotriol 50

µg/g and betamethasone (as diproprionate) 0.5 mg/g) versus its vehicle; 13-May-2003.

LEO Study No. MCB 0203 FR.

22. Clinical Study Report. A phase 2 study comparing treatment with LEO 90100 with

betamethasone dipropionate in LEO 90100 vehicle and calcipotriol in LEO 90100

vehicle in subjects with psoriasis vulgaris. A multi-centre, prospective, randomised,

double-blind, 3-arm, parallel group, 4-week study in subjects with psoriasis vulgaris;

19-Apr-2013. Leo Study No. LEO 90100-7.

23. Clinical Study Report. LEO 90100 Compared with Calcipotriol plus Betamethasone

Dipropionate Ointment, LEO 90100 Vehicle and Ointment Vehicle in Subjects with

Psoriasis Vulgaris. A phase 2 study comparing treatment with LEO 90100 with

calcipotriol plus betamethasone ointment, LEO 90100 vehicle and ointment vehicle in

subjects with psoriasis vulgaris; 10-Jun-2013. Leo Study No. LEO 90100-35.

Trial ID: LP0053-66 18-Jun-2014 of 121

1 Tables and Figures, Baseline Characteristics and Investigational Product

Data

List of Tables

Table 1–1: Age: skin sensitisation analysis set......................................................................... 84

Table 1–2: Sex and skin type: skin sensitisation analysis set................................................... 85

Table 1–3: Ethnic origin and race: skin sensitisation analysis set............................................ 86

Table 1–4: Height, weight and Body Mass Index: skin sensitisation analysis set ................... 87

Table 1–5: Baseline blood pressure and heart rate: skin sensitisation analysis set .................. 88

Table 1–6: Diagnoses at baseline: skin sensitisation analysis set ............................................ 89

Table 1–7: Baseline skin assessment of dermal response by treatment group: skin sensitisation analysis set........................................................................................................ 90

List of Figures

Figure 1-1: Trial Analysis sets.................................................................................................. 91

Figure 1-2: Disposition of subjects .......................................................................................... 92

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 1–1: Age: skin sensitisation analysis set

Age (Years)


(n=213)

Mean 43.5 SD 12.5 Median 44.0 Minimum 19 Maximum 65 Number 213

03FEB14:17:57:54 LP0053-66 age 1 1.doc

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 1–2: Sex and skin type: skin sensitisation analysis set


(n=213)

Sex and Skin typeNumber of subjects %

SexMale 54 25.4 Female 159 74.6 Total 213 100.0

Skin typeII 33 15.5 III 178 83.6 IV 2 0.9 Total 213 100.0

03FEB14:17:52:24 LP0053-66 SexST 1 2.doc

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 1–3: Ethnic origin and race: skin sensitisation analysis set


(n=213)

Ethnicity and RaceNumber of subjects %

EthnicityNot Hispanic or Latino 213 100.0 Total 213 100.0

RaceWhite 213 100.0 Total 213 100.0

04FEB14:14:44:31 LP0053-66 ethnrace 1 3.doc

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 1–4: Height, weight and Body Mass Index: skin sensitisation analysis set

Height Weight and BMI


(n=213)

Height (cm) Mean 167.0 SD 8.6 Median 166.0 Minimum 150 Maximum 197 Number 213 Weight (kg) Mean 67.6 SD 13.8 Median 65.0 Minimum 43 Maximum 136 Number 213 BMI (kg/m²) Mean 24.2 SD 4.5 Median 23.4 Minimum 17.7 Maximum 48.2 Number 213

03FEB14:17:58:18 LP0053-66 HWBMI 1 4.doc

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 1–5: Baseline blood pressure and heart rate: skin sensitisation analysis set

blood pressureand heart rate


(n=213)

Systolic blood pressure (mmHg) Mean 123.4 SD 13.7 Median 123.0 Minimum 100 Maximum 162 Number 213 Diastolic blood pressure (mmHg) Mean 80.0 SD 8.6 Median 80.0 Minimum 53 Maximum 111 Number 213 Heart rate (bpm) Mean 77.8 SD 11.5 Median 77.0 Minimum 40 Maximum 123 Number 213

03FEB14:17:58:28 LP0053-66 VS 1 5.doc

1) Visit Day 1 measures before treatment application were considered as baseline measures

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 1–6: Diagnoses at baseline: skin sensitisation analysis set


(n=213)

System Organ Classification1Number ofdiagnoses

Number ofsubjects %

Cardiac disorders 5 5 2.3 Endocrine disorders 11 11 5.2 Gastrointestinal disorders 5 5 2.3 General disorders and administration site conditions

1 1 0.5

Infections and infestations 1 1 0.5 Metabolism and nutrition disorders 2 1 0.5 Musculoskeletal and connective tissue disorders

4 4 1.9

Neoplasms benign, malignant and unspecified (incl cysts and polyps

5 5 2.3

Psychiatric disorders 5 5 2.3 Reproductive system and breast disorders

1 1 0.5

Respiratory, thoracic and mediastinal disorders

4 4 1.9

Skin and subcutaneous tissue disorders 1 1 0.5 Social circumstances 57 57 26.8 Surgical and medical procedures 3 3 1.4 Vascular disorders 9 9 4.2 Total number of diagnoses2

114 Total number of subjects

81 38.0

04FEB14:10:39:20 LP0053-66 Diag 1 6.doc

1) Classification according to MedDRA version 15.1.

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 1–7: Baseline skin assessment of dermal response by treatment group: skin sensitisation analysis set

LEO90100(n=213)



Dermal ResponseNumber of subjects %



No Response 213 100.0 213 100.0 213 100.0 Total 213 100.0 213 100.0 213 100.0

03FEB14:17:52:02 LP0053-66 DRbas_1_7.doc

Trial ID: LP0053-66 18-Jun-2014 of 121

Figure 1-1: Trial Analysis sets

Screened subjects

Randomised subjects

Safety analysis set Skin sensitisation analysis set

Trial ID: LP0053-66 18-Jun-2014

Figure 1-2: Disposition of subjects

Screening visit

Visit Day 1 I 219 I I 2

Visit Day2 I 217 I I

Visit Day3 I 216 I

Visit Day4 I 216 I I

Visit Day5 I 215 I

Visit DayS I 216 I I

Visit Day9 I 215 I

Visit Day 1 0 and Visit Day 1 1 I 216 I I

Visit Day 12 I 215 I

1 Screening Failure (CRF- ) ow-up(CRF-1 Lost to foil

CRF.

1 SAE (CRF

CRF.

CRF.

CRF.

Visit Day 15 I 214 I CRFs-·

I 1 Voluntary (

Visit Day 16 I 215 I 1 Exclusion

Visit Day 17,18,19 and 22 I 214 I

Visit Day 231 6

Visit Day 36,38 and 39 I 214 I

AE follow-up visit"

Visit Day40 I 214 I .. I 2 I

1) Only for subjects who mised a visit in induction phase 2) only applicable if ongoing ADR at the subject's last visit No subjects needed to attend optional Visit Day 41 or a re-challenge visit

of 121

Trial ID: LP0053-66 18-Jun-2014 of 121

3 Tables and Figures, Safety Data

List of Tables

Table 3–1: Mean Cumulative Irritation Index (MCII) during induction phase: skin irritation analysis set........................................................................................................ 94

Table 3–2: Maximal dermal response during induction phase (Day 2-22): skin irritation analysis set........................................................................................................ 95

Table 3–3: Maximal dermal response category during induction phase (Day 2-22): skin irritation analysis set......................................................................................... 96

Table 3–4: Dermal response category by visit during induction phase: skin irritation analysis set ..................................................................................................................... 97

Table 3–5: Dermal response category by visit during induction phase: subjects excluded from skin irritation analysis set ............................................................................... 101

Table 3–6: Maximal dermal response category during challenge phase: skin sensitisation analysis set...................................................................................................... 104

Table 3–7: Dermal response category during challenge phase by time point: skin sensitisation analysis set...................................................................................................... 105

Table 3–8: Overall summary of adverse events: safety analysis set ...................................... 106

Table 3–9: Treatment emergent adverse events by MedDRA primary system organ class: safety analysis set ........................................................................................... 107

Table 3–10: Treatment emergent adverse events by MedDRA primary system organ class and preferred term: safety analysis set .................................................................. 108

Table 3–11: Relationship of treatment emergent adverse events by MedDRA primary system organ class and preferred term: safety analysis set ........................................ 110

Table 3–12: Intensity of treatment emergent adverse events by MedDRA primary system organ class and preferred term: safety analysis set ........................................ 112

Table 3–13: Treatment emergent adverse drug reactions by MedDRA primary system organ class and preferred term: safety analysis set .................................................. 114

Table 3–14: Relationship of treatment emergent adverse drug reactions by MedDRA primary system organ class and preferred term: safety analysis set ............................ 115

Table 3–15: Intensity of treatment emergent adverse drug reactions by MedDRA primary system organ class and preferred term: safety analysis set ............................ 116

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3–1: Mean Cumulative Irritation Index (MCII) during induction phase: skin irritation

analysis set

MCIILEO90100(n=213)



MCIIMean 0.102 0.019 0.018 SD 0.137 0.042 0.043 Median 0.031 0.000 0.000 Minimum 0.000 0.000 0.000 Maximum 0.781 0.344 0.313 Number 213 213 213


0.084 0.013 0.012


0.121 0.025 0.024

Comparisons1


05FEB14:11:46:44 LP0053-66 MCII 3 1.doc


Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3–2: Maximal dermal response during induction phase (Day 2-22): skin irritation analysis set


LEO90100(n=213)



Maximum scoreMean 0.44 0.16 0.13 SD 0.41 0.25 0.24 Median 0.50 0.00 0.00 Minimum 0.00 0.00 0.00 Maximum 2.00 1.00 1.00 Number 213 213 213


0.39 0.13 0.10


0.50 0.20 0.16

Comparisons1


04FEB14:16:22:53 LP0053-66 MAXII 3 2.doc


Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3–3: Maximal dermal response category during induction phase (Day 2-22): skin irritation analysis set

LEO90100(n=213)







No Response 76 35.7 148 69.5 161 75.6 Questionable or faint, indistinct erythema

92 43.2 61 28.6 48 22.5


3 1.4 0 0.0 0 0.0

Total 213 100.0 213 100.0 213 100.0

05FEB14:11:41:26 LP0053-66 MAXIIc_3_3.doc

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3–4: Dermal response category by visit during induction phase: skin irritation analysis set

LEO90100(n=213)







Visit Day 1No Response 213 100.0 213 100.0 213 100.0 Total 213 100.0 213 100.0 213 100.0

Visit Day 2No Response 210 98.6 202 94.8 204 95.8 Questionable or faint, indistinct erythema

3 1.4 11 5.2 9 4.2

Total 213 100.0 213 100.0 213 100.0


36 17.0 12 5.7 10 4.7

Well-defined erythema 3 1.4 0 0.0 0 0.0 Total 212 100.0 212 100.0 212 100.0


35 16.4 10 4.7 8 3.8



26 12.3 14 6.6 16 7.5



28 13.1 14 6.6 16 7.5

Well-defined erythema 3 1.4 1 0.5 0 0.0

05FEB14:11:47:58 LP0053-66 DRIvis 3 4.doc Continued...

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3-4: Dermal response category by visit during induction phase: skin irritation analysis set (continued)

LEO90100(n=213)







Visit Day 8Erythema with slight to moderate edema

2 0.9 0 0.0 0 0.0

Total 213 100.0 213 100.0 213 100.0


18 8.5 12 5.7 11 5.2



17 8.0 7 3.3 6 2.8



17 8.0 10 4.7 5 2.3



32 15.1 9 4.2 10 4.7



33 15.6 2 0.9 6 2.8

Well-defined erythema 8 3.8 0 0.0 1 0.5

05FEB14:11:47:58 LP0053-66 DRIvis_3_4.doc Continued...

Trial ID: LP0053-66 18-Jun-2014 of 121


LEO90100(n=213)







Visit Day 15Erythema with slight to moderate edema

1 0.5 0 0.0 0 0.0

Total 211 100.0 211 100.0 211 100.0


32 15.0 2 0.9 3 1.4


1 0.5 0 0.0 0 0.0

Total 213 100.0 213 100.0 213 100.0


46 21.6 2 0.9 3 1.4


1 0.5 0 0.0 0 0.0

Total 213 100.0 213 100.0 213 100.0


36 16.9 2 0.9 2 0.9


1 0.5 0 0.0 0 0.0

Total 213 100.0 213 100.0 213 100.0


46 21.6 2 0.9 2 0.9


1 0.5 0 0.0 0 0.0

05FEB14:11:47:58 LP0053-66 DRIvis 3 4.doc Continued...

Trial ID: LP0053-66 18-Jun-2014 of 121


LEO90100(n=213)







Visit Day 19Total 213 100.0 213 100.0 213 100.0


44 20.7 6 2.8 6 2.8


1 0.5 0 0.0 0 0.0

Total 213 100.0 213 100.0 213 100.0


1 16.7 0 0.0 0 0.0

Total 6 100.0 6 100.0 6 100.0

05FEB14:11:47:58 LP0053-66 DRIvis_3_4.doc

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3–5: Dermal response category by visit during induction phase: subjects excluded from skin irritation analysis set

LEO90100(n=5)









0 0.0 1 25.0 1 25.0

Total 4 100.0 4 100.0 4 100.0


0 0.0 1 25.0 1 25.0

Total 4 100.0 4 100.0 4 100.0


1 33.3 0 0.0 0 0.0

Total 3 100.0 3 100.0 3 100.0


0 0.0 0 0.0 1 33.3

Total 3 100.0 3 100.0 3 100.0


1 33.3 0 0.0 0 0.0

Total 3 100.0 3 100.0 3 100.0

05FEB14:11:41:47 LP0053-66 DRIvisex 3 5.doc Continued...

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3-5: Dermal response category by visit during induction phase: subjects excluded from skin irritation analysis set (continued)

LEO90100(n=5)








1 33.3 0 0.0 1 33.3

Total 3 100.0 3 100.0 3 100.0







1 100.0 0 0.0 0 0.0

Total 1 100.0 1 100.0 1 100.0


05FEB14:11:41:47 LP0053-66 DRIvisex 3 5.doc Continued...

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3-5: Dermal response category by visit during induction phase: subjects excluded from skin irritation analysis set (continued)

LEO90100(n=5)









05FEB14:11:41:47 LP0053-66 DRIvisex 3 5.doc

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3–6: Maximal dermal response category during challenge phase: skin sensitisation analysis set

LEO90100(n=213)







No reaction 159 74.6 211 99.1 209 98.1 Doubtful reaction 52 24.4 2 0.9 4 1.9 Weak positive reaction

2 0.9 0 0.0 0 0.0

Total 213 100.0 213 100.0 213 100.0

05FEB14:11:47:38 LP0053-66 MAXICc 3 6.doc

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3–7: Dermal response category during challenge phase by time point: skin sensitisation analysis set

LEO90100(n=213)







Visit Day 36No reaction 213 100.0 213 100.0 213 100.0 Total 213 100.0 213 100.0 213 100.0

Visit Day 38No reaction 170 79.8 211 99.1 209 98.1 Doubtful reaction 41 19.2 2 0.9 4 1.9 Weak positive

reaction 2 0.9 0 0.0 0 0.0

Total 213 100.0 213 100.0 213 100.0



05FEB14:11:42:07 LP0053-66 DRCvis 3 7.doc

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3–8: Overall summary of adverse events: safety analysis set

Safety Aalysis Set(n=217)

Adverse event categoryNumberof AEs1

Number of subjects (%)

All adverse events 116 86 (39.6) Severe adverse events 3 3 ( 1.4) Adverse drug reactions 30 22 (10.1) AEs leading to withdrawal from trial 1 1 ( 0.5) AEs on treatment site 30 22 (10.1) SAEs 1 1 ( 0.5)

20MAR14:11:52:48 LP0053-66 aeall_3_8.doc

1) Different adverse events within the same preferred term and system organ class and involving the same subject have been counted as one.

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3–9: Treatment emergent adverse events by MedDRA primary system organ class: safety analysis set


System Organ Class1 Number of subjects %

Infections and infestations 42 19.4Nervous system disorders 30 13.8Skin and subcutaneous tissue disorders

11 5.1

Musculoskeletal and connective tissuedisorders

9 4.1

Gastrointestinal disorders 5 2.3Respiratory, thoracic and mediastinaldisorders

5 2.3

Reproductive system and breast disorders

3 1.4

Injury, poisoning and proceduralcomplications

2 0.9

General disorders and administration siteconditions

1 0.5

Neoplasms benign, malignant and unspecified(incl cysts and polyps)

1 0.5

Psychiatric disorders 1 0.5 Total number of adverse events2 116 Total number of subjects 86 39.6

07FEB14:10:23:09 LP0053-66 aesoc 3 9.doc



Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3–10: Treatment emergent adverse events by MedDRA primary system organ class and preferred term: safety analysis set



Infections and infestationsNasopharyngitis 20 9.2Folliculitis 20 9.2Influenza 3 1.4Gastroenteritis 1 0.5Oral herpes 1 0.5Pharyngitis 1 0.5SOC total 42 19.4

Nervous system disordersHeadache 27 12.4Neuralgia 2 0.9Migraine 1 0.5Sciatica 1 0.5VIIth nerve paralysis 1 0.5SOC total 30 13.8

Skin and subcutaneous tissue disordersPruritus 8 3.7Urticaria 1 0.5Prurigo 1 0.5Skin irritation 1 0.5SOC total 11 5.1

Musculoskeletal and connective tissuedisordersMyalgia 4 1.8Back pain 3 1.4Arthralgia 2 0.9SOC total 9 4.1

Gastrointestinal disordersToothache 2 0.9Gastritis 1 0.5Gastrooesophageal reflux disease 1 0.5Rectal haemorrhage 1 0.5SOC total 5 2.3

Respiratory, thoracic and mediastinaldisordersAsthma 1 0.5Oropharyngeal pain 2 0.9Rhinitis allergic 2 0.9

07FEB14:10:25:58 LP0053-66 aept 3 10.doc Continued...

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3-10: Treatment emergent adverse events by MedDRA primary system organ class and preferred term: safety analysis set (continued)



Respiratory, thoracic and mediastinaldisordersSOC total 5 2.3

Reproductive system and breast disordersDysmenorrhoea 3 1.4SOC total 3 1.4

Injury, poisoning and proceduralcomplicationsFoot fracture 1 0.5Ligament sprain 1 0.5SOC total 2 0.9

General disorders and administration siteconditionsPyrexia 1 0.5SOC total 1 0.5

Neoplasms benign, malignant and unspecified(incl cysts and polyps)Mycosis fungoides 1 0.5SOC total 1 0.5

Psychiatric disordersAnxiety 1 0.5SOC total 1 0.5

Total number of adverse events2 116

Total number of subjects 86 39.6

07FEB14:10:25:58 LP0053-66 aept_3_10.doc



Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3–11: Relationship of treatment emergent adverse events by MedDRA primary system organ class and preferred term: safety analysis set


System Organ Class(SOC)Preferred Term1

Notrelated Possible Probable

Infections and infestationsFolliculitis 0 0 20Nasopharyngitis 20 0 0Influenza 3 0 0Gastroenteritis 1 0 0Oral herpes 1 0 0Pharyngitis 1 0 0

Nervous system disordersHeadache 27 0 0Neuralgia 2 0 0Migraine 1 0 0Sciatica 1 0 0VIIth nerve paralysis 1 0 0

Skin and subcutaneous tissuedisordersPruritus 0 0 8Prurigo 1 0 0Skin irritation 0 0 1Urticaria 0 1 0

Musculoskeletal and connectivetissue disordersMyalgia 4 0 0Back pain 3 0 0Arthralgia 2 0 0

Gastrointestinal disordersToothache 2 0 0Gastritis 1 0 0Gastrooesophageal refluxdisease

1 0 0

Rectal haemorrhage 1 0 0Respiratory, thoracic andmediastinal disordersOropharyngeal pain 2 0 0Rhinitis allergic 2 0 0Asthma 1 0 0

Reproductive system and breastdisordersDysmenorrhoea 3 0 0

07FEB14:10:38:07 LP0053-66 aerel 3 11.doc Continued...

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3-11: Relationship of treatment emergent adverse events by MedDRA primary system organ class and preferred term: safety analysis set (continued)



Notrelated Possible Probable

Injury, poisoning andprocedural complicationsFoot fracture 1 0 0Ligament sprain 1 0 0

General disorders andadministration siteconditionsPyrexia 1 0 0

Neoplasms benign, malignantand unspecified (incl cystsand polyps)Mycosis fungoides 1 0 0

Psychiatric disordersAnxiety 1 0 0

Total number of adverseevents2

86 1 29

07FEB14:10:38:07 LP0053-66 aerel_3_11.doc



Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3–12: Intensity of treatment emergent adverse events by MedDRA primary system organ class and preferred term: safety analysis set


System Organ Class(SOC)Preferred Term1 Mild Moderate Severe

Infections and infestationsFolliculitis 12 7 1Nasopharyngitis 15 5 0Influenza 3 0 0Gastroenteritis 1 0 0Oral herpes 1 0 0Pharyngitis 0 1 0

Nervous system disordersHeadache 18 8 1Neuralgia 1 1 0Migraine 0 1 0Sciatica 1 0 0VIIth nerve paralysis 0 1 0

Skin and subcutaneous tissuedisordersPruritus 5 3 0Prurigo 1 0 0Skin irritation 1 0 0Urticaria 0 1 0

Musculoskeletal and connectivetissue disordersMyalgia 4 0 0Back pain 2 1 0Arthralgia 2 0 0

Gastrointestinal disordersToothache 2 0 0Gastritis 1 0 0Gastrooesophageal refluxdisease

1 0 0

Rectal haemorrhage 0 0 1Respiratory, thoracic andmediastinal disordersOropharyngeal pain 2 0 0Rhinitis allergic 1 1 0Asthma 1 0 0

Reproductive system and breastdisordersDysmenorrhoea 1 2 0

07FEB14:10:46:13 LP0053-66 aeint 3 12.doc Continued...

Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3-12: Intensity of treatment emergent adverse events by MedDRA primary system organ class and preferred term: safety analysis set (continued)


System Organ Class(SOC)Preferred Term1 Mild Moderate Severe

Injury, poisoning andprocedural complicationsFoot fracture 0 1 0Ligament sprain 0 1 0

General disorders andadministration siteconditionsPyrexia 1 0 0

Neoplasms benign, malignantand unspecified (incl cystsand polyps)Mycosis fungoides 0 1 0

Psychiatric disordersAnxiety 1 0 0

Total number of adverseevents2

78 35 3

07FEB14:10:46:13 LP0053-66 aeint_3_12.doc



Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3–13: Treatment emergent adverse drug reactions by MedDRA primary system organ class and preferred term: safety analysis set

LEO90100(n=217)



System Organ Class (SOC)Preferred Term1




Infections and infestationsFolliculitis 20 9.2 0 0.0 0 0.0SOC total 20 9.2 0 0.0 0 0.0

Skin and subcutaneous tissue disordersPruritus 8 3.7 0 0.0 0 0.0Urticaria 1 0.5 1 0.5 0 0.0Skin irritation 0 0.0 1 0.5 0 0.0SOC total 9 4.1 2 0.9 0 0.0

Total number of drug reactions2 29 2

Total number of subjects 21 9.7 2 0.9 0 0.0

07FEB14:10:52:24 LP0053-66 Adrpt 3 13.doc



Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3–14: Relationship of treatment emergent adverse drug reactions by MedDRA primary system organ class and preferred term: safety analysis set

LEO90100(n=217)




Not related Possible Probable



Infections and infestationsFolliculitis 0 0 20 0 0 0 0 0 0

Skin and subcutaneous tissuedisordersPruritus 0 0 8 0 0 0 0 0 0Urticaria 0 1 0 0 1 0 0 0 0Skin irritation 0 0 0 0 0 1 0 0 0

Total number of adverse drugreactions2

0 1 28 0 1 1 0 0 0

07FEB14:10:55:53 LP0053-66 ADRrel_3_14.doc



Trial ID: LP0053-66 18-Jun-2014 of 121

Table 3–15: Intensity of treatment emergent adverse drug reactions by MedDRA primary system organ class and preferred term: safety analysis set

LEO90100(n=217)



System Organ Class(SOC)Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe

Infections and infestationsFolliculitis 12 7 1 0 0 0 0 0 0

Skin and subcutaneous tissuedisordersPruritus 5 3 0 0 0 0 0 0 0Urticaria 1 0 0 0 1 0 0 0 0Skin irritation 0 0 0 1 0 0 0 0 0

Total number of adverse drugreactions2

18 10 1 1 1 0 0 0 0

07FEB14:10:50:43 LP0053-66 ADRint_3_15.doc



Trial ID: LP0053-66 18-Jun-2014 of 121

0 End-of-Text Listings

Trial ID: LP0053-66 18-Jun-2014 of 121

Table of Contents

0-1 Subjects Withdrawn due to AE .........................................................................................................................................................................119

Treatment group=All Randomised..............................................................................................................................................................................119

0-2 Deaths..............................................................................................................................................................................................................................120

0-3 Serious Adverse Events .......................................................................................................................................................................................121

Treatment group=All Randomised..............................................................................................................................................................................121

Trial ID: LP0053-66

Listing 0-1: Subjec ts Withdrawn due to AE Treatment group~1 Randomised

Centre/ Subjec t ID Location

Preferred term/ rted term

RECTAL HAEMORRHAGE/ Pr oct o rrhagia

06FEB2014 : 17 : 46: 4B PrograJDS-Listinqs ae (where=AEACNOTB n e " )

18-Jnn-2014

Duratio n Re1atio

n No t re l ated

Intensit Ac tion taken

Severe Unknown Outcome No t reco vered

Seriou s Yes

of 121

Days sinc e first/ lates t dose

3/1

Trial ID: LP0053-66 18-Jun-2014 of 121

Listing 0-2: Deaths

Date of program execution Empty List06FEB2014:17:46:48 No data for this listing

06FEB2014:17:46:48 Programs-Listings empty

Trial ID: LP0053-66

Listing 0-3: Serious Adverse Events Treatment group~l Randomised

Centre/ Subjec t ID Location

Preferred term/ rted term

RECTAL HAEMORRHAGE/ Pr oct o rrhagia

06FEB2 014 : 17 : 4 6: 48 PrograJDS-Listinqs a e (where=first (upcase(aeser) ) = 'Y' )

18-Jnn-2014

Duratio n Relatio

n No t re l ated

Intensit Ac tion taken

Severe Unknown Outcome No t recovered

Seriou s Yes

of 121

Days sinc e first/ lates t dose

3/1

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