public assessment report for paediatric studies submitted in

NL/W/0007/pdWS/001 CMDh /14

Public Assessment Report for paediatric studies submitted in accordance

with Article 46 of Regulation (EC) No1901/2006, as amended

Humatrope Growth hormone

somatropin

NL/W/0007/pdWS/001

Marketing Authorisation Holder: Lilly Deutschland

GmbH

Rapporteur: The Netherlands

Finalisation procedure (day 90): 17 September 2009

Date of finalisation of PAR 4 August 2011

NL/W/007/pdWS/001 CMDh/ /14

ADMINISTRATIVE INFORMATION

Invented name of the medicinal product:

Humatrope

INN (or common name) of the active substance(s):

somatropin

MAH: Lilly Deutschland GmbH

Currently approved Indication(s) Paediatric Patients Humatrope is indicated for the long-term treatment of children who have growth failure due to an inadequate secretion of normal endogenous growth hormone. Humatrope is also indicated for the treatment of short stature in children with Turner Syndrome, confirmed by chromosome analysis. Humatrope is also indicated for the treatment of growth retardation in prepubertal children with chronic renal insufficiency. Humatrope is also indicated for the treatment of patients who have growth failure associated with SHOX deficiency, as confirmed by DNA analysis. Humatrope is also indicated for growth disturbance (current height SDS <-2.5 and parental adjusted height SDS <-1) in short children born small for gestational age (SGA), with a birth weight and/or length below -2 SD, who failed to show catch up growth (height velocity SDS <0 during the last year) by 4 years of age or later. Adult Patients Humatrope is indicated for replacement therapy in adults with pronounced growth hormone deficiency. Patients with severe growth hormone deficiency in adulthood are defined as patients with known hypothalamic-pituitary pathology and at least one known deficiency of a pituitary hormone not being prolactin. These patients should undergo a single dynamic test in order to diagnose or exclude a growth deficiency. In patients with childhood onset isolated GH deficiency (no evidence of hypothalamic-pituitary disease or cranial irradiation), two dynamic tests should be recommended, except for those having low IGF-I concentrations <-2 SDS who may be considered for one test. The cut-off point of the dynamic test should be strict.

Pharmaco-therapeutic group (ATC Code):

H01AC01

Pharmaceutical form(s) and strength(s):

Powder and solvent for solution for injection


I. EXECUTIVE SUMMARY On the basis of the results of these studies no changes in the SmPC and PL are necessary. Summary of outcome

X No change

II. RECOMMENDATION The results available from these trials do not change the risk-benefit assessment for Humatrope. Humatrope is approved for most of the paediatric indications investigated in the above mentioned studies: Growth Hormone Deficiency since 1987, Turner Syndrome since 1990, and short children born Small for Gestational Age since 2006. The use of Humatrope in Prader-Willi syndrome (investigated in study B9R-HL-GDGN) is not an approved indication for Humatrope, but is for other somatropin containing products. Results presented during this art 46 procedure did not necessitate an update of the SPC. No changes to the current SPCs for Humatrope are required.

III. INTRODUCTION On 23 March 2009, the MAH submitted 4 completed paediatric studies for Humatrope, in accordance with Article 46 of Regulation (EC) No1901/2006, as amended, on medicinal products for paediatric use. The MAH stated that the submitted paediatric study(ies) do not influence the benefit risk for Humatrope and that there is no consequential regulatory action.

IV. SCIENTIFIC DISCUSSION

IV.1 Information on the pharmaceutical formulation used in the study(ies)

N/A

IV.2 Clinical aspects IV.2.1. Introduction The MAH submitted 4 final report(s) for:

Study Code Study Title

B9R-EW-GDGB Optimization of Growth Hormone Treatment in Short Children Born Small for Gestational Age Based on a Growth Prediction Model The OPTIMA Trial -12 and 24 month data

B9R-HL-GDGN An Open Label Follow-up Study of Twenty children with PWS Who Participated in Clinical Study B9R-HL-GDDV

B9R-EW-GDCT Humatrope Treatment to Final Height in Tumer's Syndrome


B9R-IT-GDFU Efficacy and Safety of a High Dosage Compared to the Label Dosage of Humatrope in Early Pubertal Stage Children with Growth Hormone Deficiency

IV.2.2. Clinical studies IV.2.2.1 Study B9R-EW-GDGB

Description Optimization of Growth Hormone Treatment in Short Children Born Small for Gestational Age Based on a Growth Prediction Model: The OPTIMA Trial Methods Objective(s): Primary: To test the research hypothesis that GH (somatropin), given as an individually adjusted dose (IAD), is non-inferior to a fixed high dose (FHD) regimen as measured by the change in height standard deviation score (SDS) after 1 year of treatment. Dose adjustment after 3 months of treatment was based on a growth prediction for the first 12 months using the “Cologne” growth prediction model. Secondary:

• To compare absolute height velocity (HV) after 1 and 2 years of treatment in the 2 treatment arms, including age, gender, pubertal development, and country as covariates.

• To investigate the change in height SDS from baseline to 1 and 2 years of treatment relative to midparental height SDS (= target height SDS).

• To compare the change in height SDS between both treatment arms from baseline to 24 months of treatment.

• To compare the change in height SDS between both treatment arms from 12 to 24 months of treatment

• To investigate the association between change in height SDS during the second year of treatment and change in height SDS during the first year of treatment.

• To compare the safety profiles of both treatment arms. Study design Randomized, open-label, multicenter Phase 3 study of outpatient GH treatment in children with short stature born small for gestational age (SGA). The study was designed to demonstrate non-inferiority of an individually adjusted GH dose (IAD) regimen versus a fixed high dose (FHD) regimen, based on the change in height SDS after the first year of GH treatment as the primary outcome measure. the study consisted of 8 visits and was divided into 4 periods: Screening, Treatment Period I (up to Month 3), Treatment Period II (up to Month 12, primary analysis), and Treatment Period III (second year of treatment). Patients assigned to the FHD group received a fixed GH dose of 0.067 mg/kg body weight per day during Study Periods I to III. Patients assigned to the IAD group started at a lower GH dose of 0.035 mg/kg per day for the initial 3 months. Individual dose adjustment occurred after 3 months, based on the 1-year growth prediction using the “Cologne” growth prediction model, and after 12 months, based on the actual change in height SDS after 1 year of treatment (see figure).


Figure 1. Study Design

Abbreviations: HGH = Humatrope, growth hormone of human origin, SDS = standard deviation score, w = week, yr = year.

Study population Diagnosis and Main Criteria for Inclusion:

• Children born SGA, as defined by birth weight below the 10th percentile and/or birth length shorter than 2 standard deviations (SD) below the mean for gestational age, based on local standards

• Short stature, as defined by a height SDS ≤-3, based on local standards • Chronological age ≥3 years • Clinically prepubertal (girls: breast development Tanner Stage 1, boys: genital development

Tanner Stage 1) • Bone age ≤9 years for girls and ≤10 years for boys • Patients with known GH deficiency, chronic diseases, tumor activity, any growth affecting current

or previous treatment or any significant signs of dysproportion or underlying non-toxic, but proven or assumed genetically based defined syndromal disease (as to the opinion of the investigator) were not eligible for enrollment.

Sample size Planned: 185 Entered (signed informed consent): 200 Randomized: 194 (100 patients FHD, 94 patients IAD; 1 patient randomized to FHD had no study drug) Completed 12 months of treatment: 175 (92 patients FHD, 83 patients IAD) Completed 24 months of treatment: 164 (85 FHD, 79 IAD) Per Protocol Set (first year) for primary analysis: 169 (89 patients FHD, 80 patients IAD) Per Protocol Set (second year): 150 (78 patients FHD, 72 patients IAD)


Treatments Humatrope [somatropin, Lilly]; IAD regimen: 0.035 mg/kg per day up to Month 3, followed by 0.067 mg/kg per day up to Month 24 if the predicted 1-year change in height SDS was <0.75. If the predicted 1-year change in height SDS was ≥0.75, patients continued on start dose of 0.035 mg/kg per day up to Month 12; if they remained below the predicted growth response of a change in height SDS ≥0.75 at Month 12, their Humatrope dose was also increased to 0.067 mg/kg per day for the second year of treatment. Humatrope was given as a single daily subcutaneous injection.

Outcomes/endpoints Efficacy: Standing height and height SDS (primary outcome: 1-year change in height SDS), height velocity (HV) and HV SDS, difference between height SDS and target height SDS. Safety: Adverse events (AEs), solicited adverse events of specific interest, vital signs, pubertal development, bone age, weight, body mass index (BMI), standard local laboratory data (including fasting glucose, oral glucose tolerance test [OGTT], insulin, lipids, total T4 or free T4 and thyroid stimulating hormone [TSH]), special laboratory data (central laboratory: IGF-I and IGFBP-3. Statistical Methods Statistical: The sample size was calculated to detect with 80% power that the 95% confidence interval (CI) of the difference in Δ height SDS between the 2 arms is completely above the non-inferiority margin of -0.5 SDS, assuming a treatment-group difference of -0.175 SDS and a common SD of 0.7. Assuming a 20% drop-out rate, the required sample size was calculated to be 185 patients. Main analysis after the first year of treatment: The primary analysis was to evaluate if the IAD regimen was non-inferior to the FHD regimen in terms of the change in height SDS after the first year of treatment. The non-inferiority margin for the difference in change of height SDS (IAD – FHD) was chosen at -0.5 SDS to reflect a lower limit of a clinically relevant difference. Between-group analyses were performed using an analysis of covariance (ANCOVA) model incorporating treatment group as fixed-factor effect and the baseline height SDS as a covariate. The Per Protocol Population (first year) was used for the confirmatory analysis. It included all patients who had no major protocol violation, who received the correct treatment as assigned to after random allocation for at least 300 days during the whole treatment period, who did not miss more than cumulative 2 weeks of treatment between start of Humatrope treatment and Visit 2 (3 months), who completed standing height measurements at least at Visit 1, Visit 2, and Visit 4, and for whom all data necessary for a growth prediction after 3 months were available. Secondary analyses: All secondary efficacy analyses after the first and second year of treatment are presented for the Per Protocol Populations (first and second year). Secondary efficacy analyses included between-group comparisons of (1) absolute HV after 1 and 2 years of treatment, using an ANCOVA model corresponding to the primary analysis but including age, gender, and pubertal development as additional factors; (2) change in height SDS from baseline to 24 months of treatment, change in height SDS from 12 to 24 months of treatment, and change in absolute HV after 1 and 2 years, all using the same ANCOVA model as for the primary analysis; (3) 1- and 2-year change of the difference between child height SDS and target height SDS, again using the same ANCOVA model as for the primary analysis. In addition, the association between change in height SDS during the first and second year of treatment was evaluated using regression analysis and an ANCOVA with the change in height SDS during the second year as independent variable and the following factors/covariables as dependent variables: change in height SDS during the first year, treatment group, and their interaction during the first year . Only patients who at least attended Visit 4/101 (12 months) were included in the analysis after the second year of treatment. The Per Protocol Population (second year) included only patients who were already in the Per Protocol Population (first year), had no major protocol violations during the second year, did not miss more than 65 cumulative days of GH treatment during the second year, and who completed standing height measurement at Visit 104. All safety analyses were based on the Safety Population (identical to the Full Analysis Set).


Results Recruitment/ Number analysed

A total of 193 patients (FHD group 99, IAD group 94 patients) received at least 1 dose of Humatrope and were included in the Full Analysis Set (first year) and the Safety Population. Of these, 175 patients (FHD 92, IAD 83) completed 12 months of treatment. Baseline data Table 1- Baseline Characteristics Full Analysis Set, First Year (N=193)

FHD Group (N=99)

IAD Group (N=94)

Age (male / female) (years) 6.7 ± 2.5 / 6.7 ± 2.3 6.9 ± 2.5 / 6.8 ± 2.5

Male /female (%) 55.6 / 44.4 50.0 / 50.0

Gestational age (weeks) 36.8 ± 4.0 37.4 ± 3.0

Birth weight SDS -2.11 ± 0.90 -2.17 ± 0.73

Birth length SDS -2.81 ± 1.27 -2.79± 1.22

Standing height (cm) 103.5 ± 12.4 103.9 ± 12.3

Height SDS -3.89 ± 0.64 -3.91 ± 0.67

HV (cm/year) 5.3 ± 1.6 5.3 ± 1.8

HV SDS -1.45 ± 1.91 -1.47 ± 2.25

Height SDS – target height SDS -2.17 ± 1.18 -2.17 ± 1.23

Absolute bone age delay (years) -2.1 ± 1.1 -1.9 ± 1.2 Abbreviations: FHD = fixed high dose of Humatrope; HV = height velocity; IAD = individually adjusted dose of Humatrope; N = number of patients with data available; SDS = standard deviation score. Note: Data for continuous variables are presented as mean ± standard deviation.

All patients were clinically prepubertal at baseline; 11 patients (5.7%) entered puberty during the first treatment year (7 FHD, 4 IAD), 16 additional patients entered puberty during the second year (8 FHD, 8 IAD). Efficacy results Efficacy Analyses - First Year of Treatment The confirmatory primary efficacy analysis was conducted on the Per Protocol Population (first year), which included 169 patients (FHD 89, IAD 80), corresponding to 87.1% of all 194 randomized patients. In the IAD group, 38 patients had their dose increased to 0.067 mg/kg per day after 3 months based on their growth prediction (Per Protocol Population, first year). Forty-two patients remained on the initial Humatrope dose of 0.035 mg/kg per day after growth prediction at Month 3. Table 2 summarizes descriptive statistics for patients’ growth response after the first year of treatment. Table 2 - Summary of Growth Response after 12 Months Per Protocol Population, First Year (N=169)

FHD Group (N=89)

IAD Group (N=80)

FHD Group (N=89)

IAD Group (N=80)

FHD Group (N=89)

IAD Group (N=80)

Baseline data Data after 12 months Difference 0-12 months

Ht (cm) 104.2 ± 12.3 103.8 ± 12.5 114.6 ± 11.8

113.2 ± 12.5 +10.4 ± 1.9 +9.4 ± 1.5

Ht SDS -3.88 ± 0.54 -3.84 ± 0.62 -2.75 ± 0.65

-2.95 ± 0.68 +1.13 ±0.40

+0.89 ±0.34

HV (cm/year)

5.2 ± 1.5 5.4 ± 1.9 10.3 ± 1.9 9.3 ± 1.5 +5.2 ± 2.4 +3.9 ± 2.7

Ht SDS – -2.15 ± 1.15 -2.12 ± 1.11 -1.03 ±

1.15 -1.24 ± 1.11 +1.12

±0.39 +0.89 ±0.35

Abbreviations: FHD = fixed high dose of Humatrope; Ht = height; HV = height velocity; IAD = individually adjusted dose of Humatrope; N = number of patients with data available; SDS = standard deviation score. Note: Data are presented as mean ± standard deviation.


Table 3 summarizes the primary and secondary efficacy analyses after the first year of treatment. Table 3 - Treatment Group Comparisons after 12 Months Per Protocol Population, First Year (N=169)

Difference between Treatment Groups (IAD minus FHD)

LS Mean 95% CI, LS Mean) p-Value (ANCOVA)

Change in Ht SDS -0.24 -0.35 to -0.12 <.0001a

Absolute HV (cm/year) -1.01 -1.49 to -0.53 <.0001b

Ht SDS – target Ht SDS -0.23 -0.35 to -0.12 .0001c Abbreviations: FHD = fixed high dose of Humatrope; Ht = height; HV = height velocity; IAD = individually adjusted dose of Humatrope; LS mean = least square mean; N = number of patients with data available; SDS = standard deviation score. a Covariate: baseline height SDS. b Covariates/factors: baseline HV, age, sex, pubertal status at Visit 4 c Covariate: Ht SDS – target Ht SDS at baseline

In the primary statistical analysis, the change in height SDS after 1 year of Humatrope treatment in the IAD group was shown to be non-inferior to the FHD group: The lower limit of the 95% CI of the LS mean difference of the change in Ht SDS between treatment groups (see Table 3) was above the predefined non-inferiority margin of -0.5. The 95% CI for the difference in change in height SDS was narrow and completely below zero, causing a statistically significant p-value of <.0001, although the actual difference between treatment groups was small. Efficacy Analyses - Second Year of Treatment A total of 164 patients (85 FHD, 79 IAD) completed the entire 24-month period, and 150 patients (78 FHD, 72 IAD) were included in the Per Protocol Population (second year). In the IAD group, 30 patients remained on the low Humatrope dose of 0.035 mg/kg per day during the second year of treatment, while 8 patients required a dose increase to 0.067 mg/kg per day at Month 12 because their actual change in height SDS at 12 months remained below the predicted ≥ 0.75 SDS (Per Protocol Population, second year). Table 4 summarizes descriptive statistics for patients’ growth parameters after the


Table 4 - Growth Response after 24 Months Per Protocol Population, Second Year (N=150)

FHD

IAD FHD IAD FHD IAD

Group Group Group Group Group Group

(N=78) (N=72) (N=78) (N=72) (N=78) (N=72)

Baseline data Data after 12 months Difference 0-12 months

Ht (cm) 103.5±12.2 104.7±12.8 113.8±11.6 114.1±12.7 121.8±11.5 122.0±13.1

Ht SDS -3.90±0.55 -3.82±0.61 -2.77±0.66 -2.91±0.67 -2.22±0.74 -2.39±0.80

HV (cm/year)

5.1±1.4 5.2±1.5 10.3±1.9 9.3±1.5 7.9±1.3a 7.7±1.5a

Ht SDS – -2.12 ± 1.19

-2.06 ± 1.06

-1.01 ± 1.17

-1.16 ± 1.07

-0.46±1.16 -0.63±1.12

a HV Month 24 = HV during second year of treatment Abbreviations: FHD = fixed high dose of Humatrope; Ht = height; HV = height velocity; IAD = individually adjusted dose of Humatrope; N = number of patients with data available; SDS = standard deviation score. Note: Data are presented as mean ± standard deviation.

Table 5 summarizes secondary efficacy analyses after the second year of treatment. Table 5 - Treatment Group Comparisons after 24 Months Per Protocol Population, Second Year (N=150)

Difference between Treatment Groups (IAD minus FHD)

LS Mean 95% CI, LS Mean p-Value (ANCOVA)

Change in Ht SDS

Baseline to Month 24 -0.25 -0.42 to -0.08 <0.01a

Month 12 to Month 24 -0.02 -0.11 to +0.07 0.6507

Absolute HV (cm/year) -0.58 -0.97 to -0.19 <0.01b

Ht SDS – target Ht SDS -0.22 -0.39 to -0.06 <0.01c Abbreviations: FHD = fixed high dose of Humatrope; Ht = height; HV = height velocity; IAD = individually adjusted dose of Humatrope; LS mean = least square mean; N = number of patients with data available; SDS = standard deviation score. a Covariate: baseline height SDS. b Covariates/factors: baseline HV, age, sex, pubertal status at Visit 4 c Covariate: Difference Ht SDS - target Ht SDS at baseline.

The observed mean change in height SDS after the second year of Humatrope treatment was +1.68 SDS in the FHD group and +1.43 SDS in the IAD group (Per Protocol Population, second year). The lower limit of the CI of the treatment group difference in change in height SDS (Table 5) was still above the predefined non-inferiority margin of -0.5 SDS. The association between the change in height SDS during the first versus second treatment year was evaluated by regression analysis, separately for each treatment group (Per Protocol Population, second year). The slopes of the regression line were 0.21 [95% CI 0.06 to 0.35] in the FHD group and 0.08 [95% CI -0.11 to 0.27] in the IAD group, correlation coefficients (r) were 0.31 and 0.10, respectively. The difference in slopes between the FHD and IAD group was not statistically significant (ANCOVA: p=0.276). Safety results No patient died during the study. Serious adverse events (SAEs) were reported for 8 patients (8.1%) in the FHD group and 9 patients (9.6%) in the IAD group (first and second year combined). Of all SAEs, none in the FHD and 4 SAEs in 3 patients of the IAD group were considered related to treatment by the investigator (1x epiphysiolysis capitis femoris, serious due to hospitalization; 2x adenoidal hypertrophy; 1x tonsillar hypertrophy). Discontinuations due to adverse events occurred in 3 patients of the FHD group (2x


related to treatment: impaired fasting glucose, mood altered; 1x not related: pain in extremity), and 1 patient of the IAD group (not related to treatment: focal glomerulosclerosis). Overall, 63 of 99 FHD group patients (63.8%, 95% CI 58.0% to 76.1%) and 54 of 94 IAD group patients (57.4%; 95% CI 51.9% to 71.2%) experienced 1 or more treatment-emergent adverse event during the 2 years of treatment (TEAE; first and second year combined). The most frequently reported TEAEs (≥5% of patients of either treatment group) during the first and second year of treatment were (first year [FHD 99, IAD 94 patients]: nasopharyngitis [FHD 10.1%, IAD 7.4%], pyrexia [FHD 3.0%, IAD 6.4%], vomiting [FHD 3.0%, IAD 6.4%], headache [FHD 5.1%, IAD 3.2%], and tonsillitis [FHD 5.1%, IAD 1.1%]; second year [FHD 91, IAD 84 patients]: nasopharyngitis [FHD 6.6%, IAD 3.6%], bronchitis [FHD 2.2%, IAD 7.1%]). In addition to the collection of spontaneously reported TEAEs, the investigators were required to record, in a prospective and proactive manner, the occurrence of solicited TEAEs of special interest potentially related to study drug: benign intracranial hypertension, slipped capital femoral epiphysis, hypoglycemia, hyperglycemia, hypothyroidism, edema, arthralgia, scoliosis, obesity, insulin resistance, hirsutism, precocious pubarche, neoplastic disease, and increasing number or growth of naevi. Table 6 summarizes the occurrence of these notable TEAEs of special interest during Humatrope treatment. No events of benign intracranial hypertension, scoliosis, obesity, precocious pubarche, or neoplastic disease were reported.

Table 6 - Notable Treatment-Emergent Adverse Events of Special Interest During the First and Second Year of Treatment Safety Population, First and Second Year Combined (N=193)

Number (%) of Patients [95% CI for Percentage]

FHD Group (N=99) IAD Group (N=94)

Any notable TEAE 9 (9.1) [4.2-16.6] 11 (11.7) [6.0-20.0]

Glucose metabolism

Blood insulin increased 4 (4.0) 3 (3.2)

Hyperinsulinaemia - 1 (1.1)

Glucose tolerance test abnormal - 1 (1.1)

Impaired fasting glucose 1 (1.0) -

Thyroid function

Blood TSH increased 1 (1.0) -

Hypothyroidism 2 (2.0) 2 (2.1)

Other

Melanocytic naevus 2 (2.0) -

Oedema - 2 (2.1)

Arthralgia 1 (1.0) -

Hirsutism - 1 (1.1)

Epiphysiolysis - 1 (1.1) Abbreviations: CI = confidence interval; FHD = fixed high dose of Humatrope; IAD = individually adjusted dose of Humatrope; N = total number of patients; TEAE = treatment-emergent adverse event; TSH = thyroid stimulating hormone.

Dose reductions due to changes in IGF-I or IGFBP-3 levels were required in 8 patients of the FHD and 2 patients in the IAD group. Otherwise, safety-relevant laboratory data (IGF-I, IGFBP-3, fasting glucose, fasting insulin, OGTT, lipids) and bone age after the first and second year of treatment did not reveal any clinically relevant differences in safety signals between the IAD and FHD group.

IV.2.2.2 Study B9R-HL-GDGN

Description An Open Label Follow-up Study of Patients Who Participated in Clinical Study B9RHL- GDDV Methods


Objective(s) The primary objective of this study was to obtain adult height measurement on all 20 subjects with Prader Willi -syndrome (PWS) who participated in the one year trial (B9R-HL-GDDV) of growth hormone (GH) treatment in 1997 – 1999. The secondary objectives of this study were

body composition (fat vs. fat-free tissue) assessed by DEXA

total weight

quality of life assessed by the 16D questionnaire

to collect safety information from all patients who participated in study B9R-HL-GDDV, including, but not restricted to

clinically significant adverse events that have been associated with growth hormone exposure as well as other events deemed clinically significant

symptoms referring to potential sleep apnea (e.g. snoring)

sleep polygraphy

phosphate levels Study design A subset of 20 subjects with PWS participated in a one year open study B9R-HL-GDDV on daily s.c. injections of GH. These subjects were thereafter treated by pediatric endocrinologists of their own district. The treatment was based on clinical practice and no general rules about dose or continuation of the GH therapy were decided. Investigator contacted patients/guardians to ask their willingness to participate in this non-drug interventional study. The subjects who had completed B9RHL- GDDV study were invited together with their guardians to the Ruusula health center for children and adolescents for one visit. After the guardian and the patient had given their written informed consents, the following procedures were be performed:

Physical examination including height, weight, blood pressure

Laboratory tests

Total body DEXA measurement

Distribution to each patient of the instructions and equipment for performing the sleep polygraphy examination at home

Medical history was obtained, including, but not limited to the following:

Use of growth hormone since their last visit in GDDV and reasons for potential discontinuation

Occurrence of any of the following clinically significant adverse events associated with GH exposure since their last study visit:

- Hyperglycemia - Impaired glucose tolerance, impaired fasting glucose - Diabetes mellitus - Hypothyroidism - Benign intracranial hypertension - Scoliosis - Slipped capital femoral epiphysis - Neoplastic disease - Sleep apnea

Other events considered clinically significant, including, but not limited to - death - initial or prolonged inpatient hospitalization - a life-threatening experience (that is, immediate risk of dying) - persistent or significant disability/incapacity - congenital anomaly/birth defect

Hospitals of the patient’s own district and the endocrinologist in charge were contacted to obtain all relevant health records.


Study population /Sample size

Planned: 20 Completed: 19

Treatments (non-drug interventional study). Outcomes/endpoints

Efficacy: Adult height measurement, and for those subjects who have achieved their final height, the result as compared to the predicted values from the previous study, body composition (fat vs. fat-free tissue) assessed by DEXA, total weight. Safety: Serious adverse events that have occurred after the B9R-HL-GDDV -study, clinically significant adverse events that have been associated with GH exposure, including but not limited to symptoms related to potential sleep apnea, hyperglycemia, impaired glucose tolerance, impaired fasting glucose, diabetes mellitus, hypothyroidism, benign intracranial hypertension, scoliosis, slipped capital femoral epiphysis, neoplastic disease. Bioanalytical: Clinical laboratory tests as listed in Protocol attachment GDGN 2. including phosphate levels. Statistical Methods Statistical: Descriptive statistics, a regression model describing achieved adult height vs. predicted height, Pearson’s correlation to explore the association of GH dose with body mass index, total body fat % and weight for height, Student’s t-test for non-related samples to compare quality of life among the patients and healthy population, Student’s t-test for non-related samples to compare laboratory parameters among GH users and non-users,. Bioanalytical: Standard laboratory methods Results Recruitment/ Number analysed All 20 subjects, 14 male and 6 female, who had completed the GDDV-study were contacted. One female subject refused to participate and one male subject refused from the sleep polygraphy.

Efficacy results Mean (±SD) adult height was achieved in 9 males (age 21.0 ± 1.8 y) and 4 females (19.3 ± 3.6 y). Final height (176.1 ± 4.6 cm for men and 156.4 ± 8.9 cm for women) was markedly greater than in historical controls not treated with GH (Cassidy S, Schwartz S. Prader Willi and Angelman syndromes. Disorders of genomic imprinting. Medicine 1998;77:140-151). Five out of 6 patients whose growth was continuing and 2 patients who had already achieved adult height were still receiving GH. The height SDS in the whole group was -0.3 ± 1.1 (range -3.2 to +1.3). Mean (± SD) weight corrected for height for all 20 subjects was 182.8 ± 39.1 % (range 113 to 244 %) with only 1 patient having normal weight (<120%). Mean (± SD) BMI was 34.9 ± 7.8 kg/m

2 in males and

36.7 ± 7.1 kg/m2 in females. Mean (± SD) total body fat % for the whole group was 50.4 ± 6.0 % (range

36.5 to 59.9 %). Regression equation between achieved adult height and predicted did not show any significant effect of GH on the prevention of being overweight (GH dose vs. BMI, r=-0.44, p=0.06; GH dose vs. weight for height %, r=-0.42, p=0.08), but an increasing dose appeared related to a lower total body fat % (r=-0.49, p=0.03). Overall quality of life score of these patients was significantly (p<0.001) worse than that of a healthy population sample (n=239) of the same age (Apajasalo M, Sintonen H, Holmberg C, et al. Quality of life in


early adolescence: A sixteen-dimensional health-related measure (16D) Quality of life Research 1996;5:205-211). Compared to healthy population, the patients reported more problems regarding the following QoL dimensions: Mobility (p=0.008), hearing (p=0.015), breathing (p=0.001), sleeping (p=0.009), elimination (p=0.001), school and hobbies (p=0.002), discomfort and symptoms (p= 0.011), and friends (p=0.007).

Safety results No significant differences in HbA1c, plasma glucose, or insulin levels between GH-users and nonusers were observed. All subjects whom DEXA scans were performed (n=17) had a normal bone mineral density. A sleep polygraphy was obtained from 18 subjects and was considered normal in 7 and slightly abnormal in 9 subjects. A markedly abnormal result, indicating sleep apnea, was found in 2 subjects. Most common clinically significant adverse events since GDDV -study included endocrine disorders (n=15), psychiatric disorders (n=9) and surgical and medical procedures. Four subjects had undergone a scoliosis operation. According to the investigator’s judgment, none of the adverse events were related to GH exposure or study procedures. However, most of the adverse events were related to PWS itself. Discussion on clinical aspects Long-term GH treatment in patients with PWS is safe and improves adult height and body composition. It does not prevent the development of excessive overweight, which most likely is the reason for the abnormal sleep polygraphy findings in 2 subjects. Despite GH treatment, quality of life in the patients with PWS is worse than in normal population of the same age. IV.2.2.3 Study B9R-EW-GDCT

Description A randomized, controlled trial of GH supplementation to adult height in girls with short stature due to Turner syndrome was conducted in Canada. We report results in subjects who completed the protocol and subjects who participated in follow-up. Methods One hundred fifty-four girls with Turner syndrome, aged 7–13 yr, were randomly assigned to one of two groups: 1) GH by sc injection six times per week (0.30 mg/kg/wk), and 2) control, no-GH treatment (C). Both cohorts received standardized sex steroid replacement starting at a chronological age of 13 yr. Subjects were followed until protocol completion, defined as height velocity less than 2 cm/yr and bone age 14 yr or greater. A subsequent protocol addendum requested follow-up safety and efficacy assessment in all patients at least 1 yr after the last core protocol visit. Results One hundred four patients completed the study (61 GH, 43 C), and 50 withdrew (15 GH, 35 C). At protocol completion, mean heights were 147.5 ± 6.1 (GH) and 141.0 ± 5.4 cm (C), respectively (P≤0.001). Of those who completed the protocol, 59 (40 GH, 19 C) had height data at least 1 yr after protocol completion; in that group, mean heights were 149.0 ± 6.4 (GH) and 142.2 ± 6.6 cm (C), respectively (P ≤ 0.001). At protocol completion respectively follow-up, the mean height gain due to GH, estimated by analysis of covariance, was +7.2 cm (confidence interval 6.0, 8.4) and +7.3 cm (confidence interval 5.4, 9.2), respectively (both P ≤ 0.001). Discussion on clinical aspects This is the first evidence from a randomized, controlled trial to adult height that GH supplementation with induction of puberty at a near physiological age increases the adult height of girls with Turner syndrome. (J Clin Endocrinol Metab 90: 3360–3366, 2005)


IV.2.1.4 Study B9R-IT-GDFU Study B9R-IT-GDFU was a randomized, controlled, open-label, multicenter study conducted in Italy between 2004 and 2008. Twenty-six growth Hormone Deficient Children in early pubertal stage aged 10-15.5 years were randomly assigned to one of two groups:

hGH (somatropin) replacement therapy with an in-label dose ranging from 0.025 to 0.035 mg/kg/day (LD)

hGH replacement therapy with a doubled dose (compared to the in-label one) ranging from 0.05 to 0.07 mg/kg/day (HD).

Of the 26 patients randomized, 23 completed the study (12 in the HD group, 11 in the LD group). High dosage did not significantly increase height velocity standard deviation score (SDS) after 12 months of treatment (p=0.34) and did not significantly change height SDS after 12 months of treatment (p=0.14). HD significantly promoted height velocity (p=0.04), change in standing height (p=0.03), height SDS (p=0.03), arm span length (p=0.05) to a greater extent than LD after 24 months. In conclusion doubling the dose of somatropin was not associated with any major or unexpected safety issue. However, the proportion of patients reporting adverse events and the number of events were higher with HD than the LD. Adverse reactions and discontinuations due to adverse events occurred only with the HD.

V. MEMBER STATES OVERALL CONCLUSION AND RECOMMENDATION

V.1 Overall conclusion The results available from these trials do not change the risk-benefit assessment for Humatrope. Humatrope is approved for most of the paediatric indications investigated in the above mentioned studies: Growth Hormone Deficiency since 1987, Turner Syndrome since 1990, and short children born Small for Gestational Age since 2006. The use of Humatrope in Prader-Willi syndrome (investigated in study B9R-HL-GDGN) is not an approved indication for Humatrope, but it is for other somatropin containing products. Results presented during this art. 46 procedure did not necessitate an update of the SPC. No changes to the current SPCs for Humatrope are required. There were no requests for supplementary information.

V.2 Recommendation No further action required.

List of abbreviations AE Adverse event BMI Body Mass Index DEXA Dual Energy X-ray Absorptiometry FHD Fixed High Dose GH Growth Hormone HV Height Velocity IAD Individually Adjusted Dose OGTT Oral Glucose Tolerance Test PWS Paediatric Work Sharing SAE Serious Adverse Event SDS Standard Deviation Score SGA Small for Gestational Age TEAE Treatment-Emergent Adverse Event

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