PFIZER INC. These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert. For publications based on this study, see associated bibliography. PROPRIETARY DRUG NAME /GENERIC DRUG NAME: Genotropin / Somatropin PROTOCOL NO.: CTN 89-050 PROTOCOL TITLE: Efficacy and Safety of the Authentic Recombinant Human Somatropin Genotropin in Children with Familial Short Stature Study Centres: 17 centres in Germany Study Initiation Date and Primary Completion or Completion Dates: 16 July 1990 to 18 December 1996 Phase of Development: Phase 3 Study Objective(s): The primary objective was to determine the effect of growth hormone treatment on statural height for bone age in comparison with the untreated control group after 3 years. The secondary objective was to evaluate the safety of growth hormone treatment. Additional secondary objectives were defined in the Statistical Analysis Plan written by Pfizer and dated 13 December 2005 (an analysis plan had not been prepared by the time the study started). This analysis plan maintained the primary objective unchanged as stated in the protocol, and added secondary objectives and secondary end points/analyses that were not explicitly defined in the protocol, as listed below. These secondary analyses were added to allow a comparison of the results of the present study with those obtained in other more recent studies. Change of height standard deviation score (SDS) for bone age (HSDS-BA) after 12 months HSDS-BA and height SDS for chronologic age (HSDS-CA) over time Changes in HSDS-CA and after 12 and 36 months Growth velocity (GV) SDS for bone age (GVSDS-BA) and growth velocity SDS for chronologic age (GVSDS-CA) over time Change in GVSDS-BA and GVSDS-CA after 12 and 36 months Bone age acceleration Change in height (cm) and GV (cm/year) after 36 months Treatment success rate for bone age, defined as the percent of subjects who achieved an increase in HSDS-BA 1 at Months 12 and 36 Page 1
Treatment success rate for chronologic age (CA), defined as the percent of subjects who achieved an increase in HSDS-CA 1 at Months 12 and 36 Abnormal glucose tolerance over time (6, 12, 24, 36 months) METHODS Study Design: 36-month, open-label, multicenter, randomised study of Genotropin (0.047 mg/kg/day) versus untreated controls in children with familial short stature (FSS) a. Statural height was measured at Week 4 and then at 3-month intervals throughout the 36-month treatment period. Bone age was assessed at Months 12, 24, and 36. Safety was assessed by recording adverse events (AEs) at each clinic visit and by measurement of laboratory tests at periodic intervals. Number of Subjects (Planned and Analysed): 60 subjects planned, 41 enrolled, and 37 randomised (18 in Genotropin group and 19 untreated controls) Diagnosis and Main Criteria for Inclusion: Prepubertal children with idiopathic short stature (ISS), statural height < -2.5 SDS for CA, no growth hormone deficiency or chronic diseases and normal oral glucose tolerance tests before treatment. Study Treatment: Genotropin 0.047 mg/kg of body weight per day by subcutaneous injection once daily for 36 months; the site of injection was varied to prevent lipoatrophy. Control subjects did not receive any treatment. Efficacy Evaluations: Primary end point was the change in HSDS-BA after 3 years. Secondary end points were: change in HSDS-BA at Month 12; HSDS-BA and HSDS-CA over time (12, 24, and 36 months); change in HSDS-CA at Months 12 and 36; GVSDS-BA and GVSDS-CA over time (12, 24, and 36 months); change in GVSDS-BA and GVSDS-CA at Months 12 and 36; change in height (cm) and growth velocity (cm/year) at Months 12 and 36; increase in bone age (years) at Months 12 and 36; treatment success rate for bone age, defined as the percent of subjects who achieved an increase in HSDS-BA 1 at Months 12 and 36; and treatment success rate for chronologic age, defined as the percent of subjects who achieved an increase in HSDS-CA 1 at Months 12 and 36. Safety Evaluations: Incidence and seriousness of AEs and incidence of abnormal glucose tolerance findings. Abnormal glucose tolerance over time was defined as a secondary end point in the Statistical Analysis Plan (13 December 2005). a Familial short stature is a form of idiopathic short stature (ISS) in which not only the height of the child but also the height of one or both parents is below the 3rd percentile. Hereafter, FSS is referred to as ISS. Page 2
Statistical Methods: Efficacy: The primary analysis (change in HSDS-BA after 36 months) was performed on the intent-to-treat (ITT) population using the bone age values available at the time of the corresponding Month 36 height measurements. Missing values were replaced according to the last observation carried forward (LOCF) method. The change in HSDS-BA after 36 months was compared between groups using a two-sided nonparametric Wilcoxon test (with comparisons based on t-tests considered supportive). Analyses using observed cases (OC) and analyses based on the per protocol (PP) population were also performed. Height SDS-CA, GVSDS-BA, GVSDS-CA, bone age, height (cm), and growth velocity (cm/year) were analysed using the same methods as the primary end point. Success rates were compared between groups using Fisher s exact test. Safety: The numbers (%) of subjects with treatment-emergent signs and symptoms adverse events (TESS AEs) were summarised by body system and preferred term for: AEs (all causalities), AEs (treatment related, treatment group), serious AEs (all causalities), serious AEs (treatment related, treatment group), AEs leading to withdrawal, AEs summarised by severity (all causalities, without lab abnormalities), and AEs summarised by severity (treatment related, treatment group, without lab abnormalities). Two-sided 95% confidence intervals (CIs) were calculated for the incidence of TESS AEs. The analysis of abnormal glucose tolerance was done descriptively by presenting the absolute and relative frequencies and confidence limits. Page 3
RESULTS Subject Disposition and Demography: Forty-one subjects were enrolled and 37 were randomised to receive Genotropin or to serve as untreated controls (Table 1). Seventeen subjects in each group completed the study. Table 1 Subject Disposition and Subjects Analysed Number of Subjects: Genotropin Untreated Control Planned 60 Enrolled 41 Randomised to Treatment 18 19 Treated 18 19 Completed 17 17 Discontinued a 1 2 Analysed for Efficacy ITT Population, LOCF 18 18 b PP Population 16 13 Analysed for Safety 18 19 a The reason for subject discontinuation was not recorded in this study. b One subject did not have a post-baseline measurement and was thus not included in the ITT population. Abbreviations: ITT = intent-to-treat; LOCF = last observation carried forward; PP = per protocol. The groups were generally well balanced with regard to demographic and other baseline characteristics, although the proportion of females was markedly lower in the Genotropin group than in the untreated control group (3 versus 8). Efficacy Results: Primary Efficacy Results (ITT Population, LOCF): The mean change in HSDS-BA from baseline to Month 36 was increased in the Genotropin group (0.34 ± 1.60 SDS) and decreased in the untreated control group (-0.46 ± 1.58 SDS), but the difference did not reach statistical significance (p=0.192). Secondary Efficacy Results: Table 2 summarises the results of the secondary efficacy endpoints for the ITT population (LOCF). Most secondary efficacy endpoints showed strong evidence for improvement of growth with Genotropin. Genotropin significantly improved HSDS-CA, GVSDS-BA, GVSDS-CA, height (cm), and growth velocity (cm/year) compared with untreated controls. Additionally, a significantly greater percent of Genotropin-treated subjects achieved a height gain of at least 1 SDS for chronologic age at 12 and 36 months of therapy. Page 4
Table 2 Secondary Efficacy End Points Secondary End Points Genotropin Untreated Control p-value a Mean change from baseline in HSDS-BA to Month 12 0.63-0.45 0.015 Mean HSDS-BA over time Month 12-0.29-1.22 0.319 Month 24-0.32-0.93 0.393 Month 36-0.59-1.11 0.457 Mean HSDS-CA over time Month 6-2.91-3.33 0.293 Month 12-2.56-3.48 0.017 Month 24-2.28-3.47 0.002 Month 36-2.03-3.32 0.001 Mean change from baseline in HSDS-CA Month 12 0.96-0.13 <0.001 Month 36 1.49 0.03 <0.001 Mean GVSDS-BA over time Month 12 2.58-1.79 <0.001 Month 24 0.15-1.86 0.002 Month 36 0.22-1.58 0.008 Mean GVSDS-CA over time Month 12 3.81-1.01 <0.001 Month 24 0.90-1.03 0.001 Month 36 0.95-0.53 0.018 Mean change from baseline in GVSDS-BA Month 12 5.55 1.05 <0.001 Month 36 3.19 1.47 0.031 Mean change from baseline in GVSDS-CA Month 12 5.88 0.47 <0.001 Month 36 3.02 0.94 0.033 Difference in group mean change from baseline in height (cm) Mean [95% CI] Month 12 3.90 [2.98, 4.82] <0.001 b Month 36 6.11 [3.41, 8.82] <0.001 b Difference in group mean change from baseline in GV (cm/yr) Mean [95% CI] Month 12 4.33 [2.86, 5.81] <0.001 b Month 36 1.69 [0.00, 3.38] 0.050 b Mean change from baseline in bone age Month 12 1.23 1.12 0.381 Month 36 3.32 2.74 0.080 Treatment success: Change in HSDS-BA 1 Number (%) of Subjects Month 12 7 (38.9) 2 (11.8) 0.121 c Month 36 8 (44.4) 2 (11.8) 0.060 c Treatment success: Change in HSDS-CA 1 Number (%) of Subjects Month 12 10 (55.6) 0 (0) <0.001 c Month 36 15 (83.3) 0 (0) <0.001 c a p-value based on Wilcoxon test unless otherwise specified. Student s t-test Fisher s exact test Abbreviations: GV = growth velocity; GVSDS-BA = growth velocity standard deviation score for bone age; GVSDS-CA = growth velocity standard deviation score for chronologic age; HSDS-BA = height standard deviation score for bone age; HSDS-CA = height standard deviation score for chronologic age. Page 5
Safety Results: Table 3 summarises TESS AEs. Table 3 Overview of TESS AEs Number of Subjects a Subjects With: Genotropin (N=18) Untreated Control (N=19) TESS AEs (all causality) 15 10 Treatment-related TESS AEs 8 0 TESS serious AEs 2 1 Treatment-related SAEs 0 0 Study drug withdrawn due to TESS AEs b 0 0 TESS AEs maximum severity Mild 7 6 Moderate 3 4 Severe c 5 0 Treatment-related TESS AEs maximum severity Mild 3 0 Moderate 0 0 Severe c 5 0 a Number of subjects in a certain category. b No subject was discontinued from the study because of TESS AEs. c All AEs that were reported in the CRF with unknown severity were classified as severe in the analysis. Abbreviations: AE = adverse event; N = number of subjects; TESS = treatment-emergent signs and symptoms. The most apparent differences with regard to certain types of TESS AEs were more occurrences of laboratory abnormalities, infections and infestations, and nervous system disorders in the Genotropin group than in the untreated control group. The only treatmentrelated TESS AEs that occurred in more than 1 subject were infection (2 subjects) and hypothyroidism (2 subjects). Both cases of hypothyroidism were mild and did not require disruption of Genotropin therapy. No subject was permanently discontinued from the study because of TESS AEs. Serious AEs occurred in 2 subjects in the Genotropin group and 1 subject in the untreated control group. None of the events was considered treatment-related. No subject died over the course of the study. Five subjects had abnormal glucose tolerance findings. One subject in each group entered the study with abnormal findings, but these resolved by Month 6 in both subjects. Three subjects in the Genotropin group developed abnormalities in glucose tolerance during the study, which were transient in 2 of the 3 subjects. Abnormal glucose tolerance was detected at Month 36 in the third subject. Page 6
CONCLUSIONS: The change in HSDS-BA tended to be higher in the Genotropin group compared with the untreated control group, but the difference did not reach statistical significance after 36 months of treatment at a dose of 0.047 mg/kg of body weight per day. Genotropin significantly improved HSDS-CA, GVSDS-BA, GVSDS-CA, height (cm), and growth velocity (cm/year) compared with untreated controls and most other secondary efficacy end points showed strong evidence for improvement of growth with Genotropin therapy at a dose of 0.047 mg/kg of body weight per day over a 36-month treatment period. From these results an improvement of final height can be expected. Genotropin was well tolerated when given at a dose of 0.047 mg/kg of body weight per day for 36 months. Safety data for children treated with Genotropin for ISS showed a risk/benefit profile comparable to that of children treated for other Genotropin indications (e.g., growth hormone deficiency in children and adults, children born small for gestational age, children with Prader-Willi syndrome, and girls with Turner syndrome). Page 7