PhRMA Clinical Study Synopsis Protocol CTN / (A /A ) 21 August 2006 Final PFIZER INC.

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1 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/INN: Genotropin /Somatropin THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See USPI PROTOCOL NO: CTN / (A /A ) PROTOCOL TITLE: Genotropin in Short Children Born Small for Gestational Age A Long-Term Study in Belgium, a Randomized, Open, Parallel Group, Multi-Center Study Study Centers: 7 study centers in Belgium Study Initiation and Completion Dates: CTN :15 July 1991 to 23 May 1996; CTN : 24 May 1996 to 27 May 2005 Phase of Development: Phase 3 Study Objective(s): Primary: The primary objective of CTN was to evaluate the effects of somatropin treatment on linear growth in short children born small for gestational age (SGA). The primary objective of CTN was to evaluate whether somatropin treatment can normalize final height in short children born SGA. Secondary: The secondary objectives of CTN were to compare the effects of 2 doses of somatropin (0.067 and 0.1 mg/kg body weight/day) on linear growth over 24 months and to evaluate safety in the patient population studied. The secondary objectives of CTN were to evaluate safety and to evaluate whether somatropin treatment can normalize weight in the patient population studied. METHODS Study Design: This is a combined report on two studies. The first was a randomized, open-label, parallelgroup, long-term study in short children born SGA. During the first 24 months (CTN ), children were randomized to one of 3 groups: 0.1 or mg/kg/day somatropin or an untreated control group. CTN was closed after 48 months (untreated patients completed the study after 24 months). After 48 months, the patients from the 2 somatropin groups in CTN were followed within CTN until final height; during this Page 1

2 time the patients were allocated to treatment with mg/kg/day somatropin or to followup without treatment, based on height standard deviation score (SDS) and pubertal status. Patient visits occurred at screening, baseline, every 6 months and yearly (12, 24, 36, 48, 60, and 72 months after baseline). Both efficacy and safety evaluations were carried out in this study. Number of Patients (planned and analyzed): Planned: The sample size planned for the CTN trial was 50, 20 in each somatropin group and 10 untreated patients. The sample size of the CTN trial was not based on statistical considerations, as an inclusion criterion was participation in the CTN trial. Analyzed: 54 patients were enrolled of which 41 were randomized to active treatment and 2 were withdrawn prior to active treatment; 20 started somatropin treatment in the mg/kg/day dose group and 19 in the 0.1/0.067 mg/kg/day dose group. Diagnosis and Main Criteria for Inclusion: Age 2.0 to 8.0 years at time of initiation of therapy for both sexes Height SDS below -2.5 Standard Deviations (SD) Height velocity (HV) SDS below +1 SD during the 12-month observation period before inclusion, based on measurements of height at time of randomization and 12 ± 3 months earlier Birth weight and/or length under threshold values for SGA (2 SD below the applicable population mean values for gestational age Growth hormone (GH) level 10 ng/ml during any test except stimulation with growth hormone-releasing factor Study Treatment: Somatropin sterile powder, 16 IU/mL (5.3 mg/ml) after reconstitution Self-administered daily subcutaneous injection of either or 0.1 mg/kg/day Treatment duration was for a maximum of 9 years Efficacy Evaluations: In CTN , the efficacy evaluation was HV SDS and, in study CTN , it was change from baseline to final height in parental adjusted height (PAH) SDS (defined as: height SDS - target height SDS). Page 2

3 Safety Evaluations: Adverse events and assessments of hematological and clinical chemistry Statistical Methods: Efficacy: HV SDS for chronological age was the primary efficacy variable. Pre-study variables were to be taken into account by considering within-patient changes and/or by making suitable covariance adjustments, if possible. Formal statistical comparisons between and within treatment groups were to be based on nonparametric and parametric methods and were to be performed at Biostatistics and Data Management, Pfizer, Sweden. An interim analysis was to be performed when all patients had completed the 12-month visit. The reason for this analysis was to give 12-month results and not to stop the study in advance. The final height (FH) data is presented in 2 ways: as FH SDS (or final PAH SDS) for patient s age and as FH SDS (or final PAH SDS) for adult age (using the upper age limit from the height reference. Safety: FH SDS for patient s age overestimates the ultimate FH SDS for patients who have reached FH at an early-normal age, since height SDS will decrease over the years until all children (reference population) have reached FH. On the other hand, FH SDS for adult age underestimates the ultimate FH SDS for patients who increase their height after the final visit in the study. Thus, the ultimate FH SDS is probably between FH SDS for patient s age and FH SDS for adult age. Based on publications of FH in untreated historical controls, height SDS on average increases by approximately 0.5 from pre-puberty to final height for untreated short children born SGA. Using the null hypothesis µ=0.5, a one-sample t-test of change = 0.5 (assuming no treatment effect) versus change > 0.5 was performed. This was assessed by 95% confidence intervals for the mean changes in PAH SDS and height SDS from baseline to start of puberty and from baseline to final height (for patient s age and for adult age). The standard deviation for height velocity standard deviation score (HV SDS) was assumed to be 0.8 and it was possible to detect a difference of 0.82 between the 40 treated patients and 10 untreated patients. For this comparison, the mean effect for the 40 treated patients was defined to be the unweighted mean of the effects for the 2 somatropin groups. All patients remaining in the study for at least 12 months were to be evaluated for efficacy. All patients included, regardless of how long they remained in the study, were to be evaluated for safety. Safety data were summarized and listed. Page 3

4 RESULTS Subject Disposition and Demography: Of the 41 randomized patients, 2 were withdrawn prior to treatment. The safety population consists of all patients who received treatment at any time during the study; this was a total of 39 patients, 20 and 19 in the and 0.1/0.067 mg/kg/day dose groups, respectively. Seven patients in the mg/kg/day and 12 in the 0.1/0.067 mg/kg/day dose groups reached FH. The near final height (NFH) population in the two dose groups consists of 12 patients and 13 patients, respectively (Table S1). Table S1 Disposition of Patients Somatropin Dose (mg/kg/day) /0.067 Randomized patients Withdrawn prior to treatment 0 2 Started treatment Withdrawn 0-24 months 1 0 Protocol specific withdrawal criteria 1 0 Completed 24 months Withdrawn months 2 3 Protocol specific withdrawal criteria 2 3 Completed 72 months Withdrawn 72 months 1 1 Consent withdrawn 0 1 Lost to follow-up 1 0 Completed study Completed and reached final height* 7 12 Completed and reached near final height** Completed although HV > 4 cm/year 4 2 Total withdrawn from study 4 4 Withdrawn and reached final height* 0 0 Withdrawn and reached near final 0 0 height** Included in final height population* 7 12 Included in near final height population** Included in safety population *Boys: HV < 2 cm/year and age > 13 years at the last visit; Girls: HV < 2 cm/year and age > 11 years at the last visit **Boys: HV < 4 cm/year and/or bone age > 17 years and age > 13 years at the last visit; Girls: HV < 4 cm/year and/or bone age > 15 years and age > 11 years at the last visit Patients in each group were similar in terms of most of the baseline and demographic characteristics. In the somatropin mg/kg/day dose group there were 55% males and 45% females. In the somatropin 0.1/0.067 mg/kg/day dose group there were 47% males and 53% females. At baseline, the mean values of height SDS were and in the and 0.1/0.067 mg/kg/day dose groups, respectively. Page 4

5 Efficacy Results: The results shown in this report reflect combined data from both protocols. Thus, no data is shown for the 0.1 mg/kg/day group since this data was combined with the mg/kg/day data as all patients in the CTN study received either mg/kg/day or were untreated. Overall, the efficacy results were similar for the FH and NFH populations. The results for the FH population are presented in this synopsis. Primary Efficacy Results: Primary efficacy result for the CTN study was HV SDS and is shown below in Table S2. Table S2 Height Velocity SDS During First Year of Treatment by Treatment Duration (Final Height Population) 0-24 months months months > 60 months Somatropin Dose (mg/kg/day) n Mean (SD) 4.51 ( ) 6.20 (0.28) 5.82 (1.13) Median 4.51 (4.51, 6.20 (6.00, 6.40) 5.98 (4.30, 7.02) (Min, Max) 4.51) 0.1/0.067 n Mean (SD) 9.73 (0.33) 6.79 (0.50) 6.29 (2.01) Median (Min, Max) 9.73 (9.50, 9.96) 6.79 (6.43, 7.14) 5.58 (3.95, 10.33) The primary efficacy result for study CTN was change from baseline to final height in parental adjusted height (PAH) SDS. The mean changes in Height SDS from baseline to final height were 1.86 and 2.10 in the and 0.1/0.067 mg/kg/day groups, respectively (Figure S1). For the mg/kg/day group the change in Height SDS (or PAH SDS) from baseline to final height for patient s age, the 95% confidence interval ranged from 1.07 to 2.66 (p= versus value =0.5). For the 0.1/0.067 mg/kg/day group the interval was 1.71 to 2.49 and the p-value was < When using the worst-case approach (change from baseline to final height SDS for adult age), the 95% confidence interval was 0.59 to 2.41 and p-value for the mg/kg/day group and in the 0.1/0.067-mg/kg/day group, the interval ranged from 0.99 to 1.96 and the p-value was Page 5

6 Figure S1 Change in Height SDS (or PAH SDS) from Baseline to Final Height (for Patient s Age and for Adult Age); Comparison With a Change of +0.5 SD, 95% Confidence Intervals (Final Height Population) For the FH population the mean change in Height SDS (or PAH SDS) from start of puberty to near final height for patient s age was 0.14 in the mg/kg/day group and 0.02 in the 0.1/0.067-mg/kg/day group. PAH SDS increased during puberty for some patients (the maximum change in PAH SDS was 1.42) whereas there was a decrease in PAH SDS for other patients during puberty. Safety Results: The total number of adverse events during the study was 117 in the mg/kg/day group and 131 in the 0.1/0.067-mg/kg/day group. The majority of the adverse events were childhood-related diseases and infections, such as rhinitis (11 patients), pharyngitis (8 patients), otitis media (9 patients), and upper respiratory tract infections (6 patients). An overview of drug-related adverse events by is shown in Table S3. Page 6

7 Table S3 Number of Patients With Drug-Related Adverse Events (Safety Population) Preferred Term Somatropin Dose mg/kg/day n Injection Site Reaction 3 0 Personality Disorder 0 1 Breast Enlargement 1 0 Myopia 1 1 Nevus 1 2 Eczema 2 0 Surgical Intervention 1 0 Spine Malformation 3 0 Pain 0 2 Jaw Malformation 1 0 Skeletal Malformation /0.067 n No clinically relevant differences in the occurrence of adverse events were observed between the groups. A total of eight patients reported 16 serious adverse events during the study. One of these events was in the mg/kg/day group and 15 were in the 0.067/0.1-mg/kg/day group. One, skeletal malformation, was considered by the investigator to be drug-related. A summary of serious adverse events is shown in Table S4. Table S4 Summary of Serious Adverse Events (Safety Population) Preferred Term No. Events No. Patients* Dose (mg/kg/day) Surgical intervention /0.067 Convulsions /0.067 Constipation /0.067 Sinusitis /0.067 Peripheral ischemia /0.067 Osteomyelitis /0.067 Agitation /0.067 Peripheral edema /0.067 Headache /0.067 Meningitis /0.067 Herpes simplex /0.067 Skeletal malformation /0.067 Gastrointestinal disorders *Some patients experienced more than one event. No.= Number There were no deaths in the study and none of the patients discontinued from the study due to adverse events. Those adverse events judged by the investigators to be drug-related primarily involved the effect of somatropin on longitudinal bone development and glucose metabolism. The serious adverse event of unequal length of legs could possibly have been due to the effect of Page 7

8 somatropin treatment on longitudinal bone development. In the 3 patients with elevated levels of HbA1c or fasting blood glucose, the increases from baseline to month 12 were followed by decreases from months 12 to 24. No patients had clinically significant hematology values. None of the clinically significant laboratory values were judged to be serious CONCLUSIONS: Data from the patients in this report support the long-term benefits of somatropin therapy for short children born SGA. Somatropin, administered at doses of or 0.1/0.067mg/kg/day for up to 9 years induces statistically significant, dose-dependant increase in final height, transferring mean height SDS for the group well into the normal range. The reported adverse events were as expected for this study population, with the majority of events being childhood-related diseases and infections. There were 16 serious adverse events during the study, of which one, skeletal malformation, was considered by the investigator to be drug-related. Somatropin administered at dosages of and 0.1/0.067 mg/kg/day for up to 9 years, was safe and well tolerated. Page 8