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 (recombinant) THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See USPI. PROTOCOL NO.: 307-MET-0021-002 PROTOCOL TITLE: Examination of effects on growth promoting and safety of PNU-180307 in short children born small for gestational age (SGA) without epiphyseal closing Study Center(s): Twenty (20) centers in Japan Study Initiation and Completion Dates: 02 November 2001 to 11 September 2003 Phase of Development: Phase 3 Study Objective(s): Primary: To evaluate the effects on growth promotion of PNU-180307 (somatropin, Genotropin ) administered for one year to short children in Japan born SGA, without epiphyseal closing and to demonstrate similarity between the data from this study and those from clinical studies carried out overseas Secondary: To comprehensively evaluate height velocity for bone age, height standard deviation score (SDS) for bone age and height SDS for bone age; to examine the relationship between bone age and growth promotion; to pharmacodynamically evaluate the kinetics of PNU-180307 in short children born SGA without epiphyseal closing based on serum IGF-I levels; to examine changes from Baseline in the daily lives of children by means of questionnaires; and to evaluate the safety of PNU-180307 in short children born SGA METHODS Study Design: Multicenter, parallel-group, open, randomized, comparison study. The duration of treatment with PNU-180307 was 12 months. Patients were required to visit the study site on 8 occasions: Screening visit, Baseline (Day 0), Month 1, Month 2, Month 3, Month 6, Month 9 and Month 12 (last visit). Number of Patients (planned and analyzed): Planned: 70 subjects Analyzed: 67 subjects (34 subjects in the 0.033 mg/kg/day group; 33 subjects in the 0.067 mg/kg/day group) Page 1
Diagnosis and Main Criteria for Inclusion: Male children aged 3 years and < 8 years, and female children aged 3 years and < 7 years, who were born SGA before epiphyseal closing, and who were characterized by a height SDS for chronological age of -2.0 and a height velocity SDS at 1 year before the start of treatment of 0 were included in the study. Documented birth weight and length had to have been below the 10 percentile corrected for gestational age and birth weight or length -2.0 SDS for gestational age. A growth hormone (GH) peak secretion of > 10 ng/ml on at least one GH secretion stimulation test (excluding the GRF and glucagons-propranolol combination test) performed within 1 year prior to study entry was needed to enter the study. Study Treatment: PNU-180307 5.3 mg lyophilized powder for injection administered via subcutaneous injection (buttock or thigh) at a dose of 0.033 mg/kg/day or 0.067 mg/kg/day Treatment duration was 12 months. Efficacy Evaluations: Primary: Improvement in the growth-promoting effect from Baseline to Year 1 evaluated via height SDS for chronological age and height velocity SDS for chronological age Secondary: Bone age, height velocity SDS for bone age, height SDS for bone age, ratio of bone age to chronological age (bone age/chronological age), Parental-adjusted Height (PAH) SDS, height, body weight, body weight SDS for chronological age, body mass index (BMI), insulinlike growth factor-1 (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3), and questionnaire on the daily lives of short children born SGA (questionnaire on the treatment of short stature) Safety Evaluations: Adverse events (AEs), clinical laboratory values, injection site changes and oral glucose tolerance test Statistical Methods: The level of significance, unless otherwise specified, was set at 0.05 for all analyses. All 67 subjects were included in the Intent-to-Treat (ITT) population, with all but one of these subjects included in the per-protocol (PP) population. The ITT population was the primary data set used in the efficacy analyses. Efficacy: Analysis of the Primary Objective: For height velocity SDS for chronological age at Year 1, the primary analysis was the comparison of the growth-promoting effect of the treatment groups using the Wilcoxon rank sum test (two-sided). The same procedure was used to compare the change from Baseline to Year 1 in this variable between the treatment groups. Subgroup analysis stratified according to demographic factors was also performed for height velocity SDS for chronological age after 1 year of treatment. Page 2
Secondary Endpoints: Secondary end points were analyzed using descriptive statistics calculated at every observational time-point. The Wilcoxon rank sum test (two-sided) was used to compare the secondary variables after 1 year of treatment between the treatment groups and also to compare changes in variables from Baseline to Year 1 between the treatment groups. Cross tables of scores in each Assessment of Psycho-Social Activities on Short Stature (APSASS) item at the time of start and completion/discontinuation of treatment were prepared. In addition, a frequency tabulation per variable was performed for each questionnaire item. Safety: Tabulations of AEs were prepared according to treatment group/organ system/ae and also by severity. Serious AEs were listed by treatment group. Changes in clinical laboratory values were evaluated over time using descriptive statistics calculated at every observational time-point. Abnormal laboratory changes were tabulated. The verification of similarity between the data from this study and those from overseas clinical studies were conducted separately and are reported elsewhere. RESULTS Subject Disposition and Demography: A summary of subject disposition is presented in Table S1 with a summary of demographic characteristics given in Table S2. Table S1 Subject Disposition 0.033 mg group 0.067 mg group Number of patients enrolled and randomized 34 33 Number of patients who completed 33 33 Number of patients withdrawn 1 0 Withdrawn from the study due to adverse events 1 0 Table S2 Demography at Baseline Item 0.033 mg group 0.067 mg group Male 17 (50.0 %) 18 (54.5 %) Female 17 (50.0 %) 15 (45.5 %) Age (years) Mean ± SD 5.21 ± 1.57 5.39 ± 1.26 Height SDS for chronological age Mean ± SD -3.07 ± 0.73-3.13 ± 0.84 Height velocity (cm/year) Mean ± SD 5.33 ± 0.92 5.48 ± 1.20 Median (n) 5.15 (34) 5.7 (33) Height velocity SDS for chronological age Mean ± SD -1.86 ± 1.15-1.42 ± 1.58 Bone age (years) Mean ± SD 4.54 ± 1.77 4.82 ± 1.60 Bone age/chronological age <0.8 (number of subjects) 12 12 0.8 (number of subjects) 21 20 Efficacy Results: A summary of the results for changes in height velocity SDS and height SDS are presented in Table S3. Page 3
Table S3 Changes Over Time in Height Velocity SDS and Height SDS for Chronological Age (ITT) 0.033 mg group 0.067 mg group Baseline 12 Months Baseline 12 Months Test a Height Velocity SDS -1.86 ± 1.15 2.58 ± 1.85-1.43 ± 1.58 4.70 ± 2.06 p<0.0001 Change 4.44 ± 1.99 6.12 ± 2.23 p=0.0028 Height SDS -3.07 ± 0.73-2.46 ± 0.90-3.13 ± 0.84-2.21 ± 0.96 Change 0.60 ± 0.31 0.93 ± 0.33 p<0.0001 Values are Mean ± SD. a Group comparison (after 12 month of treatment, change): Wilcoxon rank sum test. Analysis of the change in height velocity measured in cm/year also showed that after 12 months of treatment, the height velocity was statistically significantly greater in the 0.067 mg group compared with the 0.033 mg group (9.67 cm/year and 8.14 cm/year, respectively; p<0.0001). There were no obvious differences between the groups for changes in bone age, height SDS for bone age or the ratio of bone age to chronological age over the course of the study. After one year of treatment, height velocity SDS for bone age and change from baseline in height velocity SDS for bone age were significantly greater in the 0.067 mg group than in the 0.033 mg group (p<0.0001 and p=0.0010, respectively). Analysis in the changes from baseline to one year in PAH SDS, height, body weight, body weight SDS for chronological age and BMI showed that significantly greater improvements were achieved for all of these parameters in the 0.067 mg group compared with the 0.033 mg group (p<0.0001 for all parameters except BMI where p=0.0117). Changes in serum IGF-I and IGFBP-3 were significantly greater in the 0.067 mg group than the 0.033 mg group (p=0.0025 and p=0.0269, respectively). Two types of questionnaires (APSASS and a questionnaire on the treatment of short stature) were used to assess the quality of life (QoL) of patients. There were no obvious differences between the groups in the QoL as assessed by these questionnaires. The questionnaire results showed that all of the groups had favorable changes in patient daily lives, suggesting that patients were positive about GH therapy. Safety Results: A total of 471 AEs were observed in 63/67 subjects (94.0%): 208 AEs in 33/34 patients (97.1%) in the 0.033 mg group and 263 AEs in 30/33 patients (90.9%) in the 0.067 mg group. The majority of the AEs were mild or moderate in intensity; in the 0.033 mg group there was one severe AE (asthma) compared with two severe AEs in the 0.067 mg group (pneumonia, infection). A summary of all causality AEs reported in at least five subjects overall is presented in Table S4, below. Page 4
Table S4 All-causality Adverse Events Observed in At Least Five Subjects Preferred term 0.033 mg group (n=34) 0.067 mg group (n=33) Total (n=67) Number of patients with adverse event (%) Upper respiratory tract infection 24 (70.6) 21 (63.6) 45 (67.2) Bronchitis 10 (29.4) 10 (30.3) 20 (29.9) Pharyngitis 7 (20.6) 10 (30.3) 17 (25.4) Otitis media 6 (17.6) 7 (21.2) 13 (19.4) Eczema 6 (17.6) 5 (15.2) 11 (16.4) Conjunctivitis 5 (14.7) 6 (18.2) 11 (16.4) Gastroenteritis 5 (14.7) 6 (18.2) 11 (16.4) Influenza-like symptoms 3 (8.8) 8 (24.2) 11 (16.4) Rhinitis 4 (11.8) 5 (15.2) 9 (13.4) Headache 2 (5.9) 5 (15.2) 7 (10.4) Sialoadenitis 1 (2.9) 5 (15.2) 6 (9.0) Asthma 4 (11.8) 2 (6.1) 6 (9.0) Fever 1 (2.9) 5 (15.2) 6 (9.0) Infection bacterial 1 (2.9) 4 (12.1) 5 (7.5) Overall, a total of 27 treatment-related adverse events were reported by 15 of 67 (22.4%) subjects. Of these, 13 events occurred in 7 (20.6%) subjects in the 0.033 mg group, and 14 events occurred in 8 (24.2%) subjects in the 0.067 mg group. The most common treatmentrelated adverse events included injection site bleeding in 3 (4.5%) subjects, headache in 2 (3.0%) subjects and molluscum contagiosum in 2 (3.0%) subjects. No deaths occurred during this study. There were 5 serious AEs, 2 subjects in the 0.033 mg group each experienced a serious AE of asthma (one moderate, one severe) and serious events of moderate otitis media, severe viral infection and severe pneumonia were reported in 3 subjects in the 0.067 mg group (1 event in each subject). None of the serious AEs was considered related to treatment. There was one withdrawal due to an AE, a case of moderate sleep disorder in a subject in the 0.033 mg group. The event resolved after discontinuation of the treatment. Thirteen abnormal changes in laboratory tests results, reported in a total of 8 subjects, were reported as adverse events. These changes were eosinophilia (2 subjects), leukocytosis (2 subjects), alkaline phosphatase increased, hypoproteinemia, endocrine disorder NOS, urine growth hormone low, albuminuria, and hematuria; each reported in a single subject. No other safety parameters, including height and body weight, showed any clinically meaningful changes. CONCLUSION(S): The results from this study demonstrated that a significantly greater growth-promoting effect was achieved with 0.067 mg/kg/day PNU-180307 compared with the lower dose of 0.033 mg/kg/day. The safety data observed in this study confirmed that treatment with PNU-180307 at either dose raised no safety-related issues. Page 5