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 / THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See USPI. PROTOCOL NO.: 307-MET-9002-026 PROTOCOL TITLE: A multi-center, randomized, double-blind, placebo-controlled trial evaluating the metabolic and respiratory effects of Genotropin in children with cystic fibrosis Study Center(s): Eleven (11) centers in Germany Study Initiation and Completion Dates: 09 February 2001 to 05 January 2004 Phase of Development: Phase 3 Study Objective(s): Primary: To determine whether the addition of growth hormone to standard therapy had an influence on the pulmonary function parameter forced expiratory volume in 1 second (FEV1) in cystic fibrosis (CF) patients Secondary: To determine whether the addition of growth hormone to standard therapy improved exercise capacity, body weight (lean body mass), lung function, hospitalization and days off school or work, and quality of life METHODS Study Design: The trial was designed as a controlled, multi-center, randomized, double-blind parallel group study to compare the efficacy and safety of two dosage regimens of subcutaneous (sc) somatropin or placebo. After randomized allocation to one of four treatment groups (0.75 or sc somatropin or matched placebo treatments), subjects were to be treated for 24 weeks in a double blind fashion. At the end of the double-blind treatment period the randomization code was broken and comprehensive medical report was prepared. All subjects were then treated for a further 24 weeks with open-label somatropin. Number of Patients (planned and analyzed): Planned: 36 subjects (12 subjects in each of the somatropin, and placebo group) Analyzed: 63 subjects (intent-to-treat [ITT] Population consisting of 22 subjects in the
somatropin group, 20 subjects in the somatropin group and 21 subjects in the placebo group Diagnosis and Main Criteria for Inclusion: Subjects with established CF (pathological sweat test and/or CF-gene analysis) with a bone age of between 8 to 18 years. All subjects were to have dystrophy (weight for height index <90% and/or body mass index <10th and/or body weight <3rd percentile) and a high calorific intake (>120% RDA) as well as vitamin and pancreatic enzyme supplementation according to 3-day food intake protocol. Study Treatment: The study treatment was recombinant human somatropin from E coli in two-chamber cartridges with powder and solvent for injection for use in a reconstitution device and administered using the Genotropin Pen 16. Depending on the number of clicks administered, two different regimens of active treatment were administered: 1) (approximately 0.11 IU/kg body weight/day) or 2) (approximately 0.21 IU/kg body weight/day). Two different regimens of matched placebo treatment were administered depending on how many clicks of placebo treatment were administered (number matching the number of clicks used to administer each active treatment). Efficacy Evaluations: The primary efficacy evaluation was the mean change from baseline in FEV1 at the end of the 24-week double-blind treatment period (Visit 6). Secondary efficacy evaluations were: Exercise capacity Lean body mass index Forced vital capacity (FVC), vital capacity (VC), maximal expiratory flow (MEF) 50 and MEF 25-75 Number of hospitalization days Number of days off school/work Quality of life questionnaire Laboratory efficacy assessments including Insulin-like Growth Factor (IGF-1) and IGFbinding protein-3 (IGF-BP-3) Growth velocity at visit Safety Evaluations: Incidence of adverse events (AEs) and serious adverse events (SAEs). Routine examinations of physical assessment, systolic and diastolic arterial blood pressure, and heart rate were recorded at each study visit. Additionally, blood samples were taken before treatment, as well as every three months during the treatment period to measure routine laboratory parameters. Protocol 307-MET-9002-026 / Page 2 of 11
Statistical Methods: The primary goal of this study was to test the null hypothesis that the population means (i.e., mean percent change from baseline in FEV1) of somatropin and placebo are equal. The criterion for significance (α) was set at 0.025. The test was one-sided, which meant that an effect in the expected direction was interpreted. The study was conducted using a three-stage group sequential adaptive design with sample size adjustments after the planned interim analyses. The primary efficacy endpoint was the mean percent change from baseline in FEV1 at the end of the 24-week double-blind treatment period. At the first interim analysis the two null hypotheses, H01 and H02 were to be rejected and the study potentially terminated if the one-sided tests for difference of somatropin and versus placebo yielded p-values lower than 0.00026. If H01, or both H01 and H02, could not be rejected the study may have continued with a calculated sample size that was based on the effect size estimation of the interim analysis. At the second confirmatory analysis, the null hypotheses that were not rejected at the first interim analysis were to be rejected if the test statistic that was based on the inverse normal method exceeded the critical value 2.454. For the hypotheses that could not be rejected at the second stage, the sample size could have been recalculated again and the analogous procedure was to be carried out at a third (final) analysis by using the critical value 2.004. This procedure preserved the overall (experiment-wise) Type I error rate of α = 0.025. For confirmatory hypothesis testing at the interim and final analyses, the non-parametric Mann-Whitney-U Wilcoxon-Rank-Sum-W test (one-sided) was used. All other group comparisons were hypothesis generating in nature, i.e., p-values resulting from statistical tests were interpreted in the exploratory sense. RESULTS Subject Disposition and Demography: A total of 67 subjects were randomized to treatment. Three subjects discontinued before receiving any treatment, leaving 64 subjects in the safety population. Sixty-three subjects received at least one dose of study medication and were assessed at least once after baseline and comprised the ITT population (22 subjects in the somatropin group [SI group], 20 subjects in the somatropin group [S2 group] and 21 subjects in the placebo group). Six subjects discontinued from the study during the double-blind period 1 in the SI group, 3 in the SII group and 2 in the placebo group. The most frequent reasons for discontinuation were AEs (2 subjects in the SII group and one subject in the placebo group), receiving prohibited medication (2 subjects in the SII group) and other reasons (1 subject in each of the SI and SII groups). Twelve subjects were excluded from the per protocol (PP) population, 11 because of major protocol violations and one subject who terminated the study early due to a reasons not related to study medication. Subjects had a mean (SD) age of 14.2 (2.7) years with a mean (SD) body mass index of 15.4 (1.5) kg/m 2. The demographic characteristics of the different treatment groups were comparable. Protocol 307-MET-9002-026 / Page 3 of 11
Efficacy Results: End of the Double-Blind Treatment Period (Visit 6, Week 24) Primary: Mean (SD) [median] FEV1 for all subjects was 1362.0 (542.1) [1240.0] ml at baseline; differences between treatment groups were negligible. Both interim analyses failed to reject the null hypothesis. The mean (SD) [median] FEV1 percent change at the final analysis (last observation carried forward [LOCF]) compared with baseline was 3.5% (12.3%) [0.8%], 4.3% (13.4%) [-1.0%] and 1.0% (23.0%) [0.8%] in the SI, SII and placebo groups, respectively. The corresponding confidence intervals for the percentage change in FEV1 were (-2.0%, 8.9%), (-2.0%, 10.6%) and (-9.5%, 11.5%), respectively. Statistically superior efficacy of SII treatment compared with placebo was not demonstrated (p = 0.3629). Similar results were seen in the PP population. Secondary: The baseline and changes in IGF-1 and IGF-BP-3 levels at the final visit are summarized in Table S1, below. Table S1 Summary of IGF-1 and IGF-BP-3 Data at End of Double-blind Period (ITT Population) (N=19) IGF-1 Baseline -0.97 (1.55) [-1.25] -1.47 (1.05) [-1.58] -2.2 (1.48) [-1.86] Change at Visit 6 1.00 (1.06) [1.32] 1.66 (1.53) [1.93] -0.37 (1.24 [-0.25] IGF-BP-3 Baseline 1.11 (1.36) [0.98] 1.20 (0.93) [1.33] 0.51 (1.20) [0.48] Change at Visit 6 0.50 (1.12) [0.41] 0.53 (1.11) [0.50] -0.19 (0.83) [-0.08] Results are expressed as standard deviation score. Growth velocity results at Visit 6 are presented in Table S2. Table S2 Summary of Growth Velocity at End of Double-blind period (ITT Population) (N=22) Growth velocity (cm/year) 5.6 (2.9) [4.8] 6.8 (4.3) [8.0] 3.5 (2.3) [3.4] Growth velocity (SDS) 1.5 (2.6) [1.0] 2.6 (2.7) [2.2] -1.0 (7.2) [-0.2] SDS= Standard Deviation Score. Changes in lean body weight and body composition are summarized in Table S3, below. Protocol 307-MET-9002-026 / Page 4 of 11
Table S3 Summary of Lean Body Weight and Body Composition at End of Double-blind Period (ITT Population) (N=19) Body Weight Baseline (kg) 35.4 (7.5) [35.8] 36.5 (7.7) [37.2] 34.6 (6.7) [35.7] Change at Visit 6 (kg) 2.4 (1.9) [3.2] 2.2 (2.3) [2.1] 1.4 (1.7) [1.3] Lean Body Mass Baseline (kg) 31.7 (6.5) [31.9] 32.1 (6.1) [32.7] 30.1 (5.2) [29.8] Change at Visit 6 (kg) 2.5 (2.4) [3.0] 2.3 (2.5) [1.7] 1.5 (2.3) [0.8] Fat Mass Baseline (kg) 4.04 (2.46) [4.4] 5.32 (2.43) [5.1] 4.59 (2.75) [5.0] Change at Visit 6 (kg) -0.45 (2.07) [0.0] -0.75 (1.27) [0.0] 0.03 (2.3) [0.0] As revealed by Spearman correlation analysis, for subjects under 14 years of bone age, the level of IGF-1 at Visit 6 was a valuable predictor of body mass, BMI, lean body mass and height. However, this correlation was restricted to parameters that were expressed in metric units. No correlation was obtained between IGF-1 at Visit 6 and body mass and height using standard deviation score (SDS). Changes in pulmonary parameters are summarized in Table S4, below. Table S4 Summary of Pulmonary s at End of Double-blind Period (ITT Population) (N=19) Vital Capacity Baseline (ml) 2054.2 (686.4) [2020.0] 2000.5 (582.6) [1920.0] 1943.3 (576.5) [1830.0] Change at Visit 6 (%) 5.2 (12.9) [4.1] 8.8 (15.7) [4.6] 2.9 (22.4) [4.8] Forced vital capacity Baseline (ml) 2006.4 (639.5) [2030.0] 1960.0 (575.7) [2075.0] 1958.6 (609.6) [1830.0] Change at Visit 6 (%) 3.1 (13.1) [1.8] 6.0 (11.2) [7.0] -0.7 (15.1) [3.6] Flow measurement MEF50 Baseline (ml) 1280.7 (1093.4) [684.5] 1390.9 (1115.9) [975.0] 1239.8 (801.8) [910.0] Change at Visit 6 (%) -0.9 (25.8) [-2.1] -9.5 (24.4) [-10.1] 11.4 (53.0) [0.0] Flow measurement MEF25-75 Baseline (ml) 1061.3 (963.3) [528.5] 932.6 (691.8) [700.0] 1035.1 (672.2) [930.0] Change at Visit 6 (%) 1.7 (33.2) [-1.5] 5.6 (28.6) [-4.2] 9.5 (56.6) [0.2] Based on mean values, all pulmonary parameters with a considerable static component (FEV1, VC, and FVC) showed a small increase in the somatropin treatment groups that appeared to be more pronounced at a higher dose. Flow measurements showed the highest increase in the placebo group. Changes in exercise capacity are summarized in Table S5. Protocol 307-MET-9002-026 / Page 5 of 11
Table S5 Summary of Exercise Capacity at End of Double-blind Period (ITT Population) (N=19) Work Rate Baseline (W) 95.4 (27.7) [95] 86.4 (36.1) [80] 84.6 (35.3) [80] Change at Visit 6 (W) 11.4 (18.0) [14.5] 6.0 (36.2) [10.0] 1.6 (17.8) [0.0] VO 2 Baseline (ml/min) 1246.4 (441.5) [1233.0] 1100.2 (387.9) [1039.0] 1164.4 (401.5) [1065.0] Change at Visit 6 (ml/min) 124.2 (256.8) [144.0] 160.3 (274.7) [103.0] -7.1 (152.2) [-3.0] % change from baseline 9.9% 14.5% -6.3% VCO 2 Baseline (L/min) 1.4 (0.6) [1.4] 1.2 (0.5) [1.1] 1.3 (0.6) [1.2] Change at Visit 6 (L/min) 0.2 (0.4) [0.2] 0.1 (0.7) [0.1] -0.0 (0.3) [-0.0] Minute ventilation Change at Visit 6 (L/min) 6.3 (12.7) [0.9] 3.7 (10.7) [3.0] -1.1 (6.4) [-2.0] Baseline (L/min) 45.1 (11.9) [46.2] 40.0 (17.3) [34.5] 44.5 (17.6) [44.6] Tidal volume Change at Visit 6 (ml) 121.7 (144.8) [78.0] 119.9 (191.6) [70.0] -35.6 (177.3) [-43.0] Baseline (ml) 899.8 (314.9) [782.0] 864.3 (260.6) [856.5] 910.1 (307.8) [820] Subjective exertion (Borg Scale) Change at Visit 6 (points) 0.8 (2.0) [0.3] -0.9 (3.3) [-1.0] 0.6 (2.5) [0.0] Baseline (points) 17.2 (2.9) [18.0] 16.7 (2.4) [17.0] 16.2 (2.1) [16.5] O 2 -saturation Baseline (%) 90.2 (6.5) [92.5] 87.6 (9.8) [89.0] 91.3 (4.8) [92.0] Change at Visit 6 (%) 0.1 (3.7) [0.0] -1.7 (5.1) [-1.5] -1.2 (3.7) [0.3] The heart rate during the examinations at baseline rose up to 172.3 (21.4) [176] beats per minute in all subjects. During the examination at Visit 6, almost the same rates were reached. There were only minimal differences in the maximal heart rate reached between the treatment groups. The very similar heart rates and Borg scores displayed across the treatment groups at both baseline and Visit 6 indicate that the obtained exercise parameters reflect the maximum effort in all subjects. There was a small but consistent increase in exercise capacity in the somatropin groups during the six months as shown from the results for work rate, VO 2, VCO 2 and minute ventilation. An analysis of Spearmen correlation coefficients between pulmonary variables and growth related parameters / exercise capacity showed that: In all subjects, all pulmonary parameters were weakly correlated (p< 0.037) with change in body mass but not with change in lean body mass. Statistically relevant p-values were predominantly observed for all subjects and the somatropin treatment groups. In all subjects, pulmonary parameters with a large static component (FEV1, VC, and FVC) were weakly correlated with IGF-1 at Visit 6 (p< 0.05) but not with the change in IGF-1 between baseline and Visit 6. Protocol 307-MET-9002-026 / Page 6 of 11
The more dynamic pulmonary parameters, MEF50 and MEF25-75, were only correlated with IGF-1 at Visit 6 (p= 0.0232 and 0.0342, respectively) and change in IGF-1 from baseline to Visit 6 (p= 0.0320 and 0.0293, respectively) in the placebo group. All pulmonary parameters were weakly correlated (p< 0.05) with work rate at Visit 6 as well as its increase from baseline for all subjects and the somatropin treatment groups. In the placebo group, there were no statistically relevant correlations between MEF50 and MEF25-75 and the change in work rate from baseline. A summary of the number of days off school or work and number of days hospitalized is presented in Table S6, below. Table S6 Summary of Number of Days Off School or Work and Number of Days Hospitalized (ITT Population) (N=19) Days off school or work 11.4 (15.4) [4.5] 14.6 (17.4) [9.5] 14.7 (17.1) [7.0] Days hospitalized 9.3 (15.9) [0.0] 12.4 (16.1) [5.0] 11.7 (14.8) [7.0] A summary of the results of the quality of life assessments is presented in Table S7, below. Only results were there were noticeable differences between treatments are included. Table S7 Summary of major differences in quality of life results between treatment groups (ITT population) CFQ-E Everyday life Baseline 36.46 (23.54) [33.33] 86.67 (15.14) [91.67] 77.78 (18.76) [75.00] Change at Visit 6 11.67 (19.18) [16.67] -19.44 (20.97) [-16.67] -4.17 (5.89) [-4.17] Weight problems Baseline (ml/min) 12.50 (24.80) [0.00] 27.78 (25.09) [33.33] 38.10 (40.50) [33.33] Change at Visit 6 (ml/min) 33.33 (25.20) [33.33] 25.00 (50.00) [33.33] 5.56 (32.77) [0.00] CFQ 14+ Weight problems Baseline (L/min) 71.43 (22.10) [66.67] 47.22 (38.82) [66.67] 73.81 (35.03) [83.33] Change at Visit 6 (L/min) 4.76 (28.81) [0.00] 23.33 (41.72) [33.33] -7.14 (26.73) [0.00] CFQ-E questionnaire was answered by parents of children aged 8-13 years. CFQ-14+ was answered by adolescents older than 13 years Results from the CFQk-R questionnaire, answered by children aged 8 to 13 years, differed only slightly from their parents. Differences between the treatment groups were minor at baseline with a tendency towards better scores in the placebo group. Changes between baseline and Visit 6 were minor in all groups. Protocol 307-MET-9002-026 / Page 7 of 11
Efficacy Results: End of the Open Phase (Visit 8, Week 48) During the open phase of the study, subjects received somatropin at doses of either 0.75 IU /kg body or. Subjects who had been randomized to the SI or SII groups in the double-blind phase remained on the same treatment. Subjects who were originally included in the placebo to the SI group commenced treatment at the lower dose of somatropin and subjects who were originally included in the placebo to the SII group commenced treatment at the higher dose of somatropin. Analysis of the open-phase results was conducted using the following groups of subjects: Group A: SI treatment during double-blind and open phase treatment (21 subjects) Group B: SII treatment during double-blind and open phase treatment (18 subjects) Group C: SI or SII treatment in open phase, placebo during double-blind phase (20 subjects) Group D: SI treatment during open phase irrespective of previous treatment (29 subjects) Group E: SII treatment during open phase irrespective of previous treatment (30 subjects) During the open phase, improvements induced by somatropin in lean body mass (increase), fat mass (reduction) as well as on exercise capacity and lung parameters (increase) were most pronounced in subjects who had received placebo in the double-blind phase (Group C). Differences between the two dose regimens were comparably small in size. The mean number of days off school or work, and the number of days hospitalized, during the 6 months of the open phase was lower in group A and D compared with Groups B, C and E. Safety Results: Double-blind Phase A total of 14/22 (63.6%) subjects in the SI group, 12/20 (60.0%) subjects in the SII group and 13/22 (59.1%) subjects in the placebo group experienced at least one AE during the double-blind phase of the study. The majority of the AEs in all treatment groups were considered to be mild or moderate in severity. Two subjects in each group experienced at least 1 severe AE; the only severe AE reported in more than 1 subject was lung infection NOS reported in 2 subjects in each of the somatropin groups and 1 subject in the placebo group. A summary of AEs, by system organ class, reported in more than one subject in any treatment group is presented in Table S8. Protocol 307-MET-9002-026 / Page 8 of 11
Table S8 System organ class Adverse Events Reported by More Than One Subject in Any Treatment Group, Sorted by System Organ Class (Safety Analysis, Double-blind Phase) All subjects Treatment Group (N=64) (N=22) (N=22) Subjects with at least one AE 39 (60.9%) 14 (63.6%) 12 (60.0%) 13 (59.1%) Infections and infestations 26 (40.6%) 10 (45.5%) 8 (40.0%) 8 (36.4%) Respiratory, thoracic and 11 (17.2%) 2 (9.1%) 4 (20.0%) 5 (22.7%) mediastinal disorders Gastrointestinal disorders 9 (14.1%) 2 (9.1%) 3 (15.0%) 4 (18.2%) Nervous system disorders 9 (14.1%) 2 (9.1%) 2 (10.0%) 5 (22.7%) Musculoskeletal and connective 6 (9.4%) 2 (9.1%) 2 (10.0%) 2 (9.1%) tissue disorders General disorders and 5 (7.8%) 1 (4.5%) 1 (5.0%) 3 (13.6%) administration site conditions Investigations 4 (6.3%) 2 (9.1%) 0 2 (9.1%) Metabolism and nutritional disorders 2 (3.1%) 0 0 2 (9.1%) A total of 11 subjects (2 in the SI group, 1 in the SII group and 8 in the placebo group) had AEs that were considered to be probably or possibly related to study drug. The only AE that was considered probably or possibly related to treatment that was reported in more than 1 subject in any treatment group was headache NOS (with all events reported in the placebo group; 1 subject had an event probably related to treatment and 3 subjects had events possibly related to treatment). There were no deaths during the double-blind phase of this study. A total of 13/64 (20.3%) subjects experienced an SAE: (5 [22.7%] in the SI group, 4 [20.0%] in the SII group and 4 [18.2%] in the placebo group). SAEs that were reported in more than one subject in any treatment group included lung infection NOS (2 subjects in the SI group, 3 subjects in each of the SII and placebo groups) and distal ileal obstruction syndrome (2 subjects in the SII group). Clinically relevant deviations of blood glucose levels from the normal range were observed in 1 subject each in the SI and SII groups at Visit 6 (LOCF). One clinically relevant decrease in potassium levels was observed in the placebo group at Visit 6 (LOCF). No further clinically relevant changes were observed in any subject during the double-blind phase. Safety Results: Open Phase A total of 13/21 (61.9%), 13/18 (72.2%), 16/20 (80.0%), 19/29 (65.5%) and 23/30 (76.7%) subjects in Group A, B, C, D, and E, respectively experienced at least one AE during the open phase of the study. The majority of the AEs in all treatment groups were considered to be mild or moderate in severity. Two subjects each in Groups A, C and D, 5 subjects in group B and 7 subjects in Group E experienced at least 1 severe AE. The only severe AE reported in more than 1 subject was lung infection NOS that was reported in 3 subjects each in Groups B and E. Protocol 307-MET-9002-026 / Page 9 of 11
A summary of AEs, by system organ class, reported in more than one subject in any treatment group is presented in Table S9, below. Table S9 Adverse Events Reported by More Than One Subject in Any Treatment Group, Sorted by System Organ Class (Safety Analysis, Open Phase) System organ class All Treatment Group subjects a (N=59) A B (N=18) C D (N=29) E (N=30) Subjects with at least one AE 42 (71.2% 13 (61.9%) 13 (72.2%) 16 (80.0%) 19 (65.5%) 23 (76.7%) Infections and infestations 27 (45.8%) 9 (42.9%) 7 (38.9%) 11 (55.0%) 12 (41.4%) 15 (50.0%) Gastrointestinal disorders 10 (16.9%) 1 (4.8%) 4 (22.2%) 5 (25.0%) 2 (6.9%) 8 (26.7%) Respiratory, thoracic and 9 (15.3%) 5 (23.8%) 1 (5.6%) 3 (15.0%) 8 (27.6%) 1 (3.3%) mediastinal disorders Investigations 8 (13.6%) 3 (14.3%) 3 (16.7%) 2 (10.0%) 3 (10.3%) 5 (16.7%) Nervous system disorders 5 (8.5%) 1 (4.8%) 1 (5.6%) 3 (15.0%) 3 (10.3%) 2 (6.7%) General disorders and 4 (6.8%) 0 1 (5.6%) 3 (15.0%) 2 (6.9%) 2 (6.7%) administration site conditions Metabolism and nutritional 3 (5.1%) 2 (9.5%) 1 (5.6%) 0 2 (6.9%) 1 (3.3%) disorders Skin and subcutaneous tissue disorders 3 (5.1%) 0 1 (5.6%) 2 (10.0%) 1 (3.4%) 2 (6.7%) a Subjects may appear in more than one group. A total of 15 subjects (3, 7, 5, 4 and 11 subjects in Groups A, B, C, D and E, respectively) had AEs that were considered to be probably or possibly related to study drug. No AEs considered to be probably related to treatment were reported in more than 1 subject in any treatment group. Of the AEs considered to be possibly related to treatment, only blood glucose increase (2 subjects each in Groups A and D) glucose tolerance test abnormal (2 subjects in Group B and 3 subjects in Group E) and headache NOS (2 subjects in Group E) were reported by more than 1 subject in any treatment group. There were no deaths during the open phase of this study. A total of 12/59 (20.3%) subjects experienced an SAE (4 [19.0%], 6 (33.3%), 2 [10.0%], 4 [13.8%] and 8 [26.7%] in Groups A, B, C, D and E, respectively). SAEs that were reported in more than 1 subject in any treatment group included lung infection NOS (2 subjects each in Groups B and E) and respiratory tract infection NOS (2 subjects in Group C and 3 subjects in Group E). One subject in Groups A and D showed clinically relevant elevations of blood glucose levels at Visit 6, whereas at Visit 8 (LOCF), 1 subject in Groups A, B, D and E showed clinically relevant deviations from blood glucose from the normal range. Further clinically relevant elevations from the normal range were seen for gamma glutamyl transpeptidase and white blood cells in 1 subject each in Groups A and D and immunoglobulin G in 1 subject each in Groups C and E at Visit 8 (LOCF). Protocol 307-MET-9002-026 / Page 10 of 11
CONCLUSION(S): Compared with placebo, both somatropin treatment groups displayed a moderately stronger growth, increase in lean body mass and reduction of fat mass as well as an increase in exercise capacity. To a lesser extent, this also applied to the lung parameters FEV1, VC and FVC, which were correlated with IGF-1 levels at Visit 6. However, for the primary efficacy parameter, no significant superiority in the mean percentage change from baseline in FEV-1 was observed for SII treatment compared with placebo. The lack of a significant difference for the primary endpoint is most likely a consequence of the high variability in FEV1 seen in the placebo group. Additionally, the placebo effect was unexpectedly strong in this trial. However, despite these anomalous results, the overall changes in the assessed parameters were consistent with what was expected. The results of the open-label phase indicate that the effect of somatropin was most pronounced at the onset of treatment. Safety and tolerability of both somatropin doses were comparable with placebo. Based on a report completed on: 15 December 2004 Protocol 307-MET-9002-026 / Page 11 of 11