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 (recombinant) PROTOCOL NO.: 91-094 PROTOCOL TITLE: An open-labelled study evaluating the efficacy and safety of growth hormone in short prepubertal children with chronic renal insufficiency (Hungary). Study Centre: One centre from Hungary enrolled subjects in this study Study Initiation Date and Completion Dates: 01 December 1992 to 07 July 1994 Phase of Development: Phase 3 Study Objective(s): To study the effects of treatment on linear growth with Genotropin (recombinant human growth hormone [rhgh]) in prepubertal children with chronic renal insufficiency. METHODS Study Design: The study was an open-labelled, uncontrolled prospective study. Subjects were to be treated for one year. The flowchart showing the investigational events, i.e. visits and major assessments performed is shown in Table 1. Table 1: Schedule of Investigational Events Assessments Visit 0 3 6 9 12 Auxology X X X X X Bone age X X Routine biochemistry X X X X X Glomerular filtration rate (estimated) X X X Routine hematology X X X X X HbA1C X X X Abbreviation: HbA1C= glycosylated haemoglobin. Number of Subjects (Planned and Analysed): A total of 5 prepubertal short children with chronic renal insufficiency were planned to be included in the study; 5 subjects were included, all of them were analysed. Page 1
Diagnosis and Main Criteria for Inclusion: Prepubertal children of short stature (height below -2 Standard Deviation Score [SDS] or a height velocity below the 25 th centile) with chronic renal insufficiency (glomerular filtration rate [GFR] < 50 ml/min/ 1.73 m 2 body surface area estimated using the Schwartz formula). Study Treatment: The Genotropin (rhgh) 16 IU per ml cartridge was reconstituted and administered subcutaneously (s.c.) daily in a dosage of 1 IU/kg/week. The daily dose was to be adjusted to the body surface area at the study visits every 3 if necessary. Study drug was administered at home by the subject or a parent. No reference treatment was used in this study. Efficacy Evaluations: The efficacy of treatment was assessed by measuring the subject s standing height every 3. The standing height was measured on Harpenden stadiometer by the same person at every study visit. From the standing height, the height SDS, the height velocity and height velocity SDS were planned to derive. Height velocity SDS is very sensitive to age as well as pubertal stage and is only relevant when the subject's onset of puberty is similar to the reference population. As this is not the case for all the subjects in this study, height velocity SDS was not used. The Tanner curve represents normal children with a growth spurt at 11 years for girls and 12 years for boys, which is the normal onset of puberty. In this subject group, however, puberty is often delayed and for these subjects, comparison with normal Tanner curves is misguiding. Therefore the growth spurt induced by Genotropin cannot be distinguished from the normal pubertal growth spurt. Thus a special reference curve without a pubertal growth spurt had been used to evaluate all prepubertal subjects. The normal Tanner curve was used for subjects, who were pubertal at inclusion or entered puberty during study. Height SDS was calculated as: Height-Mean SD Height = the subject s actual height, mean = the expected height for subject s age and sex, SD = the standard deviation for subject s age and sex. The bone age has been determined from an X-ray of the left hand and wrist by the Tanner and Whitehouse method (TW2) before GH therapy started and after 12 therapy. There were different ways of estimating growth velocity. One way was just to calculate height velocity expressed as change in length/time unit. This is calculated by taking the difference between heights at 2 visits divided with the time intervals between the visits. All height velocities refereed in this report were based on 12 data. The change in height SDS/time was calculated as the difference in height SDS divided by the time interval. Safety Evaluations: Clinical safety assessments: The safety of the treatment was assessed by measuring weight at each 3 monthly visit. Weight SDS was then calculated in a similar manner as height SDS. In addition to this, a weight for height index was calculated. The pubertal stage of each subject was also determined at each visit. For girls the pubic hair and breast development was rated between 1 and 5 according to Tanner. For boys the pubic hair was rated between 1 and 5 according to Tanner. The testicular volumes were also measured and recorded. Page 2
Laboratory safety assessments included: Routine haematology including B-hemoglobin (B-hb) and B-leukocytes; Blood chemistry: S-calcium, S-phosphorus; Renal function: S-creatinine and S-urea as well as calculating GFR; Metabolic status: S-bicarbonate; The B-glucose levels were monitored carefully every 3 and glycosylated haemoglobin (HbA1C) every 6, as there is a concern regarding hyperglycaemia during GH treatment. The thyroid function was monitored by measuring the thyroxin (S-T4) levels. Adverse events (AEs) were asked for and recorded at each clinical visit. Statistical Methods: The end point of this study was to individually compare the pre-treatment growth with the growth after treatment. The primary efficacy variable was the individual differences of delta ( ) height SDS for chronological age before and after treatment. The secondary efficacy variables were the individual differences in height velocity as well as height SDS for bone age. Statistical analysis was not performed due to the fact that only 5 subjects were included. However descriptive statistics are presented. RESULTS Subject Disposition and Demography: A total of 5 subjects (2 boys and 3 girls) aged from 3.2 to 11.5 years with a median of 7.0 years were included in the study from 1 centre. All 5 subjects completed 1 year of treatment. Of these, 2 girls became pubertal during the study. The descriptive statistics of the demographic data at inclusion are presented in Table 2. Table 2: Subject characteristics at inclusion (0 ) (N=5) Subject Age (years) Height (cm) Height SDS Height velocity -12 to 0 (cm/year) Weight (kg) Bone age delay (years) Mean 7.8 110.4-2.4 3.9 20.8 2.0 SD 3.5 18.8 0.8 2.2 9.7 1.6 Min 3.2 82.5-3.4 1.6 9.2 0.2 Median 7.0 107.3-2.5 3.2 18.6 2.2 Max 11.5 131.1-1.5 6.7 34.3 4.0 Abbreviations: cm = centimeters, kg = kilogram, Min = minimum, Max = maximum, N=number of subjects, SD = standard deviation. The underlying renal diseases were malformations in 2 patients, various diseases in 1 patient, hereditary nephropathies in 1 patient and in 1 patient no classification could be made. Page 3
Efficacy Results: Height: At inclusion the heights of the 5 subjects ranged from 82.5 cm to 131.3 cm with a median of 107.3 cm. After 12 the range of the heights had changed to between 93.1 cm and 141.0 cm with a median of 115.0 cm. Height SDS for chronological age: The height SDS of the children at approximately 12 before the study ranged from -3.7 to -1.0. At inclusion the range of height SDS for the same children shifted downward to a minimum of -3.4 and a maximum of -1.5. It could be noticed that during the pre-treatment period, the linear growth of the subjects had a slight tendency to successively lag behind the normal population, and the gap was expanding. After one year of treatment, the range was from -2.5 to -1.1 with a median of -2.3. Height SDS for Bone Age: The height SDS for bone age ranged between -1.5 and +2.3 for the included subjects at study start. At the 12 visit the range was between -0.2 and +3.7. Height SDS for chronological age: The individual values of height SDS for chronological age are presented in Table 3. All values have been standardised to a time period of 1 year. Before treatment the height SDS showed a decreasing trend in 3 out of the 5 subjects completing the study, ie, height SDS was negative. Two subjects had a height SDS > 0 which means that they had started a catch-up. After treatment with Genotropin all subjects had a positive height SDS. However, subject no. 10 did appear to benefit less than the others. Table 3: height SDS and height velocity (cm/year) Individual values Subject No. Height SDS (per year) Pre-treatment -12 to 0 Treatment year 0 to 12 Pre-treatment -12 to 0 Height velocity (cm/year) Treatment year 0 to 12 Difference in height velocity 6-0.8 0.4 1.6 7.5 5.8 7 0.2 1.1 6.7 10.5 3.7 8-0.1 0.3 3.2 7.1 3.9 9-0.3 0.4 2.2 9.7 7.6 10 0.1 0.1 5.7 5.6-0.1 Abbreviations: cm = centimeters, SDS = standard deviation score. Height SDS for bone age: The height SDS for bone age ranged at 12 between 0.2 and 1.5. No values at study start are available since no pre-treatment height SDS for bone age was recorded. Height velocity: Individual values for height velocity are presented in Table 3. Median height velocity during the pre-treatment year was 3.9 cm/year (n=5) and the values ranged from 1.6 cm/year to 6.7 cm/year. After one year of Genotropin treatment the median height velocity increased to 8.1 cm/year (n=5) with a range of 5.6 to 10.5 cm/year. Page 4
Safety Results: Weight: At inclusion, the weight ranged between 10.0 and 32.6 kg, median 18.6 kg (n=5). During the study it increased with a range from 12.5 to 33.7 kg, median 21.2 kg (n=5). Weight SDS and weight for height index: The weight SDS ranged from -3.6 to -0.4, median -1.2 (n=5) at 0. It was rather constant during the study and was between -2.3 and -1.0, median -1.2 (n=5) at 12. The weight for height index ranged from 79 to 122%, median 102% (n=5) at 0 month. At 12 it was between 82 and 106%, median 98% (n=5). Bone age: The delay of bone age during the study is presented in Table 4. The median of the delay of bone age did not change during the study. The relation between the change in bone age and the change in chronological age ( BA/ CA) can be looked upon as a way of measuring an acceleration of the maturation of the bones. However, when the BA/ CA ratio lies around 1, there is no problem with any unwanted advancement in bone age. Table 4: Bone age delay and change in bone age related to change in chronological age Bone age delay (years) BA/ CA 0 12 0-12 N 5 5 5 Minimum 0.2 1.3 0 Median 2.2 2.5 0 Maximum 4.0 4.1 1 N = number of subjects, BA/ CA = the change in bone age/the change in chronological age. Puberty assessments: Two subjects (both girls) entered puberty in this study, both of them at an age expected for normal children. Laboratory safety variables: AEs reported with respect to clinically significant abnormalities in laboratory results are described in the AEs section below. The renal function (represented as GFR estimated using Schwarz' formula) was maintained during the study. AEs: A total of 14 AEs were reported. These 14 events were from 4 subjects and the relationship to treatment was judged to be unlikely in 13 cases. For 1 subject (no. 6) the B-glucose value was 9.8 mmol/l at the 9-month visit and this was judged by the investigator as having a possible relationship to treatment. All AEs except 1 serious AE (SAE) were related to clinically significant laboratory abnormalities such as increase in S-creatinine, S- urea, S-cholesterol and triglycerides, and decrease in S-bicarbonate and Hb. SAE: One SAE was reported, which was not considered to be related to Genotropin therapy. The subject experienced progression of disease at 6. A Tenckhoff catheter was implanted and continuous ambulatory peritoneal dialysis (CAPD) treatment was initiated. Genotropin therapy was continued as per protocol. Page 5
CONCLUSION: Treatment with daily s.c. Genotropin injections at a dosage of 1 IU/ kg/week seems to improve the growth expressed either as height SDS or height velocity in prepubertal subjects with chronic renal insufficiency. No unexpected AEs were reported during the study. Page 6