PUBLICATIONS Abstracts and publications on the psychological data available.

Transcription

1 Page 1 of 9 Synopsis TITLE OF TRIAL : The Effects of Biosynthetic Human Growth Hormone Treatment in the Management of Children with Familial Short Stature. Protocol B: A Comparative Evaluation of Growth Hormone, Anabolic Steroid and a Combination of the Two in Stimulating the Growth of Boys (with familial short stature, and short stature with no evidence of overt organic pathologies) in Late Pre-puberty. Protocol C: A Comparative Evaluation of Growth Hormone, Sex Steroid and a Combination of the Two in Stimulating Pubertal Growth and Development in Boys (with constitutional delayed growth/puberty with normal HV, with or without short stature). Protocols B and C pursued the search for an optimal GH dose to short stature started in Protocol A. The trials GHRETARD/BPD/8/UK, -/10/UK and -/9/UK are therefore reported as one trial consisting of the three protocols A, B and C. INVESTIGATOR Dr.C.J.H. Kelnar TRIAL CENTRES Royal Hospital for Sick Children, Edinburgh PUBLICATIONS Abstracts and publications on the psychological data available. TRIAL PERIOD DEVELOPMENT PHASE First patient first visit: : Last patient last visit: : Clinical Phase III Protocol B: Protocol C: OBJECTIVES : To assess the efficacy and safety of biosynthetic growth hormone (GH) in short children without significant growth delay without GH deficiency (GHD). To assess: If 12 months GH treatment (or more) accelerates height velocity (HV) compared to placebo; If GH treatment improve final height; Possible predictors of growth response; Psychological benefits and drawbacks of hgh treatment in short stature children. Protocol B: To assess the role of GH and anabolic or sex steroids alone, or in combination, in the treatment of boys with familial short stature, and short stature with no evidence of overt organic pathologies. To answer the question: Does GH therapy enhance any Oxandrolone-induced increase in HV in late male pre-puberty? Protocol C: To assess the role of GH and sex steroids alone, or in combination, in the treatment of boys with constitutional delayed growth and/or puberty with normal HV with or without short stature. Specific questions addressed in Protocols B and C: 1. Does GH therapy increase HV in late pre-puberty without compromising final height prognosis? 2. Does GH treatment enhance the slow HV achieved by endogenous or exogenous androgens in early male puberty and extend the period of the male pubertal growth spurt? 3. What, if any, are the complications of GH treatment? METHODOLOGY : The trial was a randomised, double-blind, placebo controlled trial. Three groups were compared. In each group dose was adjusted according to growth response (non-responders followed a dose escalation schedule). Non-responders after the third year were considered dropouts in all treatment groups: IU/m 2 /week, if non-responder 30 IU in year two and if still non-responder 36 IU year three

2 Page 2 of month placebo, hereafter 15 IU/m 2 /week month untreated, hereafter 15 IU/m 2 /week Protocol B: The trial was an open, randomised trial. Subjects were randomised to four groups: 1. GH 24 IU/m 2 /week (at least 12 months) 2. Oxandrolone 2.5 mg/day 3. GH + oxandrolone, as above 4. No treatment After 12 months responders continued on the same treatment. Group 1 as described for. Non-responders on oxandrolone and combination therapy were withdrawn. The untreated subjects (Group 4) started GH treatment (15 IU/m 2 /week) at Month 12. At Month 24 non-responders were withdrawn. Protocol C: Subjects were randomised to three groups. Dose was increased each year as a part of the trial design and did not depend of growth response: 1. GH IU/m 2 /week 2. Testosterone mg 3. GH + testosterone, as above NUMBER OF SUBJECTS : Randomised 37 Withdrawn 15 Completed 22-6 subjects stopped GH treatment but continued in the trial Protocols B: Randomised 43 Withdrawn 19 Completed subjects stopped GH treatment but continued in the trial Protocol C: Randomised 33 Withdrawn 27 Completed 6-25 subjects stopped GH treatment but continued in the trial DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION : Height <3th percentile for age (CA) (Tanner et al., 1975) Height velocity standard deviation score (HVSDS <0) Peak s-gh 20 mu/l during adequate a insulin-induced hypoglycaemia, clonidine stimulation or sleep test. Clinically and biochemically prepubertal Bone age (BA) (TWII) <8 years Protocol B: BA retardation <2 years compared to CA; CA-BA <2 years Prepubertal boys with a height at or below the 3 rd percentile for CA with CA <14years, BA >8 years and BA 2 years below CA. Protocol C: Boys with a CA >14 years, either prepubertal or in early puberty (testes <6 ml). TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBER Three treatment groups were compared: Group 1 24 IU/m 2 /week, hereafter 24 IU/30 IU/36 IU based on growth response Group 2 12-month placebo, hereafter 15 IU Group 3 24-month untreated, hereafter 15 IU DURATION OF TREATMENT Up to 81 months. Subjects were to be treated till final height which was changed to four years for Protocols B and C with the Amendment, dated 8 January REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBER Placebo. For dose schedule see above. EFFICACY ENDPOINTS a Not further specified.

3 Page 3 of 9 Primary Secondary Height velocity (HV) for one year periods Yearly change in standardised height ( HSDS) Standardised HV (HVSDS) Yearly change in height velocity ( HV) from pre-trial to trial period Yearly change in standardised height ( HVSDS) Tertiary Protocol B and C Primary efficacy endpoints as for. No other endpoints were defined. SAFETY ENDPOINTS - as stated in the statistical analysis plan Primary Endpoints Adverse events Adverse events, serious adverse events, treatment related adverse events Bone maturation Ratio of yearly change in bone age and chronological age from baseline to trial period Glucose metabolism HbA1 Additional Safety Body Composition Sum of skinfolds Pubertal development Age at onset of puberty, duration of GH treatment at onset of puberty. Cardiac status Diastolic and systolic blood pressure Thyroid function TSH, T 4 Protocol B and C For Protocols B and C, the primary safety variables were the ratio of yearly change in bone age and chronological age from baseline to trial period ( BA/ CA), adverse events, serious adverse events and treatment-related adverse events. Additional safety outcomes were onset of puberty. STATISTICAL METHODS All analyses were conducted on the intention-to-treat (ITT) population. Due to the number of protocol violations, a per-protocol (PP) analysis was not performed (for protocol violations and deviations see Section 6.2). Primary and secondary efficacy variables are presented in summary statistics. For, treatment groups were compared for difference in outcome, both between groups and within groups over time by an analysis of variance (ANOVA). All groups were compared the first year of the trial, GH 24 IU and the untreated group were compared the second year. Tertiary efficacy outcomes are presented by summary statistics. No statistical analyses were performed for Protocol B and C. DEMOGRAPHIC The children were small for their age at baseline. There were generally no differences in baseline characteristics between treatment groups. : Age range: 7.5 to 8.5 years. Bone age was 1.6 to 2.0 years behind chronological age. Twelve (12) children were growth retarded already in utero (IUGR). Protocol B: The children were a couple of years older than those included in, reflecting the inclusion criteria (11.3 to 11.8 years). Only boys were included. The children were comparable to in height but with lower HV. They were, however, less retarded in bone age compared to chronological age than the children included in (bone age retardation from -1.5 to -0.3 years). Eight children were growth retarded already in utero. Protocol C: Mean age was markedly higher than in Protocols A and B, as for Protocol B only boys were included. HSDS were comparable to Protocols A and B, HV comparable to Protocol B. The children were generally more retarded in bone age compared to chronological age (-2.5 to -1.9 years) than the younger children included in the Protocols A and B. Eight children were growth retarded already in utero. EFFICACY RESULTS Height Velocity

4 Page 4 of 9 During the first year of GH treatment HV increased in all three groups. The increase was similar and tailed off during the second year of the treated period. Pre-trial 1st year 2nd year Dose Group HV 0 HV 1 HV 2 24IU N NMISS MEAN STD PL/15IU N NMISS MEAN STD UNTR/15IU N NMISS MEAN STD Source: Table , Prepubertal Subjects, Appendix K All three groups were compared the first year of the trial. First year HV was higher in the GH 24 IU group than in the placebo and untreated groups (GH-Placebo: 2.78cm/year, 95%CI ( ); GH-untreated: 2.93 cm/year, 95%CI ( )). There was, however, virtually no difference in the first year HV between the placebo and the untreated groups (Placebo-untreated: 0.16 cm/year, 95%CI ( ). The second year of the trial GH 24IU and the untreated group were compared. HV was again higher in the GH 24IU group than in the untreated group (GH 24IU-untreated: 1.43cm/year, 95%CI ( )). There appeared to be no difference in growth response on 15IU compared to 24IU. Protocol B During the first year of GH treatment HV increased in all groups. The increase was largest in the GH+OX group, followed by the OX and GH group and smallest in the UNTR/GH group. The increase tailed off during the second and third years of the treated period in all groups. There seemed to be a greater effect in the first year amongst those receiving 24 IU/m 2 /week compared with those receiving 15 IU/m 2 /week. However, the fall in the second year of treatment was less sharp in those receiving 15 IU, and the mean values during the second year of treatment were similar in the two groups. Treatment Pre-Trial 1st year 2nd year 3rd year Group HV 0 HV 1 HV 2 HV 3 GH N NMISS MEAN STD OX N NMISS MEAN STD GH+OX N NMISS MEAN STD UNTR/GH N NMISS MEAN STD Source: Table , Prepubertal Subjects, Appendix K Protocol C Similar results were seen for Protocol C with the largest increases the first year of treatment, followed by a waning effect of treatment. The largest increase in HV was seen during the combination therapy (GH+T). Testosterone alone lead to a slightly higher increase in HV than GH

5 Page 5 of 9 alone. Higher mean values were seen when pubertal data were included. Treatment Pre-Trial 1st year Group HV 0 HV 1 GH N NMISS MEAN STD T N NMISS MEAN STD GH+T N NMISS MEAN STD Source: Table , Prepubertal Subjects, Appendix K There was only enough data to compare the treatment groups during the first year of the trial. GH dose level (24IU) was, therefore, comparable to the Protocols A and B. Note that fluctuations in the number of subjects summarised may change the means markedly. E.g. in the GH group, for prepubertal subjects HV 1 was 7.34 cm/year, for all subjects 8.25 cm/year and for all subjects with values Years 1 to 3 HV 1 was 9.10 cm/year. HSDS The differences in HSDS from baseline to the end of the first year were compared between the three groups. The gains in HSDS were larger in the GH 24IU group than in the placebo and untreated groups (GH-Placebo: 0.489, 95%CI ( ); GH-untreated: 0.486, 95%CI ( )). There were no differences in HSDS between placebo and the untreated group. The difference in HSDS from baseline to the end of the second year was compared for the GH 24IU and the untreated group. Again, the largest gain was seen on GH 24 IU (0.701, 95% CI: ). HSDS during GH treatment is summarised: Start of trt - Start of trt - Start of trt Start of Treat- End Year 1 End Year 2 End Year 3 ment Value of trt of trt of trt Dose Group HSDS Ht 1 -SDS Ht 2 -SDS Ht 3 -SDS 24IU N NMISS MEAN STD Start of trt - Start of trt - Start of trt Start of Treat- End Year 1 End Year 2 End Year 3 ment Value of trt of trt of trt Dose Group HSDS Ht 1 -SDS Ht 2 -SDS Ht 3 -SDS PL/15IU N NMISS MEAN STD UNTR/15IU N NMISS MEAN STD

6 Page 6 of 9 Total N NMISS MEAN STD Source: Table , Prepubertal, Appendix K Before start of treatment HSDS was about -2.5 for all treatment groups. Scores increased steadily during GH treatment, with similar gains in all treatment groups the first two years of the trial. After the second year data on HSDS were based on a low number of subjects but a trend towards a dosedependency was seen. No one reached a positive HSDS. Larger gains were seen when data on pubertal subjects were included. Protocol B Similar results were seen in HSDS as for HV. HSDS increased from baseline levels and compared to the untreated group. The increase was most marked during the first year of treatment and hereafter steady in all groups (based on all subjects with data Years 1 to 3). The largest gain in HSDS was seen for the subjects in combination therapy, and HSDS on OX was larger than HSDS on GH. Larger gains were seen with GH 24 IU than with GH 15 IU. The change in HSDS to the baseline score was statistically significant in Years 1 and 2 for the GH group and in Year 1 for the OX and GH+OX groups. Note that there was not enough data for Year 2 in the OX and GH+OX groups. Larger gains were seen when data on pubertal subjects were included. Baseline Value 1st year 2nd year Treatment Group H t0 -SDS H t1 -SDS H t2 -SDS GH N NMISS MEAN STD OX N NMISS MEAN STD GH+OX N NMISS MEAN STD UNTR/GH N NMISS MEAN STD Source: Table , Prepubertal Subjects, Appendix K Protocol C For prepubertal subjects, there was only data from baseline to the end of the first year for the T group, in which HSDS increased by only Therefore, HSDS results are presented as a summary of all subjects irrespective of puberty. Due to the inclusion of data after onset of growth relevant puberty, gains are therefore higher than the gains expected for the prepubertal subjects. E.g. the change in HSDS after the first year was 0.40 in the T group when data after onset of growth relevant puberty was included. HSDS should therefore not be compared with the prepubertal results summarised above for Protocols A and B. Treatment Baseline 1st year 2nd year Group H 0 -SDS H 1 -SDS H 2 -SDS GH N NMISS MEAN STD T N NMISS MEAN STD GH+T N

7 Page 7 of 9 NMISS MEAN STD Source: Table , All subjects, Appendix K In all treatment groups and both years, HSDS were larger than and significantly different from that at baseline. The change from baseline to the end of year 2 was higher than the change from baseline to the end of year 1. There were no differences between treatment groups in the gains in HSDS. SAFETY RESULTS Adverse Events A total of 50 adverse events were reported by 16 (48%) subjects during GH treatment. There was no difference in the overall incidence rate between groups. However, in the 24IU group all events were reported during GH treatment whereas in the placebo/15iu and untreated/15iu groups similar incidence rates were seen before and after treatment. The number of subjects with adverse events and the number of adverse events decreased with years in GH treatment. The majority of nonserious adverse events were events often seen during childhood. Two non-serious adverse events were classed as severe (24IU: upset by injections; UNTR/15IU: dyspepsia). Six (6) serious adverse events (n=5) were reported, of which 3 events were reported during the GH treatment period. One serious adverse event is considered of importance with regards to the safety of GH treatment, hepatic failure, for which the subject was withdrawn. Protocol B A total of 40 adverse events were reported by 18 (43%) subjects during GH and/or oxandrolone treatment. Adverse events were primarily reported during the treated periods. The most common adverse events were injection site pain and events related to infections. Two events were graded severe events (GH: testis disorder assessed as serious; GH+OX: arthralgia). Four serious adverse events were reported during treatment, of which one event (testis disorder) was considered to be related to the GH treatment. Five events were classed as possibly, probably or definitely treatment related, including one event of hyperglycaemia and two events of arthralgia in the GH+OX group. A higher number of serious and related events tended to be seen in the GH+OX group than in the other groups. One subject experienced three events of mild gynaecomastia after oxandrolone treatment had stopped, considered unrelated to treatment. Protocol C A total of 27 adverse events were reported by 17 (52%) subjects during treatment (GH and/or testosterone). There seemed to be a lower incidence of events in the T group than in the GH and GH+T groups. A high number of events (8) were classed as possibly, probably or definitely treatment related: two events of emotional lability in the T group, and three events in each of the GH and GH+T groups, including two events of arthralgia and injection site pain/reaction. Two events were graded as severe (emotional lability and manic reaction both in the T group). The most common adverse events were injury accidental, emotional lability, arthralgia, injection site pain, and other events. Three serious adverse events were reported (one in the GH group, and two in the T group). One serious event was reported during treatment (appendicitis in the GH group). Glucose Metabolism There were no long-term effects on glucose metabolism, based on s-glucose and HbA 1 levels. Fluctuations from baseline levels were seen in HbA 1 levels in all treatment groups. In each of the Protocols B and C, one subject (GH+OX: 13;GH: 3, respectively) had temporary increased glucose levels. Note that glucose metabolism was specified as a primary endpoint only in. Bone Maturation Bone age was generally delayed at the start of the trial but less so by the end of the trial. During treatment bone age increased at a faster rate than chronological age (ratio BA/ CA above one) but in general bone maturation was not accelerated (defined as a ratio continuously above 1.5). An accelerated bone maturation was seen for two subjects in Protocol C ( BA/ CA Year 4 - baseline: 1.76 and 1.83). Puberty Please note that the analysis of puberty does not take account of the children who did not enter

8 Page 8 of 9 puberty. Survival analyses should have been used. Due to the status of the trial new analyses on puberty were, however, not done. Therefore, data on puberty are questionable. Twenty-three (23) of the 36 children entered puberty during the trial period. Subjects appeared to reach puberty at a slightly younger age on GH 24IU (median years) than on 15IU (medians plac/15iu and untr/15iu years). Boys entered puberty at an older age than girls. Subjects in the UNTR/15IU group tended to reach puberty after a shorter duration of GH treatment than the other two groups. They started treatment two years after the start of the trial, and so were that much older when GH treatment was initiated. Please note that the analysis of puberty does not take account of the children who did not enter puberty. Therefore, no conclusions can be drawn on puberty. Protocol B All but two boys entered puberty during the trial but at an older age than seen in. A shorter duration of GH till onset of puberty was seen due to the older age of the children at inclusion. The OX and GH+OX groups seemed to reach puberty at a slightly younger age (medians and years) and after a shorter duration of treatment than subjects in the GH and UNTR/GH groups (13.32 and years). The duration of GH treatment at onset of puberty was less in the UNTR/GH group than in the GH group, which can be explained by the fact that the UNTR/GH group started treatment a year later than the GH group. Protocol C Two-thirds of the boys (21) had already entered puberty at the start of the trial. No summary table was made therefore made. None had reached growth relevant puberty. The last third (10 children) entered puberty during the first 15 months of the trial but at a fairly older age than seen for the boys in Protocols A and B (range: 14.8 to 16.1 years). CONCLUSIONS Efficacy Twelve-months treatment with GH 24IU lead to statistically significant and clinically relevant changes in HV and HSDS compared to placebo and an untreated control, with no difference between placebo and untreated. The first year increase tailed off during the second year of treatment. After 24-months treatment with GH 24IU HV and HSDS were still higher than and statistically significantly different from an untreated control group. Combination therapy appeared to induce larger gains in HV than seen during mono-therapy. GH+Oxandrolone tended to be more efficient than GH+testosterone in improving growth. Different age groups were, however, compared. Also, mono-therapy with oxandrolone and testosterone appeared to induce larger changes in HV, and for oxandrolone also HSDS, than mono-therapy with GH. The magnitude of the effect on growth with the same dose level differed across the protocols. Different age groups were, however, compared. A dose of GH 24IU may induce a further effect on growth than a dose of GH 15IU in older children. Four subjects reached final height in Protocol C (162.7, 166.2, and cm), Final height was based on the CRF pages and not by the definition HV<1cm/year. Questions 2 (GH effect on final height) and 4 (psychological benefits and drawbacks of GH treatment) in could not be evaluated. Very few subjects were followed until final height. No psychological data were available. The objective regarding the psychological benefits may be evaluated by the investigator. Question 3 regarding possible growth predictors was not addressed.

9 Page 9 of 8 Safety About half the population experienced an adverse event during the trials, representing primarily minor events often seen during childhood. More events tended to be seen in the high GH groups and first years of treatment. Adverse event incidence dropped with time in GH treatment. One serious adverse event (15IU: hepatic failure) lead to withdrawal. It was not possible to assess a relationship to the GH treatment. Thirteen (13) of the 117 events (11%) were considered related to treatment, including four events of arthralgia, one hyperglycaemic event and one serious event of testis disorder. The majority of related events (8) were seen in the older children included in Protocol C. A higher number of serious and related events tended to be seen during combination therapy with GH+OX than during mono-therapy. Bone age was generally delayed compared to chronological age at trial start but less so at endof-trial. Bone age was generally not accelerated but the ratio BA/ CA was larger during treatment than when untreated. There were no obvious differences between treatments. The ratio BA/ CA was statistically significantly different from one in the GH+OX group in Protocol B the first two years. An accelerated bone maturation (a ratio BA/ CA above 1.5) was seen for two subjects in Protocol C. For boys age at onset of puberty differed markedly between the Protocols A, B and C, reflecting the different subject populations included. In Protocol B, the OX and GH+OX groups seemed to reach puberty at a slightly younger age and after a shorter duration of treatment than subjects in the GH and UNTR/GH groups which was expected due to the oxandrolone treatment. Please note that the analysis of puberty does not take account of the children who did not enter puberty. Therefore, data on puberty are questionable. There were no changes in other safety parameters which affected the safety of GH treatment. Ethics Committee and written informed consent were obtained prior to starting the trial. The trial was conducted in accordance with the Helsinki Declaration.