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Long-term safety and efficacy of daily recombinant human growth hormone treatment in Japanese short children born small for gestational age: final report from an open and multi-center study.

ABSTRACT: Our study aimed at evaluating the safety and efficacy of GH treatment up to near adult height (NAH) for short children born small for gestational age (SGA). This was a multi-center, open-label, long-term extension study after a one-year, randomized, open-label, dose-response study. The primary objective was to assess safety, determined by adverse events and laboratory test parameters. Height parameters were evaluated as a secondary objective. The final data after all patients completed the study were reported. Overall, 61 patients were enrolled in the study. GH treatment was well tolerated. No notable changes in HbA1c levels, oral glucose tolerance tests and glucose metabolism were observed. No new safety concerns related to long-term treatment up to NAH were identified. Twenty patients (11 boys and 9 girls) reached NAH with a mean height of 159.1 cm and 146.9 cm, respectively. The mean change in height SDS from baseline to NAH was +1.9 in boys and +1.8 in girls. Long-term GH treatment for SGA short stature was confirmed to be safe and effective for the normalization of adult height.

SUBMITTER: Tanaka T

PROVIDER: S-EPMC6073065 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Long-term safety and efficacy of daily recombinant human growth hormone treatment in Japanese short children born small for gestational age: final report from an open and multi-center study.

Tanaka Toshiaki T Yokoya Susumu S Hoshino Yuko Y Hiro Shintaro S Ohki Nobuhiko N

Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 20180731 3

Our study aimed at evaluating the safety and efficacy of GH treatment up to near adult height (NAH) for short children born small for gestational age (SGA). This was a multi-center, open-label, long-term extension study after a one-year, randomized, open-label, dose-response study. The primary objective was to assess safety, determined by adverse events and laboratory test parameters. Height parameters were evaluated as a secondary objective. The final data after all patients completed the study ...[more]

PMID: 30083031

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Project description:IntroductionThis ongoing, prospective, open-label, non-comparative, multicenter phase IV study is evaluating the safety and efficacy of recombinant human growth hormone (rhGH; Omnitrope(®), Sandoz GmbH) in short children born small for gestational age (SGA). Here we report data from patients who have completed 2 years' treatment.MethodsEligibility criteria included prepubertal children born SGA with growth disturbances defined as current height standard deviation score (HSDS) <-2.5 and parental adjusted SDS <-1; birth weight and/or length <-2 SDS; and failure of catch-up growth [height velocity (HV) SDS <0 during the last year] by 4 years of age or later. The primary study objective is to assess the long-term effect of Omnitrope treatment on the development of diabetes in short children born SGA. Secondary objectives include evaluation of efficacy, incidence and severity of adverse events (AEs), occurrence of malignancies during treatment, and detection of anti-rhGH antibodies during treatment.ResultsIn total, 278 children have been enrolled and received study medication; 249 have completed 2 years of treatment. No child has developed diabetes mellitus during the first 2 years; no fasting glucose or 2-h oral glucose tolerance test value exceeded the pre-defined limits of >126 or >200 mg/dL, respectively. No adverse alterations in body mass were noted. Treatment-emergent AEs were experienced by 211 (76.2%) children; most of these were of mild-to-moderate intensity (99.3%) and considered unrelated to study medication (97.6%). Treatment with Omnitrope was effective; mean HSDS was -3.39 at baseline, -2.57 at 1 year and -2.15 at 2 years of treatment. Mean HVSDS (peak-centered) also improved, from -2.13 at baseline to +4.16 at 1 year and +2.23 at 2 years.ConclusionIn this second interim analysis, short children born SGA were safely and effectively treated with rhGH (Omnitrope), and 2 years' treatment had no major adverse impact on carbohydrate metabolism or body mass.FundingSandoz.

Project description:BackgroundThis prospective, open-label, non-comparative, multicentre, long-term phase IV study is examining the efficacy and safety of somatropin [recombinant human growth hormone (rhGH)] in short children born small for gestational age (SGA) and its impact on the incidence of diabetes. This report is the first interim analysis of patients who have completed 1 year of treatment.MethodsA total of 278 pre-pubertal patients were enrolled. Key eligibility criteria included height standard deviation score (HSDS) <-2.5; parental adjusted SDS <-1; birth weight and/or length <-2 SD and failure to show catch-up growth by ≥4 years of age. Patients were treated with rhGH 0.035 mg/kg/day. The primary objective was to evaluate the long-term effect of rhGH on carbohydrate metabolism [including fasting glucose, stimulated glucose (2-h oral glucose tolerance test, OGTT) and glycated haemoglobin (HbA1c)]. Secondary objectives included evaluation of height parameters [body height, HSDS, height velocity (HV), HVSDS]; insulin-like growth factor 1 (IGF-I) and insulin-like growth factor-binding protein 3 (IGFBP-3) serum levels during treatment; and incidence and severity of adverse events (AEs).ResultsNone of the children developed diabetes mellitus within the first year of treatment. Mean levels of fasting glucose, HbA1c and 2-h OGTT values remained stable during the study period. Treatment with rhGH was effective, as documented by all height parameters. Mean HSDS improved from -3.39 at baseline to -2.57 at Year 1. Mean HV increased markedly from 4.25 cm/year at baseline to 8.99 cm/year during the first year. Similarly, mean peak-centred HVSDS increased from -2.13 at baseline to +4.16 at Year 1. Mean IGF-I SDS and IGFBP-3 SDS also increased within the first year (by +1.80 and +0.41, respectively). 13 patients (4.7%) did not respond adequately to treatment (HVSDS <1); they were withdrawn from the study. In total, 192 children (69.3%) experienced treatment-emergent AEs; most (98.7%) were mild-to-moderate, and the majority (96.5%) were unrelated to study treatment.ConclusionThis interim analysis shows that short children born SGA can be effectively and safely treated with rhGH and that rhGH treatment has no major impact on carbohydrate metabolism after the first year of treatment.

Project description:ObjectiveGrowth hormone (GH) treatment is known to be effective in increasing stature in children with a short stature born small for gestational age (SGA). This multicentre, randomized, open-label, comparative, phase III study aimed to evaluate the efficacy and safety of Growtropin-II (recombinant human GH) and to demonstrate that the growth-promoting effect of Growtropin-II is not inferior to that of Genotropin in children with SGA (NCT ID: NCT02770157).MethodsSeventy five children who met the inclusion criteria were randomized into 3 groups in a ratio of 2:2:1 (the study group [Growtropin-II, n = 30], control group [Genotropin, n = 30], and 26-week non-treatment group [n = 15]). The study and control groups received subcutaneous injections of Growtropin-II and Genotropin, respectively for 52 weeks, whereas the non-treatment group underwent a non-treatment observation period during weeks 0 to 26 and a dosing period during weeks 27 to 52 and additional dosing till week 78 only in re-consenting children.ResultsNo significant differences in demographic and baseline characteristics between the groups were observed. The mean ± standard deviation change difference in annualized height velocity (aHV) (study group - control group) was 0.65 ±2.12 cm/year (95% confidence interval [CI], -0.53 to 1.83), whereas the lower limit for the 2-sided 95% CI was -0.53 cm/year. Regarding safety, treatment-emergent adverse events (TEAEs) occurred in 53.33% children in the study group and 43.33% children in the control group; the difference in the incidence of TEAEs between the 2 treatment groups was not statistically significant (P = .4383). A total of 17 serious adverse events (SAEs) occurred in 13.33% children in the treatment groups, and no significant difference in incidence between groups (P = .7065) was seen. Two cases of adverse drug reaction (ADR) occurred in 2 children (3.33%): 1 ADR (injection site swelling or pain) occurred in 1 child (3.33%) each in the study and control groups.ConclusionsThis study demonstrates that the change in aHV from the baseline till 52 weeks with Growtropin-II treatment is non-inferior to that with Genotropin treatment in children with short stature born SGA. Growtropin-II is well-tolerated, and its safety profile is comparable with that of Genotropin over a 1-year course of treatment.

Project description:BACKGROUND:Long-term growth hormone (GH) treatments in short children born small for gestational age (SGA) restore lipid metabolism, but also increase insulin resistance. The aim of this study was to evaluate the influence of long-term GH therapy on lipid and glucose metabolism as well as its dose dependency in short Japanese children born SGA. METHODS:Eighty Japanese children with a short stature who were born SGA participated in this study; 65 were treated with fixed GH doses of 0.033 (low) or 0.067 (high) mg/kg/day for 260 weeks; 15 were untreated controls in the first year and were randomized to one of the two treatment groups at week 52. Serum cholesterol, glucose and insulin levels were regularly measured. An oral glucose tolerance test (OGTT) was conducted annually. RESULTS:The mean age at the start of GH therapy was approximately 5.3 years. Serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in the high dose group significantly decreased over time during GH therapy. In both dose groups for TC, and in the high dose group for LDL-C, the higher the baseline values, the greater the decrease after 260 weeks. The rate of the decrease observed after 260 weeks in patients with high LDL-C levels was greater in the high dose group. Based on the results of OGTT, no patient was classified as being diabetic; however, annual increases were observed in post-OGTT insulin levels. After 260 weeks, the homeostasis model assessment as an index of insulin resistance (HOMA-IR) increased, suggesting that insulin resistance developed over time with the GH treatment, while 36.6 % of the subjects entered puberty. CONCLUSIONS:Long-term continuous GH treatment for children born SGA may have a potentially beneficial effect on several parameters in lipid metabolism and does not adversely affect glucose metabolism. TRIAL REGISTRATION:GHLIQUID-1516, GHLIQUID-1517, Japan Pharmaceutical Information Center Clinical trial registration: JapicCTI-050132. Registered 13 September 2005. Retrospectively registered. JapicCTI-050137. Registered 13 September 2005. Retrospectively registered. ClinicalTrials.gov trial registration: NCT00184717. Registered 13 September 2005. Retrospectively registered.

Project description:Abstract Treatment of persistent short stature in children born small for gestational age (SGA) requires daily growth hormone (GH) injections that can be burdensome for patients and caregivers. Once-weekly somapacitan is a long-acting GH currently in phase 3 development for replacement therapy in children with GH deficiency. We report the 26-week results of the first phase 2, multinational, randomized, open-label, controlled, dose-finding trial (NCT03878446) investigating the efficacy and safety of somapacitan as treatment for short stature in children born SGA compared with daily GH (Norditropin®, Novo Nordisk A/S). A total of 62 (35.5% female) GH-treatment-naïve, prepubertal children received 0.16, 0.20 or 0.24 mg/kg/week subcutaneous (s.c.) somapacitan, or 0.035 or 0.067 mg/kg/day s.c. daily GH for 26 weeks (main phase). All children are subsequently included in an extension to this trial. The primary outcome was annualized height velocity (HV). At week 26, the estimated mean HV was: 8.9, 11.0 and 11.3 cm/year for 0.16 mg/kg/week (n=12), 0.20 mg/kg/week (n=13) and 0.24 mg/kg/week (n=12) somapacitan, respectively, versus 10.3 and 11.9 cm/year for 0.035 mg/kg/day (n=12) and 0.067 mg/kg/day (n=13) daily GH, respectively. A dose-dependent response in the estimated mean HV was observed with both somapacitan and daily GH. The effect of somapacitan on HV was not statistically significantly different compared with daily GH. A similar pattern was observed for change from baseline in height standard deviation score (SDS) and change from baseline in HV SDS. Consistent dose-dependent increases were observed in insulin-like growth factor-I (IGF-I) SDS with both somapacitan and daily GH. Exposure-response modeling of somapacitan exposure versus HV and IGF-I SDS vs. HV indicated an exposure-dependent increase in HV for both these parameters. Somapacitan was well tolerated at all doses investigated, with no safety or local tolerability issues identified. There were no clinically relevant findings with respect to glucose metabolism, and no detection of anti-drug antibodies in any of the dose groups. In conclusion, all investigated doses of weekly somapacitan were efficacious and well tolerated throughout the study period. Based on the totality of data on improvements in height-based parameters combined with exposure-response analyses, a somapacitan dose of 0.24 mg/kg/week appears as the most efficacious dose, providing similar efficacy, safety and tolerability to daily GH 0.067 mg/kg/day after 26 weeks of treatment. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:51 p.m. - 12:56 p.m.

Dataset Information

Long-term safety and efficacy of daily recombinant human growth hormone treatment in Japanese short children born small for gestational age: final report from an open and multi-center study.

Publications

Long-term safety and efficacy of daily recombinant human growth hormone treatment in Japanese short children born small for gestational age: final report from an open and multi-center study.

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