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Multi-centre phase IV trial to investigate the immunogenicity of a new liquid formulation of recombinant human growth hormone in adults with growth hormone deficiency.

ABSTRACT: PURPOSE:To investigate whether a new liquid formulation of recombinant human growth hormone (r-hGH) induces the production of binding antibodies (BAbs) in adults with congenital or adult-onset growth hormone deficiency (GHD). METHODS:Men or women aged 19-65 years with adult growth hormone deficiency who were r-hGH-naïve or had stopped treatment ? 1 month before screening were treated with between 0.15 and 0.30 mg/day r-hGH liquid formulation for 39 weeks. The primary endpoint was the proportion of patients who developed BAbs at any time. Secondary endpoints were the proportion of patients with BAbs who became positive for neutralising antibodies, the effects on biomarkers of r-hGH exposure, safety, and adherence to treatment downloaded from the easypod™ connect software. RESULTS:Seventy-eight patients (61.5% men) with mean age 44.5 years (range 21-65) started and 68 (87.2%) completed the 39-week treatment period. 82.1% were treatment naïve; all were negative for BAbs to r-hGH at baseline. The median (interquartile range) duration of treatment [273 (267.0-277.0) days] was consistent with patients receiving the required doses, and mean treatment adherence measured using easypod™ connect was 89.3%. The proportion of patients who developed BAbs was 0% (95% confidence interval 0-4.68%) and biomarker profiles were consistent with exposure to r-hGH. 92.3% of patients reported ? 1 adverse event during treatment. Most events were mild or moderate and no new safety concerns were detected. CONCLUSIONS:The low immunogenicity profile of the liquid formulation was consistent with that for the freeze-dried formulation, and no new safety concerns were reported.

SUBMITTER: Johannsson G

PROVIDER: S-EPMC6061248 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Project description:Somatropin is recombinant human growth hormone (GH) used for the treatment of growth failure in children and GH deficiency in adults. Two concentrations of a liquid formulation have been developed: 5.83 and 8.0 mg/mL. This trial compared the pharmacokinetics (PK), safety and tolerability of these two liquid concentrations against the freeze-dried (FD) formulation in healthy volunteers.In an open-label, single-centre, three-way crossover study, volunteers (aged 18-45 years) were given subcutaneous injections of the reconstituted FD and two liquid formulations in random sequential order, each at 4 mg/dose, with a 1-week wash-out period between doses. To suppress endogenous GH secretion, intravenous somatostatin was infused continuously 1 hour before to 24 hours after each dose, achieving a cumulative dose of 3 mg. Primary PK endpoints were area under the serum concentration-time curve (AUC0-t) and maximum serum concentration (Cmax). For each of the two liquid formulations, bioequivalence with the FD formulation was concluded if the 95% confidence intervals (CIs) for the estimated test/reference ratios of geometric means of AUC0-t and Cmax were within the standard pre-specified acceptance range (0.80-1.25).Fifteen men and 15 women enrolled (safety population, n = 30; PK population, n = 28). Bioequivalence with the FD formulation could be shown for both liquid formulations. The ratios of geometric means (95% CI) were 1.046 (0.980, 1.117) and 0.991 (0.929, 1.058) for AUC0-t and 0.954 (0.875, 1.040) and 0.955 (0.876, 1.041) for Cmax for the 5.83 and 8.0 mg/mL formulations, respectively. No significant differences between the three treatments in half-lives, time to reach Cmax, clearance or volume of distribution were observed. After injection, the most common side-effects were pain or injection-site reactions (all of mild intensity). There were no clinically significant abnormal vital signs, ECG or laboratory findings. There were 56 treatment-related adverse events (AEs): 49 mild, 6 moderate and 1 severe (vomiting). No serious AEs occurred. The pattern of AEs was as expected and all resolved by study end.Both concentrations of a new liquid multi-dose formulation are bioequivalent to the FD reference formulation and all are well tolerated.NCT01034735.

Project description:INTRODUCTION:Growth hormone (GH) secretion and release is a complex and highly regulated process. Any alteration disturbing synthesis, secretion or biological action of GH, results into growth hormone deficiency (GHD). GHD is of two types-isolated growth hormone deficiency (IGHD) and combined pituitary hormone deficiency (CPHD), of which IGHDis more common. The genes implicated in its etiology are growth hormone 1(GH1) and receptor of growth hormone-releasing hormone (GHRHR). Mutations within the coding region and/or either entire or partial deletions of the GH1gene lead to IGHD. In addition, GH1 possesses upstream regulatory elements and a promoter with binding sites for various transcription factors, which control its expression. AIM:The study was planned with an aim to identify entire GH1 locus deletion, mutations in the GH1 coding region and sequence variations (polymorphisms) in the promoter region of the gene in patients with IGHD. MATERIALS AND METHODS:Thirty patients clinically diagnosed with IGHD and 30 healthy individuals who formed the controls were enrolled for the study. Genomic DNA was isolated from peripheral blood sample and processed for amplification of the desired regions followed by direct sequencing and/or restriction endonuclease digestion. RESULTS:Out of the 30 IGHD patients screened, 20% of the cases showed consanguinity and 16% had a positive family history. Seven percentage of the patients showed homozygous deletion of the GH1gene while rest of them had heterozygous deletion. Screening of the coding region of GH1 showed sequence variations in exon 1 in 20% of the patients whereas the promoter region showed the presence of polymorphisms-rs2005171 in 20%, rs2005172 in 15% and rs11568828 in 18% of the cases. The haplotype comprising rs2005171 and rs2005172 was observed in four patients. CONCLUSION:The present study is an attempt to characterize the GH1 locus in IGHD patients. To the best of our knowledge this is the first study of its kind where entire GH1locus, upstream regulatory elements and promoter region have been studied. Such an analysis would provide valuable information on the etiology of IGHD.

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Multi-centre phase IV trial to investigate the immunogenicity of a new liquid formulation of recombinant human growth hormone in adults with growth hormone deficiency.

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