Efficacy and safety of a biosimilar recombinant human growth hormone (r-hGH Cristalia) compared with reference r-hGH in children with growth hormone deficiency (CERES study): A randomized, multicentric, investigator-blind, phase 3 trial.,Growth Hormone and IGF Research

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Efficacy and safety of a biosimilar recombinant human growth hormone (r-hGH Cristalia) compared with reference r-hGH in children with growth hormone deficiency (CERES study): A randomized, multicentric, investigator-blind, phase 3 trial.
Growth Hormone and IGF Research ( IF 1.4 ) Pub Date : 2019-08-02 , DOI: 10.1016/j.ghir.2019.07.003
M A Czepielewski ₁ , Q Garret ₂ , S A C Vencio ₃ , N Rassi ₄ , J S Felicio ₅ , M S Faria ₆ , C C P Senn ₇ , M D Bronstein ₈ , M J A G Cerqueira ₉ , A C L Neves ₁₀ , J A Sgarbi ₁₁ , A M Spinola-Castro ₁₂ , M P R Cunha ₁₃ , F Bandeira ₁₄ , O Toffoletto ₁₅ , J Afiune ₁₅ , R Baradelli ₁₅ , D G Rodrigues ₁₅ , M Scharf ₇

Affiliation

Serviço de Endocrinologia, Hospital de Clínicas de Porto Alegre, UFRGS, Porto Alegre, RS, Brazil.
CEDOES, Vitória, ES, Brazil.
ICF - Instituto de Ciências Farmacêuticas de Estudos e Pesquisas Ltda, Aparecida de Goiânia, GO, Brazil.
Hospital Alberto Rassi - HGG, Goiânia, GO, Brazil.
Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil.
Hospital Universitário da Universidade Federal do Maranhão/HU/UFMA, São Luis, MA, Brazil.
Centro de Diabetes de Curitiba, Curitiba, PR, Brazil.
CPQUALI Pesquisa Clínica Ltda, São Paulo, SP, Brazil.
Instituto de Ensino e Pesquisa Clínica do Ceará, Fortaleza, CE, Brazil.
Instituto de Medicina Integral Professor Fernando Figueira - IMIP, Recife, PE, Brazil.
Unidade de Pesquisa Clínica de Marília Ltda (UpCliM), Marília, SP, Brazil.
Universidade Federal de São Paulo - UNIFESP/EPM, São Paulo, SP, Brazil.
CAEP - Centro Avançado de Estudos e Pesquisas Ltda, Campinas, SP, Brazil.
Centro de Pesquisas Médicas Básica e Clínica Ltda, Recife, PE, Brazil.
Cristália Produtos Químicos Farmacêuticos Ltda, Itapira, SP, Brazil.

Objective

The CERES study was a randomized, multicenter, investigator-blind trial aimed to evaluate the efficacy and safety of a recombinant human growth hormone (r-hGH) developed by Cristalia, as a biosimilar product, with analytical, functional and pharmacokinetics similarities comparable to Genotropin™, in children with growth hormone deficiency (GHD).

Design

A total of 135 naïve prepubertal children with GHD were recruited, of whom 97 were randomized in 14 Brazilian sites to received either r-hGH Cristalia (n = 49) or Genotropin™ (n = 48). Efficacy was evaluated considering the height standard deviation score (SDS) and growth velocity as auxological parameters, IGF-1 and IGFBP-3 were measured as pharmacodynamic parameters during 12 months treatment time. Safety was assessed by monitoring adverse events, immunogenicity, blood count with platelets, biochemical profile and hormonal levels particularly fasting glucose, insulin and HbA1C.

Results

The auxological parameters and IGF-1 and IGFBP-3 levels were comparable between both groups of patients. At end of study or the 12th month treatment, the means growth velocity was 9.7 cm/year and 9.5 cm/year, for r-hGH Cristalia and Genotropin™, respectively. The ANCOVA mean difference between the groups was 0.16 cm/year to Cristalia group (CI 95% = −0.72 to 1.03 cm/year). There was no difference in adherence among the treatment groups. The safety profile was comparable between groups.

Conclusions

The clinical similarity between r-hGH and Genotropin™ was demonstrated within 12 month of treatment. On the basis of comparability of quality, safety, and efficacy to the reference product, r-hGH from Cristalia can be considered a cost-effective therapeutic option for patients with growth disorders.

中文翻译：

生物仿制重组人生长激素（r-hGH Cristalia）与参考r-hGH在生长激素缺乏症患儿中的疗效和安全性（CERES研究）：一项随机，多中心，研究者盲的3期临床试验。

目的

CERES研究是一项随机，多中心，研究者盲试验，旨在评估Cristalia开发的作为生物仿制药的重组人生长激素（r-hGH）的功效和安全性，其分析，功能和药代动力学相似之处可与Genotropin媲美。 ™，适用于患有生长激素缺乏症（GHD）的儿童。

设计

总共招募了135名初生的GHD青春期前儿童，其中97名被随机分配到巴西的14个地区，接受了r-hGH Cristalia（n  = 49）或Genotropin™（n  = 48）。以身高标准差评分（SDS）和生长速度作为生理参数评估疗效，在治疗12个月期间测量IGF-1和IGFBP-3作为药效学参数。通过监测不良事件，免疫原性，血小板计数，生化特征和激素水平（尤其是空腹血糖，胰岛素和HbA1C）来评估安全性。

结果

两组患者的血流参数，IGF-1和IGFBP-3水平相当。在研究结束或第12个月治疗后，r-hGH Cristalia和Genotropin™的平均生长速度分别为9.7 cm /年和9.5 cm /年。与Cristalia组相比，两组之间的ANCOVA平均差异为0.16 cm /年（CI 95％= -0.72至1.03 cm /年）。治疗组之间的依从性没有差异。各组之间的安全性相当。