注射用重组人生长激素治疗特发性矮小症Ⅲ期临床试验研究

doi:10.12372/jcp.2023.22e1018

临床儿科杂志 ›› 2023, Vol. 41 ›› Issue (10): 685-691.doi: 10.12372/jcp.2023.22e1018

注射用重组人生长激素治疗特发性矮小症Ⅲ期临床试验研究

梁欢¹, 盛海², 卫海燕³, 杨玉⁴, 杜红伟⁵, 刘芳³, 杨利⁴, 王美娜⁵, 王莉², 马青², 张惠文¹(), 顾学范¹()

1.上海交通大学医学院附属新华医院上海市儿科医学研究所儿内分泌遗传科（上海 200092）
2.安徽安科生物工程（集团）股份有限公司基因工程制药安徽省重点实验室（安徽合肥 230088）
3.郑州大学附属儿童医院河南省儿童医院郑州儿童医院河南省儿童遗传代谢性疾病重点实验室（河南郑州 450000）
4.江西省儿童医院内分泌遗传代谢科（江西南昌 330006）
5.吉林大学第一医院小儿内分泌科（吉林长春 130021）

收稿日期:2022-07-25 出版日期:2023-10-15 发布日期:2023-10-08
通讯作者: 张惠文，电子信箱：zhanghuiwen@xinhuamed.com.cn;顾学范, 电子信箱：gu_xuefan@163.com
作者简介:共同第一作者：梁欢，盛海，卫海燕，杨玉，杜红伟

Phase Ⅲ clinical trial of recombinant human growth hormone for injection in treatment of idiopathic short stature

LIANG Huan¹, SHENG Hai², WEI Haiyan³, YANG Yu⁴, DU Hongwei⁵, LIU Fang³, YANG Li⁴, WANG Meina⁵, WANG Li², MA Qin², ZHANG Huiwen¹(), GU Xuefan¹()

1. Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
2. Anhui Anke Biotechnology (Group) Co., Ltd, Anhui Province Key Laboratory of Gene Engineering Pharmaceutical, Hefei 230088, Anhui, China
3. Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Henan Provincial Key Laboratory of Children’s Genetics and Metabolic Diseases, Zhengzhou 450000, Henan, China
4. Department of Endocrinology, Genetics and Metabolism, Jiangxi Provincial Children′s Hospital, Nanchang 330006, Jiangxi, China
5. Department of Pediatric Endocrinology, The First Hospital of Jilin University, Changchun 130021, Jilin, China

Received:2022-07-25 Online:2023-10-15 Published:2023-10-08

摘要/Abstract

摘要：

目的评价注射用重组人生长激素（rhGH）治疗中国青春期前特发性矮小症（ISS）的有效性和安全性。方法该研究为2016年12月27日至2020年07月30日，招募青春期前ISS患儿开展的一项随机、开放、空白对照、多中心的Ⅲ期临床试验。纳入受试者以3:3:1的比例随机分配至高剂量组、低剂量组和空白对照组，rhGH的给药周期为52周。观察治疗前后实际年龄的身高标准差积分变化（ΔHT SDS)，治疗结束时受试者的年生长速率（HV）和骨成熟情况，同时考察治疗期间药物安全性。结果共有150例受试者完成了试验。基线时各组受试者的年龄、骨龄、性别、身高、体重、体质指数及HT-SDS、年HV、胰岛素样生长因子1水平差异均无统计学意义（P>0.05）。全数据集分析（FAS）和符合方案集（PPS）分析均发现，第26、39、52周，高剂量组、低剂量组和对照组之间ΔHT SDS的差异均有统计学意义（P<0.001）；两两比较发现，高剂量和低剂量组的ΔHT SDS均高于对照组，差异均有统计学意义（P<0.05）。FAS分析发现，第13、26、39、52周，高剂量组、低剂量组和对照组之间HV的差异均有统计学意义（P<0.001）；两两比较发现，高剂量和低剂量组的HV均高于对照组，差异均有统计学意义（P<0.05）。第52周，各组之间骨成熟差异无统计学意义（P>0.05）。研究过程中，无严重不良反应发生。结论注射用rhGH治疗ISS疗效确切，患儿用药52周后有明显的身高增长，但对终身高的作用和安全性尚需更多的观察与评估。

关键词: 特发性矮小症, 重组人生长激素, 有效性, 安全性

Abstract:

Objective To evaluate the efficacy and safety of recombinant human growth hormone (rhGH) for injection in the treatment of prepubertal children with idiopathic short stature (ISS) in China. Methods This study was a randomized, open-label, controlled, multicenter, phase Ⅲ clinical trial of prepubertal ISS from December 27, 2016 to July 30, 2020. Participants were randomly assigned to the high-dose group, low-dose group and control group in a ratio of 3:3:1, and the administration cycle of rhGH was 52 weeks. Changes in height standard deviation scores (ΔHT-SDS) of actual age before and after treatment, annual height velocity (HV) and bone maturity at the end of treatment were observed. At the same time, the rhGH safety during treatment was investigated. Results A total of 150 participants completed the trial. At baseline, there were no significant differences in age, bone age, sex, height, weight, body mass index, HT-SDS, annual HV and insulin-like growth factor 1 levels among all groups (P>0.05). Both full analysis set (FAS) and per protocol set (PPS) analysis found statistically significant differences in ΔHT SDS among the high-dose, low-dose and control groups at week 26, 39 and 52 (P<0.001). Pairwise comparison showed that ΔHT SDS in the high-dose and low-dose groups were higher than those in the control group, and the differences were statistically significant (P<0.05). FAS analysis showed statistically significant differences in HV among the high-dose, low-dose and control groups at week 13, 26, 39, and 52 (P<0.001). Pairwise comparison showed that HV in the high-dose and low-dose groups was higher than that in the control group, and the differences were statistically significant (P<0.05). At week 52, there was no significant difference in bone maturity among all groups (P>0.05). During the study, no serious adverse reaction occurred in each group. Conclusions The rhGH injection is effective in treating ISS, and there is a significant growth in stature after 52 weeks of treatment, but more observation and evaluation of the effect and safety of lifetime height are needed.

Key words: idiopathic short stature, recombinant human growth hormone, efficacy, safety

梁欢, 盛海, 卫海燕, 杨玉, 杜红伟, 刘芳, 杨利, 王美娜, 王莉, 马青, 张惠文, 顾学范. 注射用重组人生长激素治疗特发性矮小症Ⅲ期临床试验研究[J]. 临床儿科杂志, 2023, 41(10): 685-691.

LIANG Huan, SHENG Hai, WEI Haiyan, YANG Yu, DU Hongwei, LIU Fang, YANG Li, WANG Meina, WANG Li, MA Qin, ZHANG Huiwen, GU Xuefan. Phase Ⅲ clinical trial of recombinant human growth hormone for injection in treatment of idiopathic short stature[J]. Journal of Clinical Pediatrics, 2023, 41(10): 685-691.

图/表 4

图1

表1

表2

表3

参考文献 23

[1]	Wit JM, Clayton PE, Rogol AD, et al. Idiopathic short stature: definition, epidemiology, and diagnostic evaluation[J]. Growth Horm IGF Res, 2008, 18(2): 89-110. doi: 10.1016/j.ghir.2007.11.004 pmid: 18182313
[2]	Cohen P, Rogol AD, Deal CL, et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop[J]. J Clin Endocrinol Metab, 2008, 93(11): 4210-4217. doi: 10.1210/jc.2008-0509
[3]	Wu S, Liu QQ, Gu W, et al. A Retrospective analysis of patients with short stature in the south of China between 2007 and 2015[J]. Biomed Res Int, 2018, 2018: 5732694.
[4]	陈伟伟, 刘焕欣, 刘晶, 等. 儿童身材矮小的病因分析及遗传学诊断[J]. 中国当代儿科杂志, 2019, 21(4): 381-386.
[5]	Finkelstein BS, Imperiale TF, Speroff T, et al. Effect of growth hormone therapy on height in children with idiopathic short stature: a meta-analysis[J]. Arch Pediatr Adolesc Med, 2002, 156(3): 230-240. doi: 10.1001/archpedi.156.3.230
[6]	Grimberg A, DiVall SA, Polychronakos C, et al. Guidelines for growth hormone and insulin-like growth factor-i treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-Ⅰdeficiency[J]. Horm Res Paediatr, 2016, 86(6): 361-397. doi: 10.1159/000452150
[7]	Lee MM. Clinical practice. Idiopathic short stature[J]. N Engl J Med, 2006, 354(24): 2576-2582. doi: 10.1056/NEJMcp060828
[8]	Wu D, Chen RM, Chen SK, et al. Final adult height of children with idiopathic short stature: a multicenter study on GH therapy alone started during peri-puberty[J]. BMC Pediatr, 2020, 20(1): 138. doi: 10.1186/s12887-020-02034-8 pmid: 32222149
[9]	Ying YQ, Hou L, Liang Y, et al. Efficacy and safety of recombinant human growth hormone in treating Chinese children with idiopathic short stature[J]. Growth Horm IGF Res, 2018, 42-43: 80-85.
[10]	Gubitosi-Klug RA, Cuttler L. Idiopathic short stature[J]. Endocrinol Metab Clin North Am, 2005, 34(3): 565-580. doi: 10.1016/j.ecl.2005.04.003
[11]	中华医学会儿科学分会内分泌遗传代谢学组, 中华儿科杂志编辑委员会, 梁雁. 基因重组人生长激素儿科临床规范应用的建议[J]. 中华儿科杂志, 2013, 51(6): 426-432.
[12]	Albertsson-Wikland K, Aronson AS, Gustafsson J, et al. Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency[J]. J Clin Endocrinol Metab, 2008, 93(11): 4342-4350. doi: 10.1210/jc.2008-0707
[13]	Common Terminology Criteria for Adverse Events (CTCAE) Version 5[EB/OL]. US Department of Health and Human Services, National Institutes of Health, National Cancer Institute, 2017 [2022-07-25]. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50.
[14]	Chung WY, Yoo HW, Hwang JS, et al. Effect of growth hormone therapy on height velocity in Korean children with idiopathic short stature: a phase Ⅲ randomised controlled trial[J]. Horm Res Paediatr, 2018, 90(1): 44-53. doi: 10.1159/000491016
[15]	Kim J, Suh BK, Ko CW, et al. Recombinant growth hormone therapy for prepubertal children with idiopathic short stature in Korea: a phase Ⅲ randomized trial[J]. J Endocrinol Invest, 2018, 41(4): 475-483. doi: 10.1007/s40618-017-0786-8 pmid: 29103133
[16]	Kim HS, Yang SW, Yoo HW, et al. Efficacy of short-term growth hormone treatment in prepubertal children with idiopathic short stature[J]. Yonsei Med J, 2014, 55(1): 53-60. doi: 10.3349/ymj.2014.55.1.53
[17]	Child CJ, Quigley CA, Cutler GB Jr, et al. Height gain and safety outcomes in growth hormone-treated children with idiopathic short stature: experience from a prospective observational study[J]. Horm Res Paediatr, 2019, 91(4): 241-251. doi: 10.1159/000500087
[18]	Yuan J, Fu J, Wei H, et al. A randomized controlled phase 3 Study on the efficacy and safety of recombinant human growth hormone in children with idiopathic short stature[J]. Front Endocrinol (Lausanne), 2022, 13: 864908. doi: 10.3389/fendo.2022.864908
[19]	Deodati A, Cianfarani S. Impact of growth hormone therapy on adult height of children with idiopathic short stature: systematic review[J]. BMJ, 2011, 342: c7157. doi: 10.1136/bmj.c7157
[20]	Maniatis AK, Casella SJ, Nadgir UM, et al. Safety and efficacy of lonapegsomatropin in children with growth hormone deficiency: enliGHten trial 2-year results[J]. J Clin Endocrinol Metab, 2022, 107(7): e2680-e2689. doi: 10.1210/clinem/dgac217 pmid: 35428884
[21]	Mauras N, Attie KM, Reiter EO, et al. High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: a randomized, multicenter trial. Genentech, Inc., Cooperative Study Group[J]. J Clin Endocrinol Metab, 2000, 85(10): 3653-3660.
[22]	Darendeliler F, Ranke MB, Bakker B, et al. Bone age progression during the first year of growth hormone therapy in pre-pubertal children with idiopathic growth hormone deficiency, Turner syndrome or idiopathic short stature, and in short children born small for gestational age: analysis of data from KIGS (Pfizer International Growth Database)[J]. Horm Res, 2005, 63(1):40-47. pmid: 15627781
[23]	Ross JL, Lee PA, Gut R, et al. Attaining genetic height potential: analysis of height outcomes from the ANSWER Program in children treated with growth hormone over 5 years[J]. Growth Horm IGF Res, 2015, 25(6): 286-293. doi: 10.1016/j.ghir.2015.08.006 pmid: 26363846

项目	对照组(n=24)	低剂量组(n=72)	高剂量组(n=72)	统计量	P
年龄($\bar{x}±s$)/岁	6.8±1.9	7.3±2.0	7.4±2.2	F=0.81	0.446
男性[n(%)]	17(70.8)	49(68.1)	53(73.6)	χ²=0.54	0.765
汉族[n(%)]	24(100.0)	68(94.4)	71(98.6)	χ²=3.01	0.223
骨龄($\bar{x}±s$)/岁	5.8±1.9	5.9±2.1	5.9±1.9	F=0.02	0.985
身高($\bar{x}±s$)/cm	110.8±10.0	113.4±10.1	114.4±11.0	F=1.04	0.356
HT-SDS($\bar{x}±s$)	-2.4±0.5	-2.4±0.6	-2.3±0.5	F=0.56	0.574
HV[M(P₂₅~P₇₅)]/cm·a^-1	2.6(1.8~3.7)	2.9(1.9~3.8)	3.1(2.4~3.8)	H=3.24	0.198
体重($\bar{x}±s$)/kg	19.5±5.0	20.3±5.1	20.1±4.6	F=0.25	0.780
体质指数($\bar{x}±s$)/kg·m^-2	15.6±2.0	15.5±2.2	15.1±1.3	F=1.10	0.334
IGF-1[M(P₂₅~P₇₅)]/ng·mL^-1	102.5(66.9~127.5)	89.55(68.7~117.0)	89.70(59.0~110.0)	H=1.59	0.451
IGFBP3[M(P₂₅~P₇₅)]/ng·mL^-1	2 670.0(2 130.0~2 850.0)	2 630.0(2 220.0~3 040.0)	2 220.0(1 840.0~2 760.0)	H=6.61	0.037

项目	对照组	低剂量组	高剂量组	F值	P
ΔHT-SDS(PPS)
第13周	0.3±0.3	0.4±0.4	0.4±0.3	1.08	0.343
第26周	0.1±0.2	0.5±0.3¹⁾	0.5±0.2¹⁾	28.35	<0.001
第39周	0.3±0.3	0.7±0.4¹⁾	0.8±0.4¹⁾	16.36	<0.001
第52周	0.1±0.2	0.8±0.3¹⁾	0.9±0.3¹⁾	63.45	<0.001
ΔHT-SDS(FAS)
第13周	0.2±0.3	0.4±0.4	0.3±0.3	1.19	0.306
第26周	0.1±0.2	0.5±0.3¹⁾	0.5±0.2¹⁾	22.71	<0.001
第39周	0.3±0.3	0.7±0.4¹⁾	0.7±0.4¹⁾	13.47	<0.001
第52周	0.1±0.2	0.8±0.4¹⁾	0.8±0.4¹⁾	41.89	<0.001
HV(FAS)/cm·a^-1
第13周	7.4±2.7	11.5±4.3¹⁾	12.3±3.3¹⁾	15.20	<0.001
第26周	6.6±1.7	10.3±2.6¹⁾	10.7±2.1¹⁾	29.98	<0.001
第39周	6.1±1.3	9.8±1.9¹⁾	10.4±1.8¹⁾	56.05	<0.001
第52周	5.8±1.1	9.3±1.6¹⁾	10.1±1.3¹⁾	75.45	<0.001
ΔBA/ΔCA(FAS)
第26周	-	1.1±0.4	1.1±0.5	-	-
第52周	0.97±0.4	1.1±0.3	1.2±0.5	2.40	0.094

指标	对照组(n=24)	低剂量组(n=72)	高剂量组(n=72)	χ²值	P
TEAE	14(58.3)	64(88.9)	62(86.1)	12.80	0.002
ADR	0(0)	14(19.4)	12(16.7)	5.34	0.069
SAE	0(0)	3(4.2)	4(5.6)	-	0.680¹⁾
SADR	0(0)	0(0)	0(0)	-	-
导致退出试验TEAE	0(0)	0(0)	1(1.4)	-	-
导致退出试验ADR	0(0)	0(0)	1(1.4)	-	-
导致剂量调整TEAE	0(0)	0(0)	0(0)	-	-
导致剂量调整ADR	0(0)	0(0)	0(0)	-	-
导致药物暂停TEAE	0(0)	42(58.3)	41(56.9)	27.37	<0.001
导致药物暂停ADR	0(0)	10(13.9)	11(15.3)	4.06	0.131
严重程度≥3级TEAE	0(0)	3(4.2)	4(5.6)	-	0.680¹⁾
严重程度≥3级ADR	0(0)	0(0)	1(1.4)	-	-

注射用重组人生长激素治疗特发性矮小症Ⅲ期临床试验研究

Phase Ⅲ clinical trial of recombinant human growth hormone for injection in treatment of idiopathic short stature

RichHTML

PDF (PC)

赞

可视化

摘要/Abstract

引用本文

使用本文

图/表 4

参考文献 23

相关文章 9

Metrics

本文评价

推荐阅读 0

[1]	于丽婷, 沈星伟, 王卓, 张顺国, 高怡瑾. 福沙匹坦预防儿童肿瘤患者高致吐化疗药物相关恶心呕吐有效性和安全性评估[J]. 临床儿科杂志, 2023, 41(8): 604-609.
[2]	查新祎, 王依闻, 毛朋亮, 陈鸣艳, 蒋玮, 王华伟, 胡雪峰, 施丽萍, 朱雪萍, 钱继红. 乳糖酶添加剂对早产儿乳糖不耐受有效性及安全性：一项前瞻性、多中心、随机对照研究[J]. 临床儿科杂志, 2023, 41(1): 34-41.
[3]	陈钰波, 李宇宁. 益生菌在婴幼儿消化道炎症性和功能性疾病中应用进展[J]. 临床儿科杂志, 2022, 40(11): 869-874.
[4]	孙洁，牛乐乐，鲍鹏丽，等. Crouzon 综合征合并生长激素缺乏症1 例报告及重组人生长激素治疗随诊[J]. 临床儿科杂志, 2021, 39(7): 533-.
[5]	梁祎，刘晶，冷丽娜，等. 重组人生长激素替代治疗对矮身材儿童非对称性二甲基精氨酸水平的影响[J]. 临床儿科杂志, 2021, 39(12): 923-.
[6]	翟亦晖，徐虹，沈茜，等. 重组人生长激素在慢性腹膜透析儿童中的应用[J]. 临床儿科杂志, 2019, 37(5): 381-.
[7]	何玥综述陈超审校. 新生儿高流量鼻导管通气的安全性研究进展[J]. 临床儿科杂志, 2019, 37(1): 67-70.
[8]	王立敏,赵一明,吕秀敏,李桂梅. 生长激素缺乏症患儿重组人生长激素治疗前、后肾上腺皮质功能的变化[J]. 临床儿科杂志, 2016, 34(12): 881-.
[9]	任思思，王栋芳，钟朝晖. 吸附无细胞百白破灭活脊髓灰质炎和b型流感嗜血杆菌（结合）联合疫苗的安全性和免疫原性的meta分析[J]. 临床儿科杂志, 2014, 32(3): 271-277.