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 Published:2023-10-15 Online: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.

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参考文献 23

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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

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