中国循证儿科杂志 ›› 2021, Vol. 16 ›› Issue (5): 368-373.

• 论著 • 上一篇    下一篇

51号外显子跳读药物治疗杜氏肌营养不良的疗效和安全性Meta分析

唐亮1, 陈晓晴1谭伟强2    

  1. 1 广州中医药大学第一附属医院新生儿科 广州,510405;2 广州中医药大学针灸康复临床医学院 广州,510405
  • 收稿日期:2021-09-06 修回日期:2021-10-25 出版日期:2021-10-25 发布日期:2021-10-25
  • 通讯作者: 陈晓晴

Exon 51 skipping for Duchenne muscular dystrophy: A meta-analysis

TANG Liang1,CHEN Xiaoqing1, TAN Weiqiang2   

  1. 1 Department of Neonatology, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China;2 Acupuncture and Rehabilitation Clinical School of Guangzhou University of Chinese Medicine, Guangzhong 510405, China
  • Received:2021-09-06 Revised:2021-10-25 Online:2021-10-25 Published:2021-10-25
  • Contact: CHEN Xiaoqing

摘要: 背景:目前51号外显子跳读药物治疗杜氏肌营养不良(DMD)的临床研究较少,其疗效及安全性尚不明确。 目的:系统评价51号外显子跳读药物治疗DMD的疗效和安全性。 设计:系统评价/Meta分析。 方法:计算机检索英文数据库(PubMed、Embase、The Cochrane Library、clinicaltrials.gov)和中文数据库(中国知网、中国生物医学文献数据库、万方数据库和维普中文期刊全文数据库),纳入51号外显子跳读药物Eteplirsen、Drisapersen、Suvodirsen和SRP-5051治疗DMD的RCT,检索时间为建库至2021年10月21日。按照 Cochrane 手册推荐的RCT偏倚风险评估工具评价纳入文献的偏倚风险。采用RevMan 5.3软件进行Meta分析。 主要结局指标:治疗24周时6 min步行试验(6MWT)距离、北极星移动评价量表(NSAA)评分。 结果:共纳入5篇RCT文献322例DMD患儿,Eteplirsen 1篇,Drisapersen 4篇。文献偏倚风险评价:关于Drisapersen文献均采用中央随机化系统, 关于Eteplirsen文献未说明随机化方法以及是否实施分配隐藏,选择偏倚风险高;除1篇文献未对结局评估者施盲外,其余文献均对研究对象、研究实施者和研究评估者施盲,实施偏倚和测量偏倚风险低;5篇RCT均为注册研究,均无数据缺失,故失访偏倚和报告偏倚风险低。Meta分析显示,试验组与对照组相比,治疗24周时6MWT距离平均变化值(MD=-9.16,95%CI:-21.94~3.62,P=0.16)和NSAA评分(MD=1.20,95%CI:-2.35~4.75,P=0.51)差异均无统计学意义。 Drisapersen组肾毒性(29.0% vs 16.0%,RR=2.2,95%CI:1.2~4.0,P=0.01)和局部不良反应(52.4% vs 12.0%,RR=7.4,95%CI:3.4~15.7,P<0.001)发生率高于对照组,差异有统计学意义。 结论:51号外显子跳读药物治疗24周时的疗效不确定,并可能出现肾毒性、局部不良反应等。

关键词: 杜氏肌营养不良, Eteplirsen, Drisapersen, 随机对照试验, Meta分析

Abstract: Background: There are few clinical studies on the efficacy and safety of exon 51 skipping therapy for Duchenne muscular dystrophy(DMD),and the efficacy and safety are not clear. Objective: To systematically evaluate the efficacy and safety of exon 51 skipping therapies for DMD. Design: Systematic review and meta-analysis. Methods: PubMed, Embase, The Cochrane Library, clinicaltrials.gov, CBM, CNKI, WanFang Data and VIP databases were electronically searched to collect RCTs related to exon 51 skipping Eteplirsen, Drisapersen, Suvodirsen and SRP-5051 for DMD. The retrieval period was from the establishment of the database to October 21, 2021. The risk of bias assessment tool for RCT recommended by the Cochrane Handbook was used to evaluate the the included literature. Then meta-analysis was performed using RevMan 5.3 software. Main outcome measures: Changes in 6-minute walk test (6MWT) and North Star Ambulatory Assessment (NSAA) scores from baseline to 24 weeks after treatment. Results: A total of 5 RCTs involving 322 DMD children were included, investigating Eteplirsen in one study and Drisapersen in 4 studies. As for literature risk of bias evaluation, the specific method of randomization and whether allocation concealment was implemented were not explained in one literature about Eteplirsen. Except for one study that did not blind the evaluator of outcome, all the other studies were blind to the study object, the study implementor and the study evaluator, and the risk of implementation bias and measurement bias was low. All 5 RCTs were registered with no missing data, so the risk of loss of follow-up bias and reporting bias were low. The results of meta-analysis showed that there were no significant differences in changes in 6MWT(MD=-9.16, 95%CI: -21.94~3.62, P=0.16) and NSAA scores (MD=1.20, 95%CI: -2.35~4.75, P=0.51) between the treated group and placebo group. Incidence of renal toxicity (29.0% vs 16.0%, RR=2.2, 95%CI:1.2~4.0, P=0.01)and injection site reactions (52.4% vs 12.0%, RR=7.4, 95%CI:3.4~15.7,P<0.001) in the Drisapersen group was higher than that in placebo group, and the difference was statistically significant. Conclusion: The therapeutic effect of exon 51 skipping on DMD at 24 week is not significant, and there may be side effects such as renal toxicity and injection site reactions.

Key words: Duchenne muscular dystrophy, Eteplirsen, Drisapersen, Randomized controlled trial, Meta-analysis