国产注射用A型肉毒毒素治疗脑卒中后上肢痉挛的安全性和疗效的随机双盲对照研究

Abstract

目的 评价国产注射用A型肉毒毒素200 U注射剂量(如合并拇指肌张力障碍的受试者注射240 U)治疗脑卒中后上肢痉挛的安全性和有效性.方法 本研究是一项多中心、分层区组随机、双盲、安慰剂平行对照的临床试验,所有受试者(来自2014年9月至2016年2月的15家临床中心)签署知情同意后书后采用分层区组随机法按2∶1比例随机分配到试验组(给予国产注射用A型肉毒毒素200 U或240 U,n=118)和对照组(辅料成分,不含A型肉毒毒素,n=60).试验分2个阶段:核心试验(1周筛选期、12周双盲治疗期);扩展试验(对核心阶段的两组患者序贯进行开放治疗,观察期6周).受试者在注射后第1、4、6、8、12、16、18周来院随访,并对患者腕部屈肌、四指屈肌、拇指屈肌进行改良Ashworth量表(Modified Ashworth Scale,MAS)、功能残疾量表、总体评估量表评分.主要疗效指标为试验组和对照组治疗第6周时的MAS评分较基线的变化值.结果 (1)主要疗效指标显示,试验组治疗第6周腕屈肌肌张力MAS评分较基线变化-1.00(-2.00,-1.00)分,对照组较基线变化0.00(-0.50,0.00)分,差异有统计学意义(Z=6.618,P＜0.01),试验组疗效优于对照组.(2)安全性结果显示:核心阶段:试验组有10例发生13次不良反应,发生率为8.47％(10/118),对照组有3例发生3次不良反应,发生率为5.00％ (3/60),全部为轻到中度不良反应,无重度不良反应发生,试验组与对照组在不良反应发生率上差异无统计学意义.扩展阶段:3例患者发生4次不良反应,发生率为1.95％(3/154),严重程度全为轻度,无重度不良反应发生.结论 国产注射用A型肉毒毒素治疗脑卒中后上肢痉挛是安全、有效的.

Objective To evaluate the safety and efficacy of botulinum toxin type A for injection in the treatment of post-stroke upper limb spasticity (dosage was 200 U,or 240 U if combined with thumb spasticity).Methods The study was a multi-center,stratified block randomized,double-blind,placebocontrolled trial.All the qualificd subjects were from 15 clinical centers from September 2014 to February 2016.They were randomized (2∶1) to injections of botulinum toxin type A made in China (200-240 U;n =118) or placebo (n =60) in pivotal phase after informed consent signed.The study was divided into two stages.The pivotal trial phase included a one-week screening,12-week double-blind treatment,followed by an expanded phase which included six-week open-label treatment.The tone of the wrist,finger,thumb flexors was assessed at baseline and at weeks 0,1,4,6,8,12,16 and 18 using Modified Ashworth Scale (MAS),disability in activities of daily living was rated using the Disability Assessment Scale and impaction on pain,muscle tone and deformity was assessed using the Global Assessment Scale.The primary endpoint was the score difference between botulinum toxin type A and placebo groups in the tone of the wrist flexor using MAS at six weeks compared to baseline.Results Muscle tone MAS score in the wrist flexor of botulinum toxin type A and placebo groups at six weeks changed-1.00 (-2.00,-1.00) and 0.00 (-0.50,0.00) respectively from baseline.Botulinum toxin type A was significantly superior to placebo for the primary endpoint (Z =6.618,P ＜ 0.01).The safety measurement showed 10 subjects who received botulinum toxin type A had 13 adverse reactions,with an incidence of 8.47％ (10/118),and three subjects who received placebo had three adverse reactions,with an incidence of 5.00％ (3/60) during the pivotal trial phase.All adverse reactions were mild to moderate,none serious.There was no significant difference in adverse reactions incidence between the botulinum toxin type A and the placebo groups.During the expanded phase three subjects had four adverse reactions and the incidence was 1.95％.All adverse reactions were mild,none serious.Conclusion Botulinum toxin type A was found to be safe and efficacious for the treatment of post-stroke upper limb spasticity.Clinical Trial Registration:China Drug Trials,CTR20131191