Supplementary Material for: Frequency and Clinical Impact of Serious Adverse Events on Post-Stroke Recovery with NeuroAiD (MLC601) versus Placebo: The CHInese Medicine Neuroaid Efficacy on Stroke Recovery Study

Background: Most comparative clinical trials are designed to assess the treatment effect for efficacy endpoints, with less emphasis on the analysis of safety outcomes. However, an extensive analysis of safety data could demonstrate beneficial results in terms of effectiveness by reducing serious adverse events (SAEs), and their unfavourable clinical impact on the study population. We aimed to conduct an exploratory analysis of the CHInese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study safety database comparing the frequency of SAEs and their clinical impacts among subjects having received MLC601 or placebo during the first 3 months post-stroke. Methods: Analyses were performed by using the safety database of the multicentre, randomised, double-blind, placebo-controlled CHIMES study of 3 months of NeuroAiD versus placebo in subjects with acute ischaemic stroke of intermediate severity in the preceding 72 h. SAEs as reported by investigators at any time-point during the 3-month study were analysed on their frequency and that of any of their outcomes (death, and life threatening, new and/or prolonged hospitalisation, disability, and medical importance, in surviving subjects), as well as their time to onset and resolution. Results: Of the 1,099 subjects in the CHIMES study, 1,087 were included in the safety analysis (MLC601 = 542) and (placebo = 545); the 12 who did not receive study treatment were excluded. There was a total of 135 subjects with SAEs (MLC601 = 60, placebo = 75). At baseline, overall, subjects with SAEs were older and had lower MMSE score. In the MLC601 group, they had higher NIHSS score, and more frequently a history of ischaemic heart disease and hyperlipidaemia. The number of SAEs per subjects was statistically significantly lower in the MLC601 group than placebo one, especially for subjects with ≥2 SAEs (6.7 vs. 29.3%; p p Conclusions: This post hoc analysis of SAEs from the CHIMES study database shows that subjects receiving a 3-month course of MLC601 experienced fewer SAEs, with lower rates of harmful clinical impacts, especially in terms of hospitalisation duration. These findings could translate to a benefit in terms of reduction of both healthcare burden and additional medical costs.

研究背景：多数对比性临床试验的设计初衷为评估疗效终点对应的治疗效应，对安全性结局的分析关注度相对不足。然而，若对安全性数据开展全面分析，则可通过减少严重不良事件（serious adverse events，SAEs）及其对研究人群的不良临床影响，从有效性维度展现获益效果。本研究旨在针对“中医神经辅助治疗对卒中恢复的疗效（CHInese Medicine Neuroaid Efficacy on Stroke recovery，CHIMES）”研究的安全性数据库展开探索性分析，对比卒中后前3个月内接受MLC601或安慰剂的受试者中SAEs的发生频率及其临床影响。
研究方法：本分析依托一项多中心、随机、双盲、安慰剂对照的CHIMES研究安全性数据库开展，该研究纳入发病72小时内的中等程度急性缺血性卒中受试者，对比了为期3个月的NeuroAiD与安慰剂的干预效果。针对3个月研究周期内研究者报告的所有SAEs，本分析对其发生频率、各类结局（包括死亡、危及生命事件、新发和/或延长的住院治疗、残疾，以及存活受试者的医学重要性不良事件）的发生情况，以及SAEs的发生时间与缓解时间展开了分析。
研究结果：CHIMES研究共纳入1099名受试者，其中1087名被纳入安全性分析队列（MLC601组542例，安慰剂组545例），12名未接受研究干预的受试者被排除。共计135名受试者发生SAEs，其中MLC601组60例，安慰剂组75例。基线层面，整体而言，发生SAEs的受试者年龄更大，简易精神状态检查表（Mini-Mental State Examination，MMSE）评分更低。在MLC601组中，发生SAEs的受试者美国国立卫生研究院卒中量表（National Institutes of Health Stroke Scale，NIHSS）评分更高，且缺血性心脏病、高脂血症的既往病史占比更高。每例受试者的SAEs数量在MLC601组中显著低于安慰剂组，尤其是SAEs≥2次的受试者（6.7% vs. 29.3%；p
研究结论：本项针对CHIMES研究数据库中SAEs的事后分析显示，接受3个月疗程MLC601治疗的受试者SAEs发生率更低，不良临床影响的占比更小，尤其体现在住院时长方面。上述研究结果可转化为医疗负担与额外医疗成本均得以降低的临床获益。