Cooper Ben S, Boni Maciej F, Pan-ngum Wirichada, Day Nicholas P J, Horby Peter W, Olliaro Piero, Lang Trudie, White Nicholas J, White Lisa J, Whitehead John
Mahidol Oxford Tropical Medicine Research Unit (MORU), Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom; Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Viet Nam.
PLoS Med. 2015 Apr 14;12(4):e1001815. doi: 10.1371/journal.pmed.1001815. eCollection 2015 Apr.
Experimental treatments for Ebola virus disease (EVD) might reduce EVD mortality. There is uncertainty about the ability of different clinical trial designs to identify effective treatments, and about the feasibility of implementing individually randomised controlled trials during an Ebola epidemic.
A treatment evaluation programme for use in EVD was devised using a multi-stage approach (MSA) with two or three stages, including both non-randomised and randomised elements. The probabilities of rightly or wrongly recommending the experimental treatment, the required sample size, and the consequences for epidemic outcomes over 100 d under two epidemic scenarios were compared for the MSA, a sequential randomised controlled trial (SRCT) with up to 20 interim analyses, and, as a reference case, a conventional randomised controlled trial (RCT) without interim analyses. Assuming 50% 14-d survival in the population treated with the current standard of supportive care, all designs had similar probabilities of identifying effective treatments correctly, while the MSA was less likely to recommend treatments that were ineffective. The MSA led to a smaller number of cases receiving ineffective treatments and faster roll-out of highly effective treatments. For less effective treatments, the MSA had a high probability of including an RCT component, leading to a somewhat longer time to roll-out or rejection. Assuming 100 new EVD cases per day, the MSA led to between 6% and 15% greater reductions in epidemic mortality over the first 100 d for highly effective treatments compared to the SRCT. Both the MSA and SRCT led to substantially fewer deaths than a conventional RCT if the tested interventions were either highly effective or harmful. In the proposed MSA, the major threat to the validity of the results of the non-randomised components is that referral patterns, standard of care, or the virus itself may change during the study period in ways that affect mortality. Adverse events are also harder to quantify without a concurrent control group.
The MSA discards ineffective treatments quickly, while reliably providing evidence concerning effective treatments. The MSA is appropriate for the clinical evaluation of EVD treatments.
埃博拉病毒病（EVD）的实验性治疗可能会降低EVD死亡率。不同临床试验设计识别有效治疗方法的能力，以及在埃博拉疫情期间实施个体随机对照试验的可行性尚不确定。
采用两阶段或三阶段的多阶段方法（MSA）设计了一个用于EVD的治疗评估方案，该方案包括非随机和随机因素。比较了MSA、进行多达20次中期分析的序贯随机对照试验（SRCT）以及作为参考案例的无中期分析的传统随机对照试验（RCT）在两种疫情情景下正确或错误推荐实验性治疗的概率、所需样本量以及100天内疫情结果的影响。假设接受当前支持性护理标准治疗的人群中14天生存率为50%，所有设计正确识别有效治疗方法的概率相似，而MSA推荐无效治疗的可能性较小。MSA导致接受无效治疗的病例数量减少，高效治疗方法的推出速度更快。对于效果较差的治疗方法，MSA很有可能纳入RCT部分，导致推出或拒绝的时间稍长。假设每天有100例新的EVD病例，与SRCT相比，对于高效治疗方法，MSA在前100天内可使疫情死亡率降低6%至15%。如果测试的干预措施要么非常有效要么有害，MSA和SRCT导致的死亡人数都比传统RCT少得多。在提议的MSA中，非随机部分结果有效性的主要威胁在于，在研究期间转诊模式、护理标准或病毒本身可能会以影响死亡率的方式发生变化。没有同期对照组，不良事件也更难量化。
MSA能迅速摒弃无效治疗方法，同时可靠地提供有关有效治疗方法的证据。MSA适用于EVD治疗的临床评估。
