Thorlund Kristian, Sheldrick Kyle, Meyerowitz-Katz Gideon, Singh Sonal, Hill Andrew
Department of Health Research Methods, Evidence & Impact, McMaster University, Hamilton, Ontario, Canada.
University of New South Wales, Kensington, Australia.
Am J Trop Med Hyg. 2022 Mar 11;106(5):1301-4. doi: 10.4269/ajtmh.21-1339.
Oral therapies for the early treatment of COVID-19 may prevent disease progression and health system overcrowding. A new oral therapeutic named molnupiravir has been promoted as providing an approximately 50% reduction in death or the need for hospitalization. The clinical trial evaluating this drug was stopped early at the recommendation of the Data Safety and Monitoring Board after approximately 50% of the sample had been recruited. At the point of discontinuing the trial, approximately 90% of the planned sample had been recruited and had available follow-up data accessible. We discuss issues about the study conduct, analysis, and interpretation, including 1) the authors and sponsors presented the interim analysis as the primary analysis; 2) communication between sponsors and the Data Safety and Monitoring Board was insufficient; 3) the treatment effects reverse when examining only the post-interim analysis population, and are substantially attenuated when examining the full data; 4) the choice of primary analysis is incorrect; 5) analysis of lost-to-follow-up patients favors the study drug; and 6) other known molnupiravir trials were not presented in the primary study findings. As a result of methodological and statistical concerns, it seems that external trials, separate from those supported by the sponsoring company, are required to determine the utility of this drug.
用于新冠病毒病早期治疗的口服疗法可能会预防疾病进展和医疗系统过度拥挤。一种名为莫努匹韦的新型口服疗法已被宣传为可使死亡或住院需求降低约50%。在约50%的样本被招募后,根据数据安全与监测委员会的建议,评估该药物的临床试验提前终止。在试验终止时,约90%的计划样本已被招募且有可获取的随访数据。我们讨论了有关该研究的实施、分析和解读的问题,包括:1) 作者和赞助商将中期分析作为主要分析呈现;2) 赞助商与数据安全与监测委员会之间的沟通不足;3) 仅检查中期分析后的人群时治疗效果逆转,而检查完整数据时效果大幅减弱;4) 主要分析的选择不正确;5) 对失访患者的分析有利于研究药物;6) 主要研究结果中未呈现其他已知的莫努匹韦试验。出于方法学和统计学方面的担忧,似乎需要开展独立于制药公司支持的外部试验来确定该药物的效用。