Suissa Samy
Departments of Epidemiology and Biostatistics and of Medicine, Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
COPD. 2021 Dec;18(6):597-601. doi: 10.1080/15412555.2021.1982886. Epub 2021 Sep 27.
Recent trials reported significant reductions in all-cause mortality with single-inhaler triple therapy for chronic obstructive pulmonary disease (COPD). However, reviews of these trials identified inconsistencies in the findings and methodological issues with the design and analysis, including the "adverse impact of inhaled corticosteroid (ICS) withdrawal rather than the addition" of the triple therapy. Indeed, ICS were discontinued in over 70% of the patients in these trials and 40% already using triple therapy, muddying the interpretation of the data. The "adaptive" clinical trial design is an efficient approach that allows continual modification of the study treatment allocation during follow-up. In this article, we propose the "adaptive selection" trial design, which applies the adaptive concept to the selection of patients into the trial by adapting the randomization choices to the treatment already used by the patients. With such a design, patients already on triple therapy would be excluded outright from trials of triple therapy effectiveness, while the others are randomly allocated to specific treatment arms according to their current treatment, avoiding issues of treatment withdrawal effects. Adaptive selection trials should be the norm for studies of COPD therapies. This approach would avoid the vexing effects of treatment withdrawal that have afflicted the recent triple therapy trials. This concept of adaptive selection has been applied in COPD to the question of whether patients can be safely de-escalated from ICS. It is time to also apply it to studies of the effectiveness of treatment escalation.
近期试验报告称，慢性阻塞性肺疾病（COPD）单吸入器三联疗法可显著降低全因死亡率。然而，对这些试验的综述发现，研究结果存在不一致性，设计和分析存在方法学问题，包括三联疗法的“吸入性糖皮质激素（ICS）撤药而非加用的不良影响”。事实上，在这些试验中，超过70%的患者停用了ICS，40%的患者已经在使用三联疗法，这使得数据的解读变得模糊不清。“适应性”临床试验设计是一种有效的方法，它允许在随访期间不断修改研究治疗分配。在本文中，我们提出“适应性选择”试验设计，即将适应性概念应用于患者入选试验的选择过程，通过根据患者已使用的治疗方法调整随机化选择。采用这种设计，已经接受三联疗法的患者将被直接排除在三联疗法有效性试验之外，而其他患者则根据其当前治疗随机分配到特定治疗组，避免治疗撤药效应问题。适应性选择试验应该成为COPD治疗研究的规范。这种方法将避免困扰近期三联疗法试验的治疗撤药的棘手影响。适应性选择的这一概念已在COPD中应用于患者是否可以安全地减少ICS使用剂量的问题。现在也应该将其应用于治疗升级有效性的研究。
