Weir Isabelle R, Dufault Suzanne M, Phillips Patrick P J
Center for Biostatistics in AIDS Research in the Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, CA, USA.
Trials. 2024 Mar 12;25(1):180. doi: 10.1186/s13063-024-07999-w.
Randomized trials for the treatment of tuberculosis (TB) rely on a composite primary outcome to capture unfavorable treatment responses. However, variability between trials in the outcome definition and estimation methods complicates across-trial comparisons and hinders the advancement of treatment guidelines. The International Council for Harmonization (ICH) provides international regulatory standards for clinical trials. The estimand framework outlined in the recent ICH E9(R1) addendum offers a timely opportunity for randomized trials of TB treatment to adopt broadly standardized outcome definitions and analytic approaches. We previously proposed and defined four estimands for use in this context. Our objective was to evaluate how the use of these estimands and choice of estimation method impacts results and interpretation of a large phase III TB trial.
We reanalyzed participant-level data from the REMoxTB trial. We applied four estimands and various methods of estimation to assess non-inferiority of both novel 4-month treatment regimens against standard of care.
With each of the four estimands, we reached the same conclusion as the original trial analysis that the novel regimens were not non-inferior to standard of care. Each estimand and method of estimation gave similar estimates of the treatment effect with fluctuations in variance and differences driven by the methods applied for handling intercurrent events.
Our application of estimands defined by the ICH E9 (R1) addendum offers a formalized framework for addressing the primary TB treatment trial objective and can promote uniformity in future trials by limiting heterogeneity in trial outcome definitions. We demonstrated the utility of our proposal using data from the REMoxTB randomized trial. We outlined methods for estimating each estimand and found consistent conclusions across estimands. We recommend future late-phase TB treatment trials to implement some or all of our estimands to promote rigorous outcome definitions and reduce variability between trials.
ClinicalTrials.gov NCT00864383. Registered on March 2009.
结核病（TB）治疗的随机试验依赖于综合主要结局来捕捉不良治疗反应。然而，各试验在结局定义和估计方法上的差异使得跨试验比较变得复杂，并阻碍了治疗指南的推进。国际协调理事会（ICH）为临床试验提供国际监管标准。最近的ICH E9（R1）增编中概述的估计量框架为结核病治疗的随机试验提供了一个及时的机会，使其能够采用广泛标准化的结局定义和分析方法。我们之前曾为此提出并定义了四个估计量。我们的目的是评估这些估计量的使用以及估计方法的选择如何影响一项大型III期结核病试验的结果和解释。
我们重新分析了REMoxTB试验中参与者层面的数据。我们应用了四个估计量和各种估计方法来评估两种新型4个月治疗方案相对于标准治疗的非劣效性。
使用这四个估计量中的每一个，我们都得出了与原始试验分析相同的结论，即新型方案并不优于标准治疗。每个估计量和估计方法对治疗效果的估计相似，但方差波动和差异是由处理并发事件所采用的方法驱动的。
我们对ICH E9（R1）增编定义的估计量的应用为解决主要结核病治疗试验目标提供了一个形式化框架，并且可以通过限制试验结局定义的异质性来促进未来试验的一致性。我们使用REMoxTB随机试验的数据证明了我们提议的实用性。我们概述了估计每个估计量的方法，并在各估计量之间得出了一致的结论。我们建议未来的晚期结核病治疗试验实施我们的部分或全部估计量，以促进严格的结局定义并减少试验之间的差异。
ClinicalTrials.gov NCT00864383。于2009年3月注册。
