Weir Isabelle R, Dufault Suzanne M, Phillips Patrick Pj
Harvard University T H Chan School of Public Health.
University of California San Francisco.
Res Sq. 2023 Nov 9:rs.3.rs-3486707. doi: 10.21203/rs.3.rs-3486707/v1.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.Trial registration: NCT00864383.
背景：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）提供临床试验的国际监管标准。近期ICH E9（R1）增编中概述的估计目标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。我们之前曾为此背景提出并定义了四个估计目标。我们的目的是评估这些估计目标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读。 方法：我们重新分析了REMoxTB试验中参与者层面的数据。我们应用四个估计目标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。 结果：使用四个估计目标中的每一个，我们都得出了与原试验分析相同的结论；即新型方案并不优于标准治疗。每个估计目标和估计方法都给出了相似的治疗效果估计值，方差波动和差异由处理并发事件所应用的方法驱动。 结论：我们对ICH E9（R1）增编定义的估计目标的应用为解决结核病主要治疗试验目标提供了一个形式化框架，并可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目标的方法，并在各估计目标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目标，以促进严格的结局定义并减少试验间的变异性。试验注册号：NCT00864383。
Clin Trials. 2022-6
Clin Trials. 2022-10
Ther Innov Regul Sci. 2020-3
Clin Trials. 2022-10
N Engl J Med. 2021-5-6
PLoS One. 2020-10-22
N Engl J Med. 2014-10-23
N Engl J Med. 2014-10-23
N Engl J Med. 2014-10-23
Zotero 插件