Center for Biostatistics in AIDS Research in the Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Clin Infect Dis. 2021 Dec 6;73(11):2131-2139. doi: 10.1093/cid/ciab576.
Phase IIb trials of tuberculosis therapy rely on early biomarkers of treatment effect. Despite limited predictive ability for clinical outcomes, culture conversion, the event in which an individual previously culture positive for Mycobacterium tuberculosis yields a negative culture after initiating treatment, is a commonly used endpoint. Lack of consensus on how to define the outcome and corresponding measure of treatment effect complicates interpretation and limits between-trial comparisons. We review common analytic approaches to measuring treatment effect and introduce difference in restricted mean survival times as an alternative to identify faster times to culture conversion and express magnitude of effect on the time scale. Findings from the PanACEA MAMS-TB trial are reanalyzed as an illustrative example. In a systematic review we demonstrate variability in analytic approaches, sampling strategies, and outcome definitions in phase IIb tuberculosis trials. Harmonization would allow for larger meta-analyses and may help expedite advancement of new tuberculosis therapeutics.
结核病治疗的 IIb 期临床试验依赖于治疗效果的早期生物标志物。尽管对临床结果的预测能力有限，但培养物转换（即个体在开始治疗后先前培养出结核分枝杆菌阳性的培养物产生阴性培养物的事件）是一种常用的终点。对于如何定义结果以及相应的治疗效果衡量标准，缺乏共识，这使得解释变得复杂，并限制了试验之间的比较。我们回顾了常用的治疗效果衡量分析方法，并引入了受限平均生存时间差异作为一种替代方法，以确定更快的培养物转换时间，并在时间尺度上表达对治疗效果的影响程度。PanACEA MAMS-TB 试验的结果被重新分析作为一个说明性的例子。在系统综述中，我们展示了 IIb 期结核病试验中分析方法、抽样策略和结果定义的可变性。协调将允许进行更大的荟萃分析，并可能有助于加速新的结核病治疗方法的发展。
