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Abstract：
Regimens for the treatment of rifampicin-resistant tuberculosis currently rely on the use of QT-prolonging agents. Using data from the randomized controlled trial, TB-PRACTECAL, we investigated differences in QTcF among participants in the three interventional arms: BPaL (bedaquiline, pretomanid, and linezolid), BPaLC (BPaL with clofazimine), and BPaLM (BPaL with moxifloxacin). Additionally, we assessed whether age, body mass index, and country were causally associated with QTcF prolongation. The trial included participants from South Africa, Uzbekistan, and Belarus. A post hoc analysis of electrocardiogram data was undertaken. Random effects regression was used to model QTcF longitudinally over 24 weeks and causal frameworks guided the analysis of non-randomized independent variables. 328 participants were included in BPaL-based arms. The longitudinal analysis of investigational arms showed an initial QTcF steep increase in the first week. QTcF trajectories between weeks 2 and 24 differed slightly by regimen, with highest mean peak for BPaLC (QTcF 446.5 ms). Overall, there were 397 QTcF >450 ms (of 3,744) and only one QTcF >500 ms. The odds of QTcF >450 ms among participants in any investigational arm, was 8.33 times higher in Uzbekistan compared to Belarus (95% confidence interval: 3.25-21.33). No effect on QTcF prolongation was found for baseline age or body mass index (BMI). Clinically significant QTc prolongation was rare in this cohort of closely monitored participants. Across BPaL-based regimens, BPaLC showed a slightly longer and sustained effect on QTcF prolongation, but the differences (both in magnitude of change and trajectory over time) were clinically unimportant. The disparity in the risk of QTc prolongation across countries would be an important factor to further investigate when evaluating monitoring strategies.
RESULTS: This study is registered with ClinicalTrials.gov as NCT02589782.
RESULTS: This study is registered with ClinicalTrials.gov as NCT02589782.
摘要：
目前治疗利福平耐药结核病的方案依赖于使用QT延长剂。使用随机对照试验的数据，TB-预制,我们调查了三个介入组参与者之间QTcF的差异：BPaL(bedaquiline，Pretomanid,和利奈唑胺)，BPaLC（BPaL与氯法齐明），和BPaLM（BPaL与莫西沙星）。此外,我们评估了年龄，身体质量指数,和国家与QTcF延长有因果关系。该试验包括来自南非的参与者，乌兹别克斯坦,白俄罗斯。对心电图数据进行事后分析。使用随机效应回归对24周内的QTcF进行纵向建模，因果框架指导非随机独立变量的分析。328名参与者被纳入基于BPaL的武器。对研究组的纵向分析表明，最初的QTcF在第一周急剧增加。第2周和第24周之间的QTcF轨迹因方案而异，BPaLC的平均峰值最高（QTcF446.5ms）。总的来说,有397个QTcF>450ms（3,744个），只有一个QTcF>500ms。在任何调查部门的参与者中，QTcF>450ms的几率，乌兹别克斯坦是白俄罗斯的8.33倍（95%置信区间：3.25-21.33）。基线年龄或体重指数（BMI）对QTcF延长没有影响。在这一密切监测的参与者队列中，临床上显着的QTc延长很少见。在基于BPaL的方案中，BPaLC对QTcF延长有稍长和持续的影响，但差异(随时间变化的幅度和轨迹)在临床上并不重要.在评估监测策略时，各国QTc延长的风险差异将是进一步调查的重要因素。
结果：本研究在ClinicalTrials.gov注册为NCT02589782。
结果：本研究在ClinicalTrials.gov注册为NCT02589782。
