UCSF Center for Tuberculosis, University of California San Francisco, San Francisco, USA.
, Leuven, Belgium.
BMC Med. 2020 Nov 4;18(1):314. doi: 10.1186/s12916-020-01770-z.
The STREAM trial demonstrated that a 9-11-month "short" regimen had non-inferior efficacy and comparable safety to a 20+ month "long" regimen for the treatment of rifampicin-resistant tuberculosis. Imbalance in the components of the composite primary outcome merited further investigation.
Firstly, the STREAM primary outcomes were mapped to alternatives in current use, including WHO programmatic outcome definitions and other recently proposed modifications for programmatic or research purposes. Secondly, the outcomes were re-classified according to the likelihood that it was a Failure or Relapse (FoR) event on a 5-point Likert scale: Definite, Probable, Possible, Unlikely, and Highly Unlikely. Sensitivity analyses were employed to explore the impact of informative censoring. The protocol-defined modified intention-to-treat (MITT) analysis population was used for all analyses.
Cure on the short regimen ranged from 75.1 to 84.2% across five alternative outcomes. However, between-regimens results did not exceed 1.3% in favor of the long regimen (95% CI upper bound 10.1%), similar to the primary efficacy results from the trial. Considering only Definite or Probable FoR events, there was weak evidence of a higher risk of FoR in the short regimen, HR 2.19 (95%CI 0.90, 5.35), p = 0.076; considering only Definite FoR events, the evidence was stronger, HR 3.53 (95%CI 1.05, 11.87), p = 0.030. Cumulative number of grade 3-4 AEs was the strongest predictor of censoring. Considering a larger effect of informative censoring attenuated treatment differences, although 95% CI were very wide.
Five alternative outcome definitions gave similar overall results. The risk of failure or relapse (FoR) may be higher in the short regimen than in the long regimen, highlighting the importance of how loss to follow-up and other censoring is accounted for in analyses. The outcome of time to FoR should be considered as a primary outcome for future drug-sensitive and drug-resistant TB treatment trials, provided sensitivity analyses exploring the impact of departures from independent censoring are also included.
STREAM 试验表明，与 20 个月以上的“长”疗程相比，9-11 个月的“短”疗程在治疗利福平耐药结核病方面具有非劣效性和相当的安全性。综合主要结局组成部分的不平衡值得进一步研究。
首先，将 STREAM 的主要结局映射到当前使用的替代方案，包括世卫组织规划成果定义和其他最近为规划或研究目的提出的修改方案。其次，根据在 5 分李克特量表上发生失败或复发（Failure or Relapse，FoR）事件的可能性，对结局进行重新分类：确定、可能、可能、不太可能和极不可能。采用敏感性分析来探讨信息性删失的影响。所有分析均采用方案定义的修改意向治疗（intention-to-treat，MITT）分析人群。
在五种替代结局中，短疗程的治愈率在 75.1%至 84.2%之间。然而，两种疗程之间的结果差异不超过 1.3%，有利于长疗程（95%CI 上限为 10.1%），与试验的主要疗效结果相似。仅考虑确定或可能的 FoR 事件，短疗程发生 FoR 的风险有微弱升高的证据，风险比（HR）为 2.19（95%CI 0.90，5.35），p=0.076；仅考虑确定的 FoR 事件，证据更强，HR 为 3.53（95%CI 1.05，11.87），p=0.030。3-4 级不良事件（AE）的累积数量是删失的最强预测因素。考虑到信息性删失的影响较大，虽然 95%CI 非常宽，但会减弱治疗差异。
五种替代结局定义得出了相似的总体结果。短疗程的失败或复发（Failure or Relapse，FoR）风险可能高于长疗程，这凸显了在分析中如何考虑失访和其他删失的重要性。FoR 时间的结局应被视为未来药物敏感和耐药结核病治疗试验的主要结局，前提是还包括探索独立性删失偏离的敏感性分析。
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