Investigation of the efficacy of the short regimen for rifampicin-resistant TB from the STREAM trial

BMC Medicine

C-Y Chiang¹  F. Conradie²  A. Van Deun³  S. K. Meredith⁴  S. Ahmed⁴  R. L. Goodall⁴  A. J. Nunn⁴  I. D. Rusen⁵  P. P. J. Phillips⁶ 

[1] Division of Pulmonary Medicine, Department of Internal Medicine, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan;Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;International Union against Tuberculosis and Lung Disease (the Union), Paris, France;Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa;Leuven, Belgium;MRC Clinical Trials Unit at UCL, London, UK;Research Division, Vital Strategies, New York, USA;UCSF Center for Tuberculosis, University of California San Francisco, San Francisco, USA;

关键词: MDR-TB;    Tuberculosis;    Short regimen;    Non-inferiority;    Causal inference;    Inverse probability of censoring weighting;    Multiple imputation;   

DOI  :  10.1186/s12916-020-01770-z

来源: Springer

【 摘 要 】

BackgroundThe 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.MethodsFirstly, 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.ResultsCure 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.ConclusionFive 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.

【 授权许可】

CC BY