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

P P J Phillips,R L Goodall,I D Rusen,A J Nunn,A Van Deun,S Ahmed,F Conradie,S K Meredith,C-Y Chiang

doi:10.1186/s12916-020-01770-z

Abstract

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.

Highlights

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
Participants were randomized in a ratio of 2:1 to a “short” 9–11-month regimen or the locally used standard of care “long” regimen that followed 2011 World Health Organization (WHO) guidelines for the treatment of Multi DrugResistant TB (MDR-TB) [3, 17]
This included all randomized patients with a positive culture at baseline, except for patients randomized in error, patients with isolates taken before randomization or up to week 4 that were subsequently found to be susceptible to rifampicin or resistant to both fluoroquinolones and second-line injectables on phenotypic drug susceptibility testing (DST)

Summary

Introduction

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. The STREAM trial evaluated a 9–11-month “short” regimen for the treatment of rifampicin-resistant TB and demonstrated non-inferior efficacy and comparable safety to the current standard 20+ month “long” regimen [3]. The primary efficacy endpoint was a composite unfavorable outcome which included death, relapse, and treatment failure, in addition to treatment modifications for adverse events and poor adherence. There were, some differences in the components of the composite outcome that merited further investigation; notably bacteriological unfavorable outcomes were more common on the short regimen whereas an unfavorable outcome due to loss to follow-up was more common on the long regimen. There are three additional motivations for the further analyses described

Methods

Results

Discussion

Conclusion