Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial.

"Declaration of interests: SBS received a grant from the UK Foreign & Commonwealth Development Office for tuberculosis research through his institution. All other authors declare no competing interests."

"We wish to acknowledge the key contributions to STREAM stage 2 of three people who have died since the trial began: Donald Enarson of the International Union Against Tuberculosis and Lung Disease, Brian Danneman from Janssen Research & Development, and Iqbal Master of King Dinuzulu Hospital Complex, South Africa. All three guided us during the development of the trial but sadly are not here to see the results. STREAM stage 1 was funded by the US Agency for International Development (USAID) through the Cooperative Agreement GHN-A-00–08–0004–00. Stage 2 of STREAM was jointly funded by USAID and Janssen Research & Development. Additional funding for STREAM was provided by the Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement, which is also part of the EDCTP2 programme supported by the EU. The MRC Clinical Trials Unit at University College London was supported by the MRC (MC_UU_12023/26). We thank all the participants, community action board members, and collaborators, without whom the STREAM study would not have been possible. Declaration of interests: SBS received a grant from the UK Foreign & Commonwealth Development Office for tuberculosis research through his institution. All other authors declare no competing interests."

"All comparisons were restricted to participants randomly assigned concurrently. Analyses other than the primary outcome were stratified by randomisation protocol alone. Baseline characteristics and treatment adherence were summarised using counts and percentages or medians and IQRs. All analyses were done in STATA, version 17.0. An independent Trial Steering Committee oversaw the study with advice from an independent Data Monitoring Committee who regularly reviewed unblinded trial data. This trial is registered with ISRCTN, ISRCTN18148631. Methods: We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631."