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IntroductionThe TriAD study will assess the Xpert MTB/XDR (Xpert XDR; Cepheid) assay to detect tuberculosis (TB) drug resistance in sputum testing positive for TB to rapidly triage and treat patients with a short all-oral treatment regimen.Methods and analysisIn this study, approximately 4800 Xpert MTB/RIF or Ultra MTB-positive patients (irrespective of rifampicin (RIF) resistance (RR) status) from several clinical sites across South Africa, Nigeria and Ethiopia will be enrolled over 18–24 months and followed-up for approximately 6 months post-TB treatment completion. Participants will be enrolled into one of two cohorts based on Xpert MTB/RIF and Xpert XDR results: Mycobacterium tuberculosis (M.tb) positive participants with RR in Cohort 1 (n=880) and M.tb positive RIF susceptible TB patients with isoniazid mono-resistance irrespective of presence of resistance to fluoroquinolones, second-line injectable drugs or ethionamide in Cohort 2 (n=400). Cohort 1 will be compared with historical cohorts from each implementing sites. The primary study outcomes include time to initiation of an appropriate treatment regimen by resistance profile and the proportion of patients with favourable treatment outcomes compared with historical cohorts from each of the implementing sites. Secondary outcomes include feasibility, acceptability and cost-effectiveness of this approach to inform policies and guidelines for programmatic implementation of this triage and treat model for drug-resistant tuberculosis management. Utility of the tuberculosis molecular bacterial load assay (TB-MBLA) for real-time treatment response assessment will also be evaluated.Ethics and disseminationThe University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC) and local research committees have provided ethical review and approval (BREC/00002654/2021, HREC 210805, NHREC/01/01/2007 and EPHI-IRB-459–2022). The South African Health Products Regulatory Authority (SAHPRA) have granted regulatory approval for the TRiAD Study (SAHPRA MD20211001). Trial results will be disseminated through conference presentations, peer-reviewed publications and the clinical trial registry.Trial registration numberClinicaltrials.gov; Trial registration number: NCT05175794; South African National Clinical Trials Register (SANCTR DOH-27-012022-4720)

Background The standard of care (SOC) treatment for drug-susceptible pulmonary tuberculosis (DS-TB) consists of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). New treatment regimen options for DS-TB are needed as HRZE is long in duration (6 months), associated with frequent adverse events, unforgiving of adherence lapses, and complicated by rifamycin-based drug-drug interactions. The recent resurgence of TB drug development, particularly in the context of drug-resistant TB, offers promise for additional regimens for persons with DS-TB, provided they are sufficiently effective and well-tolerated. We spotlight wave 1 of the RAD-TB platform trial (ACTG A5409, NCT06192160) that will investigate new chemical entities for the treatment of DS-TB. Methods In wave 1 of the RAD-TB platform, adult participants initiating treatment for DS-TB will be randomized to SOC (HRZE, Arm 1) or one of five experimental arms for the 8-week intensive phase. The experimental treatment arms will consist of a bedaquiline and pretomanid backbone (BPa) in combination with one of three oxazolidinones. Arm 2 will study linezolid (BPaL) at a dose of 600 mg daily, Arms 3A and 3B will study TBI-223 at 1200 mg and 2400 mg daily, respectively, and Arms 4A and 4B will study sutezolid at 800 mg and 1600 mg daily, respectively. The primary efficacy objective is to compare sputum culture time to positivity (TTP) slope over the first 6 weeks of treatment for each experimental treatment arm to SOC. The primary safety objective is to compare new Grade 3 or higher adverse events over the first 8 weeks of treatment for each experimental treatment arm to SOC. After the intensive phase, all participants will receive the standard isoniazid and rifampicin (HR) continuation phase for 18 weeks. Participants will be followed for 52 weeks after TB treatment initiation to assess long-term outcomes. Discussion Wave 1 of the RAD-TB platform aims to identify the optimal oxazolidinone(s), with regard to both efficacy and safety, to combine with the BPa backbone for the treatment of DS-TB. Subsequent waves of this platform trial may add a fourth drug to the regimen, study new diarylquinolines to substitute for bedaquiline, or study novel agents from other TB drug classes. Trials registration ClinicalTrials.gov NCT06192160 . Registered on January 5, 2024.