Randomised trial to evaluate the effectiveness and safety of varying doses of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant or treatment intolerant/non-responsive multidrug-resistant pulmonary tuberculosis: study protocol

INTRODUCTION: Drug-resistant tuberculosis (DR-TB) is a global public health problem. Patients suffer for months if undiagnosed or treated inadequately, transmitting DR-TB in the community before succumbing to the disease. Early diagnosis, prompt treatment initiation and completion play a significant role in treatment success. However, extended regimens with injectable result in poor treatment adherence and outcomes. Our objective is to evaluate the effectiveness, safety and tolerability of various doses and duration of linezolid (LZD) in combination with bedaquiline (BDQ) and pretomanid (Pa) after 26 weeks of treatment in adults with pre-extensively drug-resistant or treatment intolerant/non-responsive multidrug-resistant pulmonary TB. METHODS AND ANALYSIS: A multicentric, randomised pragmatic clinical trial in India will enrol participants in one of the three arms—control arm (arm 1): BDQ, Pa and LZD 600 mg daily for 26 weeks or intervention arms (arm 2): BDQ, Pa and LZD 600 mg for 9 weeks followed by 300 mg for 17 weeks or arm 3: BDQ, Pa and LZD 600 mg for 13 weeks followed by 300 mg for 13 weeks. The primary endpoint is the proportion of patients with favourable outcomes as sustained cure and treatment completion. The secondary endpoint is unfavourable outcomes, including deaths, treatment failure, toxicity/adverse events and lost to follow-up till 48 weeks post-treatment. ETHICS AND DISSEMINATION: The study has been approved by the ethics committees of participating institutes and the National Institute for Research in TB. The trial results will help establish evidence towards a safe and effective dose of LZD that can be used in a fully, all-oral short course regimen for highly DR-TB patients. The results of this study will be shared with the National TB Elimination Programme of the country and the WHO guidelines development group through publications and dissemination meetings. TRIAL REGISTRATION NUMBER: NCT05040126.