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BACKGROUND: Newer oxazolidinones will be required to advance regimens in pan-TB indications. The addition of host-directed agents may help promote the recovery of lung function during TB treatment and prevent post-TB lung disease. METHODS: The panTB-HM trial assesses the capacity of three novel regimens containing the oxazolidinone sutezolid and the antioxidant N-acetylcysteine (NAC) to meet the target criteria proposed by WHO for pan-TB indications (including use without rifamycin susceptibility testing and of 4 months or less duration) in a phase 2C trial. DISCUSSION: This trial is ground-breaking in its objectives and design for a 4-month pan-TB indication (in a non-inferiority comparison to standard treatment) and its evaluation of lung function recovery (in a superiority comparison). TRIAL REGISTRATION: ClinicalTrials.gov NCT05686356. Registered on 13 Jan 2023.