A Study of Quabodepistat-containing Regimens for the Treatment of Drug-resistant Pulmonary Tuberculosis

This is a Phase 3, randomized, open-label, active-controlled, multicenter trial evaluating the efficacy, safety, and tolerability of quabodepistat-containing regimens for the treatment of rifampicin-resistant or multidrug-resistant pulmonary tuberculosis. Participants are assigned to 1 of 2 cohorts based on fluoroquinolone susceptibility. In the fluoroquinolone-susceptible cohort, participants are randomized 1:1 to receive either a 4-month experimental regimen of bedaquiline, pretomanid, quabodepistat, and moxifloxacin or a 6-month control regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin. In the fluoroquinolone-resistant cohort, participants are randomized 3:1 to receive either a 6-month experimental regimen of bedaquiline, pretomanid, and quabodepistat or a 6-month control regimen of bedaquiline, pretomanid, and linezolid. A total of approximately 532 participants are planned, including 432 participants in the fluoroquinolone-susceptible cohort and approximately 100 participants in the fluoroquinolone-resistant cohort. The primary efficacy endpoint is the proportion of participants with an unfavorable outcome by 12 months post-randomization. Prespecified agency-specific definitions are used for the classification of regimen changes, sputum culture conversion, relapse, and reinfection. All unfavorable outcome events will be confirmed by a blinded Endpoint Adjudication Committee.

Inclusion Criteria: 1. Able to provide written informed consent prior to initiation of any trial-related procedures or treatments, and able, in the opinion of the investigator, to comply with all trial requirements (if under 18 years of age: participant assent AND parent/legal guardian consent are required). 2. Male or female participants aged ≥14 years at screening. 3. Body weight ≥30.0 kg at screening. 4. Documented pulmonary TB: Mycobacterium tuberculosis (Mtb) confirmed by Xpert MTB/RIF Ultra with a semi-quantitative result of "low," "medium," or "high" on the screening sputum sample. 5. Rifampicin resistance detected by Xpert MTB/RIF Ultra test conducted on the screening sputum. 6. Chest radiograph consistent with evidence of active TB disease, in the opinion of the investigator. 7. Able to provide a sputum sample. 8. Participants of reproductive potential (PORP) must agree to use 2 different approved methods of birth control and continue for 12 weeks after the last dose of quabodepistat (QBS) or the other drugs administered in the trial interventions. 9. Willing to have an HIV test unless a prior HIV-positive result can be confirmed. 10. Participants living with HIV must be receiving a stable antiretroviral regimen containing dolutegravir, lamivudine or emtricitabine, and tenofovir for at least 3 months before signing informed consent or assent; must have HIV-1 RNA below 200 copies/mL at screening; and must have a CD4 count greater than 100 cells/µL at screening. Exclusion Criteria: 1. Known or suspected resistance to any drugs administered in the treatment interventions (bedaquiline \[BDQ\], pretomanid \[PMD\], linezolid \[LZD\], or quabodepistat \[QBS\]) or the respective drug classes, confirmed by laboratory testing or based on epidemiologic history (e.g., known source case with resistance). 2. Prior treatment for drug-resistant TB, except where the study Medical Monitor confirms an adequate washout period for prior medications. 3. Clinical evidence of extrapulmonary TB considered severe by the investigator (e.g., pleural, pericardial, miliary, abdominal, urogenital, osteoarticular TB, or TB meningitis). 4. Laboratory test results of: ALT or AST \>2.5 × ULN; Total bilirubin \>1.5 × ULN; eGFR \