Rationale: Pretomanid is a new nitroimidazole with proven treatment-shortening efficacy in drug-resistant tuberculosis. Pretomanid-rifamycin-pyrazinamide combinations are potent in mice but have not been tested clinically. Rifampicin, but not rifabutin, reduces pretomanid exposures. Objectives: To evaluate the safety and efficacy of regimens containing pretomanid-rifamycin-pyrazinamide among participants with drug-sensitive pulmonary tuberculosis. Methods: A phase 2, 12-week, open-label randomized trial was conducted of isoniazid and pyrazinamide plus 1) pretomanid and rifampicin (arm 1), 2) pretomanid and rifabutin (arm 2), or 3) rifampicin and ethambutol (standard of care; arm 3). Laboratory values of safety and sputum cultures were collected at Weeks 1, 2, 3, 4, 6, 8, 10, and 12. Time to culture conversion on liquid medium was the primary outcome. Measurements and Main Results: Among 157 participants, 125 (80%) had cavitary disease. Median time to liquid culture negativity in the modified intention-to-treat population (n = 150) was 42 (arm 1), 28 (arm 2), and 56 (arm 3) days (P = 0.01) (adjusted hazard ratio for arm 1 vs. arm 3, 1.41 [95% confidence interval (CI), 0.93-2.12; P = 0.10]; adjusted hazard ratio for arm 2 vs. arm 3, 1.89 [95% CI, 1.24-2.87; P = 0.003]). Eight-week liquid culture conversion was 79%, 89%, and 69%, respectively. Grade ≥3 adverse events occurred in 3 of 56 (5%), 5 of 53 (9%), and 2 of 56 (4%) participants. Six participants were withdrawn because of elevated transaminase concentrations (five in arm 2, one in arm 1). There were three serious adverse events (arm 2) and no deaths. Conclusions: Pretomanid enhanced the microbiologic activity of regimens containing a rifamycin and pyrazinamide. Efficacy and hepatic adverse events appeared highest with the pretomanid and rifabutin-containing regimen. Whether this is due to higher pretomanid concentrations merits exploration. Clinical trial registered with www.clinicaltrials.gov (NCT02256696).

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