LAUSR

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. OBJECTIVE Evaluate the safety and efficacy of pretomanid-rifamycin-pyrazinamide containing regimens among participants with drug-sensitive pulmonary tuberculosis. METHODS Phase 2 twelve-week open-label randomized trial of isoniazid, pyrazinamide, plus (a) pretomanid and rifampicin (Arm 1); (b) pretomanid and rifabutin (Arm 2) or (c) rifampicin and ethambutol (standard of care, Arm 3). Safety labs and sputum cultures were collected at Weeks 1, 2, 3, 4, 6, 8, 10, 12. Time to culture conversion on liquid media was the primary outcome. RESULTS Among 157 participants, 125 (80%) had cavitary disease. Median time to liquid culture negativity in the modified intention to treat (mITT) population (n=150) was 41 (Arm 1), 28 (Arm 2), and 55 (Arm 3) days (p=0.01)(adjusted hazard ratios of 1.41 (0.93-2.12, p=0.10), Arm 1 vs. Arm 3) and 1.89 (1.24-2.87, p=0.003, Arm 2 vs. Arm 3)). Eight-week liquid culture conversion was 79%, 89%, and 69%, respectively. Grade >3 adverse events occurred in 3/56 (5%), 5/53 (9%), and 2/56 (4%) of participants. Six participants were withdrawn owing to elevated transaminases (5 in Arm 2, 1 in Arm 1).There were 3 serious adverse events (Arm 2) and no deaths. CONCLUSIONS Pretomanid enhanced the microbiologic activity of rifamycin-pyrazinamide containing regimens. 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 registration available at www. CLINICALTRIALS gov, ID: NCT02256696.