• Susan E Dorman, Payam Nahid, Ekaterina V Kurbatova, Stefan V Goldberg, Lorna Bozeman, William J Burman, Kwok-Chiu Chang, Michael Chen, Mark Cotton, Kelly E Dooley, Melissa Engle, Pei-Jean Feng, Courtney V Fletcher, Phan Ha, Charles M Heilig, John L Johnson, Erica Lessem, Beverly Metchock, Jose M Miro, Nguyen Viet Nhung, April C Pettit, PhillipsPatrick P JPPJUniversity of California, San Francisco, California, USA., Anthony T Podany, Anne E Purfield, Kathleen Robergeau, Wadzanai Samaneka, Nigel A Scott, Erin Sizemore, Andrew Vernon, Marc Weiner, Susan Swindells, Richard E Chaisson, and AIDS Clinical Trials Group and the Tuberculosis Trials Consortium.
• Medical University of South Carolina, Charleston, SC, USA. Electronic address: dorman@musc.edu.
• Contemp Clin Trials. 2020 Mar 1; 90: 105938.

IntroductionPhase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen.Methods/DesignS31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients. Both of the four-month regimens contain high-dose rifapentine instead of rifampin, with ethambutol replaced by moxifloxacin in one regimen. All drugs are administered seven days per week, and under direct observation at least five days per week. The primary outcome is tuberculosis disease-free survival at twelve months after study treatment assignment. A total of 2500 participants will be randomized; this gives 90% power to show non-inferiority with a 6.6% margin of non-inferiority.DiscussionThis phase 3 trial formally tests the hypothesis that augmentation of rifamycin exposures can shorten tuberculosis treatment to four months. Trial design and standardized implementation optimize the likelihood of obtaining valid results. Results of this trial may have important implications for clinical management of tuberculosis at both individual and programmatic levels.Trial RegistrationNCT02410772. Registered 8 April 2015,https://www.clinicaltrials.gov/ct2/show/NCT02410772?term=02410772&rank=1.Copyright © 2020 Elsevier Inc. All rights reserved.

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