Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis

Abstract

Background: Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis.

Methods: In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months.

Results: Among 2516 participants who had undergone randomization, 2343 had a culture positive for Mycobacterium tuberculosis that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group.

Conclusions: The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).

Figure 1.. Screening, Randomization, and Follow-up.

MTB denotes Mycobacterium tuberculosis.

Figure 2.. Primary and Secondary Efficacy Analyses and Time to an Unfavorable Outcome.

Panel A shows the results of the primary efficacy analysis in the microbiologically eligible and the assessable analysis populations and of the secondary analyses in the intention-to-treat and the per-protocol analysis populations (top, rifapentine–moxifloxacin regimen vs. control regimen; bottom, rifapentine regimen vs. control regimen). The noninferiority margin of 6.6 percentage points is designated by the dashed vertical line. Participants were classified as having an unfavorable outcome if they had M. tuberculosis–positive cultures from two sputum specimens obtained at or after week 17 without an intervening negative culture, died or were withdrawn from the trial or lost to follow-up during the treatment period, had an M. tuberculosis–positive culture when last seen, died from tuberculosis during the post-treatment follow-up, or received additional treatment for tuberculosis. The microbiologically eligible analysis population included all the participants except those who had no evidence of M. tuberculosis–positive cultures, who had tuberculosis that was resistant to isoniazid, rifampin, or fluoroquinolones, or who were enrolled in violation of the eligibility criteria; the participants with an outcome status that was not assessable were reclassified as having had an unfavorable outcome. The assessable analysis population included the participants in the microbiologically eligible population except those whose outcome status had been reclassified from not assessable to unfavorable. The per-protocol 75% and per-protocol 95% analysis populations included the participants in the assessable population, except those who did not complete 75% or 95% of the assigned treatment doses, respectively, unless the reason for inadequate treatment was death or bacteriologic treatment failure. Panel B shows the results for the time to unfavorable outcome for the microbiologically eligible population. Data were censored for the participants who could not be assessed. HIV denotes human immunodeficiency virus. The inset shows the same data on an expanded y axis.