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A 4-month rifapentine-moxifloxacin-based regimen was found to be noninferior to the standard 6-month regimen for drug-susceptible pulmonary tuberculosis (TB), according to the results of a multinational, phase 3 study published in The New England Journal of Medicine.
This open-label, randomized, noninferiority trial (ClinicalTrials.gov Identifier: NCT02410772) included people with newly diagnosed pulmonary TB from 13 countries across 4 continents, including the United States, to compare 3 treatment regimens: 1) a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (standard regimen); 2) a 4-month regimen with high-dose rifapentine (1200 mg), isoniazid, pyrazinamide, and ethambutol (rifapentine without moxifloxacin regimen); and 3) a 4-month regimen with high-dose rifapentine (1200 mg), isoniazid, pyrazinamide, and moxifloxacin (400 mg; rifapentine with moxifloxacin regimen). The researchers hypothesized that rifapentine with or without moxifloxacin would be noninferior to the standard regimen, with a noninferiority margin of 6.6 percentage points.
The primary efficacy outcome was TB-free survival at 12 months, with the absence of cure defined as an unfavorable outcome; the primary safety outcome was an adverse event of grade 3 or higher during the treatment period.
The analysis included 2343 participants in the microbiologically eligible population whose composition was 71% men and 72% Black, with a median age of 31.0 years (range, 13.7-81.4).
A total of 194 participants were coinfected with HIV, and 1703 had cavitation based on chest radiography. By treatment regimen, 768 participants received the standard regimen, 784 received rifapentine without moxifloxacin, and 791 received rifapentine with moxifloxacin.
The analysis included 2234 participants in the assessable population, which excluded participants who did not meet the 12-month follow-up but had a negative culture when last seen, those who died during follow-up from a cause unrelated to TB, and those who had a change in treatment regimen. In terms of treatment regimen, 726 participants received the standard regimen, 752 received rifapentine without moxifloxacin, and 756 received rifapentine with moxifloxacin.
In both analysis populations, the rifapentine-with-moxifloxacin regimen was noninferior to the standard regimen in terms of unfavorable outcomes. In the microbiologically eligible population, an unfavorable outcome was reported in 15.5% vs 14.6%, respectively, with an adjusted absolute difference of 1.0 percentage point (95% CI, -2.6 to 4.5). In the assessable population, an unfavorable outcome was reported in 11.6% vs 9.6%, respectively, with an adjusted absolute difference of 2.0 percentage points (95% CI, -1.1 to 5.1).
The findings were consistent in secondary analyses, which included all assessable participants with at least 95% or 75% adherence to the dosing schedule.
The rifapentine-without-moxifloxacin regimen was not reported to be noninferior to the standard regimen in either population.
There was no significant difference in adverse events of grade 3 or higher among participants who received rifapentine with moxifloxacin vs the standard regimen (18.8% vs 19.3%; adjusted difference, -0.6 percentage points; 95% CI, -4.3 to 3.2). The researchers did note that a grade 3 or higher serum total bilirubin level was more common in participants who received both rifapentine-based regimens.
Time to culture negativity was shorter in both rifapentine-based regimens vs the standard regimen.
Limitations of this study included its nonblinded analysis and the small sample size of participants coinfected with HIV, which limited the power to compare regimens.
Because “drug costs may be higher for the rifapentine-moxifloxacin regimen,” an economic analyses will be needed to “provide information about the extent to which incrementally higher drug costs are offset by a shorter regimen,” concluded the researchers.
Disclosure: This research was partially supported by Sanofi. Please see the original reference for a full list of disclosures.
Reference
Dorman SE, Nahid P, Kurbatova EV, et al; AIDS Clinical Trials Group; Tuberculosis Trials Consortium. Four-month rifapentine regimens with or without moxifloxacin for tuberculosis. N Engl J Med. 2021;384(18):1705-1718. doi:10.1056/NEJMoa2033400
