Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis

Abstract

Background: For decades, poor treatment options and low-quality evidence plagued care for patients with rifampin-resistant tuberculosis. The advent of new drugs to treat tuberculosis and enhanced funding now permit randomized, controlled trials of shortened-duration, all-oral treatments for rifampin-resistant tuberculosis.

Methods: We conducted a phase 3, multinational, open-label, randomized, controlled noninferiority trial to compare standard therapy for treatment of fluoroquinolone-susceptible, rifampin-resistant tuberculosis with five 9-month oral regimens that included various combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z). Participants were randomly assigned (with the use of Bayesian response-adaptive randomization) to receive one of five combinations or standard therapy. The primary end point was a favorable outcome at week 73, defined by two negative sputum culture results or favorable bacteriologic, clinical, and radiologic evolution. The noninferiority margin was -12 percentage points.

Results: Among the 754 participants who underwent randomization, 699 were included in the modified intention-to-treat analysis, and 562 in the per-protocol analysis. In the modified intention-to-treat analysis, 80.7% of the patients in the standard-therapy group had favorable outcomes. The risk difference between standard therapy and each of the four new regimens that were found to be noninferior in the modified intention-to-treat population was as follows: BCLLfxZ, 9.8 percentage points (95% confidence interval [CI], 0.9 to 18.7); BLMZ, 8.3 percentage points (95% CI, -0.8 to 17.4); BDLLfxZ, 4.6 percentage points (95% CI, -4.9 to 14.1); and DCMZ, 2.5 percentage points (95% CI, -7.5 to 12.5). Differences were similar in the per-protocol population, with the exception of DCMZ, which was not noninferior in that population. The proportion of participants with grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxic events occurred in 11.7% of participants overall and in 7.1% of those receiving standard therapy.

Conclusions: Consistent results across all the analyses support the noninferior efficacy of three all-oral shortened regimens for the treatment of rifampin-resistant tuberculosis. (Funded by Unitaid and others; endTB ClinicalTrials.gov number, NCT02754765.).

Figure 1. Participant flow diagram of study arms and analysis populations

RIF denotes rifampin, FQ fluoroquinolone, mITT modified-intention-to-treat, PP per protocol; *bedaquiline, clofazimine, delamanid and/or linezolid

Figure 2. Forest plots of primary efficacy analyses at Week 73, by experimental group versus control

Shows the results of the primary efficacy analysis in the modified-intention-to treat and complementary analysis in the per-protocol analysis populations (a. 9BLMZ vs. control, b. 9BCLLfxZ vs. control, c. 9BDLLfxZ vs. control, d. 9DLLfxZ vs. control, e. 9DCMZ vs. control). The noninferiority margin of -12 percentage points is designated by the dashed vertical line. Participants were classified as having a favorable outcome at week 73 if one of the following was true: 1) their last two culture results were negative and were taken from sputum samples collected on separate visits, the latest between Week 65 and Week 73; 2) the last culture result (from a sputum sample collected between Weeks 65 and 73) was negative and either there was no other post-baseline culture result or the penultimate culture result was positive due to laboratory cross contamination; and bacteriological, radiological and clinical evolution is favorable; or 3) there was no culture result from a sputum sample collected between Week 65 and Week 73 or the result of that culture was positive due to laboratory cross contamination, and the most recent culture result was negative, and bacteriological, radiological and clinical evolution was favorable. The modified-intention-to treat population included randomized participants with culture-positive, FQ-susceptible and MDR/RR-TB whose isolated M. tuberculosis strains were not determined to be resistant to bedaquiline, clofazimine, delamanid, fluoroquinolone, or linezolid. Participants who did not have a pre-treatment sputum culture positive for M. tuberculosis were also excluded from the modified-intention-to treat population. The per-protocol population was the modified-intention-to treat population excluding participants who, for reasons other than treatment failure or death, do not complete a protocol-consistent course of treatment. A protocol-consistent course of treatment was 80% of expected doses taken within 120% of the intended regimen duration. Participants who received more than 7 days of either a prohibited concomitant medication or a study drug not prescribed according to protocol were also excluded from the per-protocol population. Confidence interval widths have not been adjusted for multiplicity and should not be used in place of hypothesis testing.