How do two all-oral regimens compare for rifampicin resistant/multidrug-resistant tuberculosis? A stepped wedge non inferiority cluster randomized trial in Pakistan

Abstract Background Pakistan is among the countries with the highest burden of Rifampicin resistant/multidrug-resistant tuberculosis (RR/MR TB) globally. Based on WHO recommendations for all oral shorter regimens, we have compared two all oral regimens i.e., a standard 11-month bedaquiline-based regimen with a modified 9-month regimen with 2 months of linezolid instead of ethionamide for RR/MR TB, to assess their effectiveness, safety, and quality of life under programmatic conditions in Pakistan. Method A stepped-wedge, cluster-randomized, non-inferiority trial was conducted at ten drug-resistant tuberculosis sites in Punjab, Pakistan, and recruited participants from 30/07/2020 till 20/03/2022. Sites served as clusters, transitioning sequentially from standard to modified regimen as per predefined schedule. Eligible participants were adults aged 15 years or older with confirmed RR/MR TB. The primary outcome was the between-group difference in efficacy, defined as the proportion of participants achieving treatment success without recurrence at 12 months after treatment completion, using a prespecified non-inferiority margin of 12 percentage points. The analysis was done employing the intention to treat principles and a marginal Poisson model with generalized estimating equations and log-link was done to estimate the relative risk. Secondary outcomes included mortality, treatment failure, adverse events, and quality of life. Result A total of 438 patients were enrolled in the trial (i.e., 204 in intervention arm with modified regimen and 234 patients in control arm with standard regimen). Cure rates were similar between groups i.e., 73% modified versus 75% standard. Favourable outcome occurred in 77.5% of the modified group and 76.1% of the standard group; adjusted risk ratio was 1.03 (95% CI: 0.94–1.13) and adjusted risk difference was + 1.58 percentage points (95% CI: −5.78 -+8.95), meeting the non-inferiority criterion. No recurrence occurred in the modified group during follow-up. Serious adverse events occurred in 11.3% and 10.3% of participants in the modified and standard groups, respectively, with broadly comparable safety profiles. Quality of life improved substantially and similarly in both groups. Conclusion A modified nine-month all-oral regimen for RR/MR TB was non-inferior to the standard eleven-month regimen, with comparable safety and sustained improvement in quality of life, supporting it as a feasible option within routine tuberculosis programmes. Trial registration International Standard Randomised Controlled Trial Number registry, ISRCTN17334530. Registered 8 February 2021.