High-dose rifampicin (R) and isoniazid (H) are known to be safe but were not yet combined in a single regimen. TRIDORE (TRIple-DOse RE-treatment) is an ongoing pragmatic open-label multistage randomized clinical trial. The primary objective of this study is to determine whether a 6-month first-line regimen with triple-dose of both rifampicin and isoniazid (intervention arm; 6RHZE) is non-inferior in terms of safety compared to a normal-dose regimen (6RHZE) in previously treated patients with rifampicin-susceptible (Rs) recurrent tuberculosis (TB). Between March 2021 and February 2022, 127 consenting patients were randomly assigned to either the intervention or control arm: 62 and 65 were treated with 6RHZE and 6RHZE, respectively. Of 127, 111 (87.4%) were male and median age (IQR) was 37 (30-48) years. The median BMI at enrolment was 18.1 (16.3-19.7) kg/m. Drug-related severe adverse events (grade 3-5) were significantly more frequent when 6RHZE was used (5/62 vs 0/65, p=0.03, difference weighted for site 8%; (95%CI:1.0,14.3)). The study Data and Safety Monitoring Board (DSMB) recommended publishing our interim safety data analysis. We show that the combination of triple-dose rifampicin with triple-dose isoniazid in a retreatment regimen for patients with Rs-TB causes excess drug-related adverse events.
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