Optimizing Rifapentine Dosage for Drug-Susceptible Tuberculosis: Preliminary Findings from an Adaptive Randomized Controlled Trial

Abstract Background: The four-month regimen of rifapentine, isoniazid, pyrazinamide, and moxifloxacin has been conditionally recommended for drug-susceptible tuberculosis (DS-TB). However, concerns have arisen regarding the pill burden and safety of high-dose daily rifapentine. A randomized controlled trial with an adaptive seamless design (Optimizing RIfapentine-based regimen and shortENing the Treatment of DS-TB [ORIENT], NCT05401071) has been conducted to evaluate the safety and efficacy of shorter regimens of different doses of rifapentine for DS-TB. Design/Methods: In stage 1 of this phase II/III, multicenter, open-label trial, a total of 400 participants with DS-TB were randomly assigned to receive either the standard 6-month regimen or 4-month investigator regimens composed of isoniazid, moxifloxacin, pyrazinamide and rifapentine at a daily dose of 10, 15, or 20mg/kg. Intensive 96-hour sampling was conducted for pharmacokinetic analysis among patients receiving rifapentine. The primary safety outcome was the incidence of permanent regimen discontinuation due to safety reasons by week 8. An arm was set to terminate early if the proportion of treatment-related serious adverse events (SAEs) exceeded 20% or the proportion of treatment-related liver failure or death exceeded 10%. Results: Participant enrollment in stage 1 was completed on September 29, 2024. Of these, 392 participants received at least one dose and were evaluated in the safety analysis. The incidences of primary safety outcome event were 2.1% (2/97), 5.0% (5/101), 5.3% (5/95), in the rifapentine 10, 15, 20 mg/kg groups, and 2.0% (2/99) in the control group, respectively. At least one treatment-related SAE occurred in 2.1% (2/97), 2.0% (2/101), 6.3% (6/95) in the rifapentine 10, 15, and 20 mg/kg groups, and 2.0% (2/99) in the control group, respectively. Drug-induced liver injury was the most frequently reported SAE. The proportions of patients with culture conversion at week 8 were 72.5% (29/40), 79.1% (34/43), 82.9% (29/35) in the rifapentine 10, 15, and 20 mg/kg groups, and 85.3% (29/34) in the control group. At steady state, the median Cmax values were 20.5, 32.1 and 28.9 mg/L for rifapentine doses of 10, 15, and 20 mg/d, respectively. The median rifapentine AUC0-24 values were 344, 491, and 517 h·mg/L in the rifapentine 10, 15, and 20 mg/kg groups, respectively. Conclusions: All investigational groups were well-tolerated and not terminated early for safety reasons, although the rifapentine 20 mg/kg rifapentine group had the highest incidence of SAEs. Rifapentine doses of 15 and 20 mg/kg demonstrated high AUC0-24 and Cmax values at steady state, with comparable culture conversion rates.