Optimizing (O) rifapentine-based (RI) regimen and shortening (EN) the treatment of drug-susceptible tuberculosis (T) (ORIENT) using an adaptive seamless design: study protocol of a multicenter randomized controlled trial

Abstract

Background: Standard treatment for drug-susceptible tuberculosis (DS-TB) includes a multidrug regimen requiring at least 6 months of treatment, and this lengthy treatment easily leads to poor adherence. There is an urgent need to simplify and shorten treatment regimens to reduce interruption and adverse event rates, improve compliance, and reduce costs.

Methods: ORIENT is a multicenter, randomized controlled, open-label, phase II/III, non-inferiority trial involving DS-TB patients to evaluate the safety and efficacy of short-term regimens compared with the standardized six-month treatment regimen. In stage 1, corresponding to a phase II trial, a total of 400 patients are randomly divided into four arms, stratified by site and the presence of lung cavitation. Investigational arms include 3 short-term regimens with rifapentine 10 mg/kg, 15 mg/kg, and 20 mg/kg, while the control arm uses the standardized six-month treatment regimen. A combination of rifapentine, isoniazid, pyrazinamide, and moxifloxacin is administered for 17 or 26 weeks in rifapentine arms, while a 26-week regimen containing rifampicin, isoniazid, pyrazinamide, and ethambutol is applied in the control arm. After the safety and preliminary effectiveness analysis of patients in stage 1, the control arm and the investigational arm meeting the conditions will enter into stage 2, which is equivalent to a phase III trial and will be expanded to recruit DS-TB patients. If all investigational arms do not meet the safety conditions, stage 2 will be canceled. In stage 1, the primary safety endpoint is permanent regimen discontinuation at 8 weeks after the first dose. The primary efficacy endpoint is the proportion of favorable outcomes at 78 weeks after the first dose for both two stages.

Discussion: This trial will contribute to the optimal dose of rifapentine in the Chinese population and suggest the feasibility of the short-course treatment regimen containing high-dose rifapentine and moxifloxacin for DS-TB.

Trial registration: The trial has been registered on ClinicalTrials.gov on 28 May 2022 with the identifier NCT05401071.

Keywords: Drug-susceptible tuberculosis; Non-inferiority; Randomized controlled trial; Short-course regimen; Tuberculosis.

Fig. 1

ORIENT study schematic. The trial plans to recruit DS-TB patients susceptible to rifampicin, isoniazid, pyrazinamide, ethambutol, and fluoroquinolones. Participants will be randomly divided into different arms as shown in the figure. Abbreviations in this figure: DS-TB: drug-susceptible tuberculosis. 8wHRZE/18wHR: rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol (E) for 8-week intensive phase and rifampicin and isoniazid for 18-week continuous phase. 8wHPZM/9wHPM: rifapentine (P), isoniazid(H), pyrazinamide (Z), and moxifloxacin (M) for 8-week intensive phase and rifapentine, isoniazid and moxifloxacin for 9-week continuous phase. 8wHPZM/18wHPM: rifapentine (P), isoniazid (H), pyrazinamide (Z), and moxifloxacin (M) for 8-week intensive phase and rifapentine, isoniazid and moxifloxacin for 18-week continuous phase