The PRESCIENT trial is a Phase IIc, open-label, randomized trial that will compare an 8-week regimen of bedaquiline (BDQ), clofazimine (CFZ), pyrazinamide (PZA), and delamanid (DLM) with standard treatment for drug-susceptible pulmonary tuberculosis. Eligible participants will be randomized in a 1:1 ratio to BDQ, CFZ, PZA, and DLM (BCZD) or standard anti-TB therapy. Randomization will be stratified by presence of lung cavitation and HIV status.~Participants will be randomized to one of two arms:~Arm 1 (Experimental): BDQ 200 mg for 8 weeks + PZA 1000 - 2000 mg (according to weight) for 8 weeks + CFZ 300 mg for 2 weeks, followed by 100 mg for 6 weeks + DLM 200 mg for 8 weeks, all given once daily.~Arm 2 (Standard of Care): RIF, INH, EMB and PZA for 8 weeks, followed by RIF and INH for 18 weeks.~Medications will be given daily in fixed dose combinations at standard weight-based doses. Adherence will be supported through automated reminders and monitored remotely in real time with Wisepill electronic adherence monitoring devices. Participants in the experimental arm with evidence of poor clinical response at the end of therapy, defined as persistent symptoms consistent with active TB, lack of improvement or worsening disease on chest X-ray, or sputum smear positivity on two samples, will be re-treated with standard TB therapy, as will be those with positive Mtb culture collected at week 8 or later. The primary analysis is a superiority efficacy comparison of time to liquid culture conversion through 8 weeks in the experimental (BCZD) arm vs. the standard therapy arm. Participants will have extended post-treatment follow up to evaluate clinical efficacy as a secondary composite outcome measure at 56 weeks after randomization (48 weeks after completion of experimental therapy, when most relapses are expected to occur). The other key secondary outcome is safety, measured as the proportion with new Grade 3 or higher adverse events; we shall focus on QTcF prolongation as an adverse event of special interest. Through an efficient Phase IIc design, the PRESCIENT trial will test microbiological efficacy, evaluate safety, and detect treatment-emergent resistance with the ultra-short BCZD regimen. PRESCIENT will provide rapid evidence for microbiological efficacy as well as key information on safety and clinical treatment outcomes to inform the feasibility and promise of a subsequent phase III treatment-shortening trial.
The PRESCIENT trial is a Phase IIc, open-label, randomized trial that will compare an 8-week regimen of bedaquiline (BDQ), clofazimine (CFZ), pyrazinamide (PZA), and delamanid (DLM) with standard treatment for drug-susceptible pulmonary tuberculosis. Eligible participants will be randomized in a 1:1 ratio to BDQ, CFZ, PZA, and DLM (BCZD) or standard anti-TB therapy.~Participants in the experimental arm with evidence of poor clinical response at the end of therapy will be re-treated with standard TB therapy. The primary analysis is a superiority efficacy comparison of time to liquid culture conversion through 8 weeks in the experimental (BCZD) arm vs. the standard therapy arm. The other key secondary outcome is safety.