PRESCIENT: A phase IIc, open-label, randomized controlled trial of ultra-short course bedaquiline, clofazimine, pyrazinamide and delamanid versus standard therapy for drug-susceptible tuberculosis

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PROJECT SUMMARY/ABSTRACT Standard first-line therapy for drug-susceptible tuberculosis (DS-TB) is highly effective but complicated by long treatment duration and rifamycin drug-drug interactions, particularly with antiretroviral therapy (ART) in high HIV- TB burden countries. A well-tolerated and efficacious rifamycin-free regimen that can shorten TB treatment duration is critically needed to achieve World Health Organization (WHO) targets towards ending TB. Our group pioneered the use of an artificial-intelligence-enabled parabolic response surface (PRS) platform allowing rapid identification of the most effective drug-dose combinations by testing only a small fraction of the total drug-dose efficacy response surface. This approach determined that drug combinations including bedaquiline (BDQ), clofazimine (CFZ), and pyrazinamide (PZA) at optimal dose ratios were more effective than standard DS-TB treatment, achieving relapse-free cure in mouse models within 3-4 weeks. Adding delamanid (DLM) as a 4th drug was equivalent in potency, achieving 100% relapse-free cure in only 3 weeks. This is substantially shorter than time to relapse-free cure in mouse studies supporting other TB treatment shortening trials. Bactericidal and sterilizing ability confirmed in other experiments, and favorable intra-lesional pharmacokinetics (PK), provides additional justification for evaluation of the BDQ-CFZ-PZA-DLM (BCZD) combination for treatment shortening. This 8-week rifamycin-free ultrashort regimen fulfills key requirements of the WHO target regimen profile for DS- TB: lower potential for drug-drug interactions, established tolerability and safety, constituent agents registered and accessible, and optimized dosing based on clinical data. We hypothesize that BCZD will demonstrate superior microbiologic efficacy relative to standard therapy during the first 8 weeks of treatment for patients with DS-TB. To test this, we shall conduct a Phase IIc, open-label, randomized controlled trial to investigate the efficacy and safety of an 8-week regimen of BCZD, paving the way for a definitive treatment-shortening trial and potentially shifting clinical practice. Our trial, called PRESCIENT, will randomize 156 adults with smear-positive DS-TB, with and without HIV, to receive BCZD for 8 weeks versus standard therapy for 26 weeks (1:1 ratio). The primary objective is a superiority efficacy comparison of time to liquid culture conversion through 8 weeks; the Phase IIc design also enables evaluation of clinical endpoints through extended post-treatment follow up to 56 weeks (Aim 1a - efficacy). Secondary objectives include rigorous assessment of safety and tolerability (Aim 1b - safety), and drug susceptibility testing and whole genome sequencing to determine frequency of treatment- emergent resistance to BCZD (Aim 1c - resistance). We shall also explore the effect of experimental drug exposure, derived from population PK models, on time to culture positivity as a measure of mycobacterial burden and treatment response, and on corrected QT interval (Aim 2 - PK/PD). PRESCIENT will be conducted at established clinical research sites in Haiti and South Africa which have access to large populations of patients with DS-TB and have the necessary expertise and infrastructure to successfully implement this project.