Project Summary/Abstract Isoniazid-monoresistant (IMR) tuberculosis (TB) comprises 1.1 million (11%) of the estimated 10 million new TB cases annually. Recent scientific advances for drug-susceptible TB (DS-TB) and rifampin-resistant TB (RR- TB) include reductions in treatment duration from 6 to 4 months for DS-TB and from 18-20 months to 6 months for RR-TB. In contrast, innovations in care have been modest for IMR-TB, which has a higher worldwide burden than RR-TB. The current standard of care (SOC) for IMR-TB recommended by the World Health Organization (WHO) is 6 months of rifampin, ethambutol, pyrazinamide, and levofloxacin (6REZLfx). This regimen requires pyrazinamide for six months, three times longer than in the SOC for DS-TB; its safety and tolerability are poorly described; and the evidence underpinning it is derived from an individual patient data meta-analysis and not from a randomized controlled clinical trial. The proposed R34 NIAID Clinical Trial Planning Grant will plan an open-label, randomized, controlled Phase 2C clinical trial that will compare the time to sputum culture conversion in liquid mycobacterial culture (Aim 1), the proportion of Grade 3 or higher adverse events (Aim 2), and the proportion of relapse-free cure at 12 months (Aim 3) among participants randomized to one of two novel 4-month intervention regimens compared to the 6-month SOC control for IMR- TB. For the first intervention arm, we will adapt the S31/A5349 trial’s 4-month isoniazid, rifapentine, pyrazinamide, and moxifloxacin (HPZM) regimen’s proven PZM backbone for IMR-TB with two key innovations: [1] optimization of rifapentine dosing from 1200 mg daily to 1500 mg daily based on analyses from the S31/A5349’s pharmacokinetic sub-study, and [2] substitution of clofazimine for isoniazid in HPZM, yielding a novel CPZM regimen which circumvents isoniazid resistance and may support a 4-month treatment duration for IMR-TB. For the second intervention arm, we will leverage preclinical and clinical data showing that a novel rifamycin-free combination of approved drugs, bedaquiline, linezolid, pyrazinamide, and moxifloxacin (BLZM), may outperform the TB-PRACTECAL trial’s 6-month bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) regimen and permit treatment shortening to 4 months for IMR-TB. The proposed trial fills a critical and unmet need in IMR-TB drug development by investigating regimens that are congruent with priorities in the NIAID Strategic Plan for Tuberculosis Research and are readily implementable in high TB burden settings. The trial addresses two research gaps identified by international (WHO) and US-based (ATS/CDC/ERS/IDSA) guidelines development groups, namely [1] the evaluation of new regimens specifically for IMR-TB in randomized controlled trials and [2] reduction of the duration of pyrazinamide in treatment regimens for IMR- TB. It also addresses the WHO target regimen profile for IMR-TB: [1] treatment shortening, [2] evaluation of reg...