# A Phase 2C Randomized, Controlled, Open-Label Trial of Novel Shortened Regimens for the Treatment of Isoniazid-Monoresistant TB (IMR-TB)

> **NIH NIH R34** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $256,504

## Abstract

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...

## Key facts

- **NIH application ID:** 10764464
- **Project number:** 1R34AI179568-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Gustavo Eduardo Velasquez
- **Activity code:** R34 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $256,504
- **Award type:** 1
- **Project period:** 2024-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764464

## Citation

> US National Institutes of Health, RePORTER application 10764464, A Phase 2C Randomized, Controlled, Open-Label Trial of Novel Shortened Regimens for the Treatment of Isoniazid-Monoresistant TB (IMR-TB) (1R34AI179568-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10764464. Licensed CC0.

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