Acetohydroxamic Acid Combined With a Short-Course Regimen for MDR-TB (AHA-PLUS)

Phase 2Not Yet RecruitingNCT07393438

Shanghai Pulmonary Hospital, Shanghai, China120 enrolled

Overview

This study is a multicenter, randomized, double-blind, placebo-controlled phase II clinical trial to evaluate the safety, tolerability, and preliminary efficacy of acetohydroxamic acid (AHA) capsules combined with short-course regimens (BDLLfxC or BDCZ) in patients with multidrug-resistant tuberculosis (MDR-TB). The primary objectives are to assess the safety and tolerability of AHA combined with short-course regimens, and to determine the recommended phase II dose (RP2D) of AHA. The secondary objectives include evaluating the 8-week sputum culture conversion rate, pharmacokinetic parameters, and exploring DNA damage repair biomarkers as potential indicators of treatment response.

Background: Multidrug-resistant tuberculosis (MDR-TB) remains a significant global health challenge. Current treatment regimens face multiple bottlenecks including serious adverse effects, long treatment duration, and high cost. Acetohydroxamic acid (AHA), a urease inhibitor, represents a novel mechanism of action against tuberculosis. Recent research has revealed that Mycobacterium tuberculosis urease C (UreC) inhibits host DNA repair by interfering with the RUVBL1-RUVBL2-RAD51 complex, promoting bacterial survival. AHA, as a urease inhibitor, may block the pathogenic effect of UreC and restore host DNA repair function. Study Design: This is a parallel dual-study design evaluating AHA combined with two different background regimens: * Study A: AHA + BDLLfxC regimen (6-9 months) * Study B: AHA + BDCZ regimen (6-9 months) Each study randomizes participants in a 1:1:1:1 ratio to low-dose (500mg/day), medium-dose (750mg/day), high-dose (1000mg/day) AHA groups, or placebo group. A double-dummy design is employed to maintain blinding, where all participants receive identical-appearing capsules regardless of treatment assignment. The study includes a 6-9 month treatment period followed by mandatory follow-up visits at 3 and 6 months post-treatment, with optional follow-up every 6 months thereafter.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age 14 to \< 65 years, male or female * Confirmed rifampicin-resistant TB (RR-TB) or multidrug-resistant TB (MDR-TB) by molecular testing (e.g., Xpert MTB/RIF) or drug susceptibility testing * Positive sputum culture for Mycobacterium tuberculosis or positive molecular test * Chest imaging consistent with active pulmonary TB, or histologically confirmed extrapulmonary TB (excluding CNS, osteoarticular, and disseminated TB) * Body weight ≥ 40 kg * Karnofsky Performance Status ≥ 50 * Adequate laboratory parameters: * Hemoglobin ≥ 8.0 g/dL * ANC ≥ 1000/mm³ * Platelets ≥ 75,000/mm³ * ALT/AST ≤ 3 × ULN * Total bilirubin ≤ 2 × ULN * Creatinine clearance ≥ 30 mL/min * QTcF interval \< 450 ms (male) or \< 470 ms (female) * HIV-negative, confirmed by approved testing * No prior exposure to bedaquiline, delamanid, or linezolid for more than 1 month * Female participants of childbearing potential must agree to use effective contraception and have a negative pregnancy test * Signed informed consent Exclusion Criteria: * Central nervous system TB (e.g., TB meningitis), osteoarticular TB, or disseminated/miliary TB * Known allergy or serious adverse reaction to any study drug or background regimen component * Known resistance to bedaquiline, delamanid, or linezolid * Use of anti-TB drugs within the past 30 days that may interfere with study assessments, except in documented treatment failure cases * Severe comorbidities, including: * NYHA Class III-IV heart failure * History or risk factors for Torsades de Pointes * Child-Pugh B or C cirrhosis * Uncontrolled diabetes (HbA1c \> 10%) * Active malignancy * Current use of QT-prolonging medications that cannot be substituted * Current use of MAO inhibitors or serotonergic drugs * BMI \< 17 kg/m² with severe malnutrition * Grade 3-4 peripheral neuropathy at baseline * Pregnant or breastfeeding women * Any condition that, in the investigator's judgment, may interfere with study completion or data interpretation

Outcomes

Primary Outcomes

Change in Mycobacterium tuberculosis sputum bacterial load

Change in quantitative Mycobacterium tuberculosis colony-forming units (CFU) in sputum, expressed as log10 CFU/mL/day, measured using standardized microbiological culture methods.

Time frame: Baseline to Day 14

Secondary Outcomes

Time to sputum culture conversion

Time from treatment initiation to the first of two consecutive negative Mycobacterium tuberculosis sputum cultures collected at least 24 hours apart, assessed using standardized culture methods.

Time frame: Baseline to Week 8

Acetohydroxamic Acid Combined With a Short-Course Regimen for MDR-TB (AHA-PLUS)

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts