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

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.

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