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

Acetohydroxamic Acid Combined With a Short-Course Regimen for the Treatment of Multidrug-Resistant Tuberculosis: A Phase II Clinical Trial

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.

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