Acetohydroxamic Acid Combined With a Short-Course Regimen for the Treatment of Multidrug-Resistant Tuberculosis: A Phase II Clinical Trial
Trial Snapshot
- Phase
- Phase 2
- Status
- Not yet recruiting
- Sponsor
- Enrollment
- 120
- Locations
- 2
- Primary Endpoint
- Change in Mycobacterium tuberculosis sputum bacterial load
Study Overview
Brief Summary
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.
Detailed Description
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
Participants, care providers, investigators, and outcomes assessors are blinded to treatment allocation. The study drug and placebo are identical in appearance, packaging, and administration schedule.
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
AHA plus Short-Course Regimen
Participants in this arm receive acetohydroxamic acid (AHA) in combination with a short-course anti-tuberculosis regimen. AHA is administered at the protocol-defined dose and schedule. All background treatments are identical to those in the control arm.
Intervention: Acetohydroxamic Acid (Drug)
Placebo plus Short-Course Regimen
Participants in this arm receive a matching placebo in combination with the same short-course anti-tuberculosis regimen used in the experimental arm. The placebo is identical in appearance, packaging, and administration schedule to maintain blinding.
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Change in Mycobacterium tuberculosis sputum bacterial load
Time Frame: Baseline to Day 14
Change in quantitative Mycobacterium tuberculosis colony-forming units (CFU) in sputum, expressed as log10 CFU/mL/day, measured using standardized microbiological culture methods.
Secondary Outcomes
- Time to sputum culture conversion(Baseline to Week 8)
Investigators
yidian liu
Principal Investigator
Shanghai Pulmonary Hospital, Shanghai, China