MDR-TB, Multidrug-Resistant Tuberculosis, Rifampicin-resistant Tuberculosis, RR-TB
Conditions
Keywords
Acetohydroxamic Acid, Short-Course Regimen, BDLLfxC, BDCZ, DNA Repair, RP2D, Phase II
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. 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.
Interventions
DRUGAcetohydroxamic Acid
Acetohydroxamic acid administered according to the protocol-defined dose and schedule, in combination with a short-course anti-tuberculosis regimen.
DRUGPlacebo
Matching placebo identical in appearance, packaging, and administration schedule to acetohydroxamic acid, administered with the same short-course anti-tuberculosis regimen.
Sponsors
Shanghai Pulmonary Hospital, Shanghai, China
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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.
Intervention model description
Participants are randomly assigned in a 1:1 ratio to receive either acetohydroxamic acid plus a short-course regimen or placebo plus the same regimen, with no crossover between groups.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mycobacterium tuberculosis sputum bacterial load | 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
| Measure | Time frame | Description |
|---|---|---|
| Time to sputum culture conversion | Baseline to Week 8 | 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. |
Countries
China
Contacts
CONTACTliu yidian, MD
PRINCIPAL_INVESTIGATORliu yidian
Shanghai Pulmonary Hospital, Shanghai, China
Outcome results
None listed