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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Acetohydroxamic Acid
  Acetohydroxamic acid administered according to the protocol-defined dose and schedule, in combination with a short-course anti-tuberculosis regimen.
• Препарат Placebo
  Matching placebo identical in appearance, packaging, and administration schedule to acetohydroxamic acid, administered with the same short-course anti-tuberculosis regimen.

Первичные конечные точки

• Change in Mycobacterium tuberculosis sputum bacterial load [Срок оценки: Baseline to Day 14]

Вторичные конечные точки (1)

• Time to sputum culture conversion [Срок оценки: Baseline to Week 8]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Китай · 2 центра

• Anhui Chest Hospital — Хэфэй
• Shanghai Pulmonary Hospital — Шанхай

Публикации

• World Health Organization. Global Tuberculosis Report 2024. Geneva: WHO, 2024.
• Liu S, Guan L, Peng C, Cheng Y, Cheng H, Wang F, Ma M, Zheng R, Ji Z, Cui P, Ren Y, Li L, Shi C, Wang J, Huang X, Cai X, Qu D, Zhang H, Mao Z, Liu H, Wang P, Sha W, Yang H, Wang L, Ge B. Mycobacterium tuberculosis suppresses host DNA repair to boost its intracellular survival. Cell Host Microbe. 2023 Nov 8;31(11):1820-1836.e10. doi: 10.1016/j.chom.2023.09.010. Epub 2023 Oct 16. PMID 37848028
• Griffith DP, Gibson JR, Clinton CW, Musher DM. Acetohydroxamic acid: clinical studies of a urease inhibitor in patients with staghorn renal calculi. J Urol. 1978 Jan;119(1):9-15. doi: 10.1016/s0022-5347(17)57366-8. PMID 23442
• WHO consolidated guidelines on tuberculosis: Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update [Internet]. Geneva: World Health Organization; 2022. Available from http://www.ncbi.nlm.nih.gov/books/NBK588564/ PMID 36630546

Идентификаторы

NCT: NCT07393438 · AHA-PLUS-MDRTB-2026 · 2025ZD1802404

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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