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| ID | Type | Description | Link |
|---|---|---|---|
| 2025ZD1802404 | Other Grant/Funding Number | China National Center for Biotechnology Development |
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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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| AHA plus Short-Course Regimen | Experimental | 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. |
|
| Placebo plus Short-Course Regimen | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Acetohydroxamic Acid | Drug | Acetohydroxamic acid administered according to the protocol-defined dose and schedule, in combination with a short-course anti-tuberculosis regimen. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Mycobacterium tuberculosis sputum bacterial load | Change in quantitative Mycobacterium tuberculosis colony-forming units (CFU) in sputum, expressed as log10 CFU/mL/day, measured using standardized microbiological culture methods. | Baseline to Day 14 |
| Measure | Description | Time Frame |
|---|---|---|
| Time to sputum culture conversion | 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. | Baseline to Week 8 |
| Measure | Description | Time Frame |
|---|---|---|
| Peak Plasma Concentration (Cmax) | Measurement of peak plasma concentration (Cmax) of acetohydroxamic acid using protocol-specified sampling and validated analytical methods. | Baseline to Day 14 |
| Changes in inflammatory biomarkers |
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:
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:
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
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| liu yidian, MD | Contact | 021-65115006 | liuyidian115@139.com |
| Name | Affiliation | Role |
|---|---|---|
| liu yidian | Shanghai Pulmonary Hospital, Shanghai, China | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Anhui Chest Hospital | Hefei | Anhui | 230000 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| Background | World Health Organization. Global Tuberculosis Report 2024. Geneva: WHO, 2024. | ||
| 37848028 | Background | 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. | |
| 23442 |
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The plan for sharing individual participant data (IPD) has not yet been finalized. Data sharing will depend on institutional policies, ethical approvals, and resource availability at the time of study completion.
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| ID | Term |
|---|---|
| D018088 | Tuberculosis, Multidrug-Resistant |
| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
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| ID | Term |
|---|---|
| C006358 | acetohydroxamic acid |
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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.
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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.
| Placebo | Drug | Matching placebo identical in appearance, packaging, and administration schedule to acetohydroxamic acid, administered with the same short-course anti-tuberculosis regimen. |
|
Changes in serum inflammatory markers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and other protocol-specified cytokines.
| Baseline to Day 14 |
| Radiographic Severity Score on Chest X-ray or CT | Radiographic severity score assessed using a standardized scoring system evaluating extent of pulmonary involvement. Higher scores indicate more severe radiographic abnormalities. | Baseline to Week 8 |
| Time to Peak Concentration (Tmax) | Measurement of time to peak plasma concentration (Tmax) of acetohydroxamic acid based on protocol-defined pharmacokinetic sampling. | Baseline to Day 14 |
| Area Under the Concentration-Time Curve (AUC) | Assessment of the area under the plasma concentration-time curve (AUC) for acetohydroxamic acid using validated pharmacokinetic analysis. | Baseline to Day 14 |
| Change in Cavity Size on Chest Imaging | Change in the maximum diameter of pulmonary cavities measured on chest X-ray or CT using protocol-specified measurement methods. | Baseline to Week 8 |
| Shanghai Pulmonary Hospital | Shanghai | Shanghai Municipality | 200433 | China |
|
| Background |
| 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. |
| 36630546 | Background | 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/ |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |