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

Study Overview

• Status: Not yet recruiting
• Conditions: Multidrug-Resistant Tuberculosis; MDR-TB; Rifampicin-resistant Tuberculosis; RR-TB
• Intervention / Treatment: Drug: Acetohydroxamic Acid; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: liu yidian, MD; Phone Number: 021-65115006; Email: liuyidian115@139.com

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China, 230000
      • Anhui Chest Hospital
      • Contact: Wang Hua, MD; Phone Number: 0551-6362-3114; Email: 1726553540@qq.com
      • Contact: Wang Hua, MD; Phone Number: 0551-6362-3114
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200433
      • Shanghai Pulmonary Hospital
      • Contact: liu yidian, MD; Phone Number: 021-65115006; Email: liuyidian115@139.com
      • Contact: Fan Liping; Phone Number: 021-65115006; Email: fkyyflp@163.com
      • Principal Investigator: liu yidian, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Acetohydroxamic Acid; Acetohydroxamic acid administered according to the protocol-defined dose and schedule, in combination with a short-course anti-tuberculosis regimen.
Placebo Comparator: 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.	Drug: Placebo; Matching placebo identical in appearance, packaging, and administration schedule to acetohydroxamic acid, administered with the same short-course anti-tuberculosis regimen.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Shanghai Pulmonary Hospital, Shanghai, China
• Investigators: Principal Investigator: liu yidian, Shanghai Pulmonary Hospital, Shanghai, China

Publications and helpful links

General Publications

• 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.
• 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.
• World Health Organization. WHO consolidated guidelines on tuberculosis. Module 4: treatment of drug-resistant tuberculosis. 2024 update. Geneva: WHO; 2024.

Study record dates

Study Major Dates

• Study Start (Estimated): February 21, 2026
• Primary Completion (Estimated): February 28, 2027
• Study Completion (Estimated): November 30, 2028

Study Registration Dates

• First Submitted: January 19, 2026
• First Submitted That Met QC Criteria: January 31, 2026
• First Posted (Actual): February 6, 2026

Study Record Updates

• Last Update Posted (Actual): February 6, 2026
• Last Update Submitted That Met QC Criteria: January 31, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Phase II; DNA Repair; RP2D; Acetohydroxamic Acid; Short-Course Regimen; BDLLfxC; BDCZ
• Additional Relevant MeSH Terms: Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Multidrug-Resistant; acetohydroxamic acid
• Other Study ID Numbers: AHA-PLUS-MDRTB-2026; 2025ZD1802404 (Other Grant/Funding Number: China National Center for Biotechnology Development)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No