A Trial of 2 Disease-Modifying Drugs (Metformin and N-acetylcysteine ) to Promote TB Lung Function Recovery

NCT07136987 | Not Yet Recruiting Phase 3 DMC

• 1 other identifier: AUR1-22-465 TB-MET-NAC
• Study Type: interventional
• Target: 1,104
• Locations: 0 countries
• Sites: N/A

Brief Summary

Tuberculosis is a leading global cause of morbidity and mortality. Even if cured, a majority patients are left with bronchiectasis and fibrosis, permanent conditions that impair lung function. Large cohort studies have confirmed that even modest loss of lung function is associated with excess mortality risk. This study will examine if two treatments, metformin and N-acetylcysteine (NAC), can promote the recovery of lung function in TB if given together with standard TB treatment. There currently are no drugs approved for this indication.

Conditions

Tuberculosis

Keywords

lung function; FEV1; relapse

Outcome Measures

Primary Outcomes (2)

• FEV1

  FEV1 after adjustment for baseline covariates including FEV1, in a superiority comparison

  month 18

• Favourable treatment outcome

  Proportion of participants achieving a favourable treatment outcome (other than death, failure, recurrence, loss, default) in a non-inferiority comparison

  18 months

Secondary Outcomes (6)

• Other measures of lung function

  Through month 18

• Microbiology

  Through month 6

• Pharmacology

  After 1 month of TB treatment

• Serious and non-serious adverse events

  Through month 18

• Radiography

  18 months

Study Arms (3)

Metformin plus SOC

EXPERIMENTAL

Metformin 1500 mg total daily for 6 months plus standard TB treatment

Drug: Metformin

N-acetylcysteine (NAC) plus SOC

EXPERIMENTAL

NAC 3600 mg total daily for 6 months plus standard TB treatment

Dietary Supplement: N-Acetylcysteine (NAC) Treatment

Control (SOC)

ACTIVE COMPARATOR

Standard TB treatment alone

Combination Product: Standard TB treatment

Interventions

Metformin DRUG

Metformin 500 mg QAM x 1 wk, then 500 mg BID x 1 wk, then 1000 mg QAM and 500 mg QPM, plus standard TB treatment

Metformin plus SOC

N-Acetylcysteine (NAC) Treatment DIETARY_SUPPLEMENT

N-acetylcysteine (NAC) 1800 mg orally twice daily plus standard TB treatment

N-acetylcysteine (NAC) plus SOC

Standard TB treatment COMBINATION_PRODUCT

Standard TB treatment

Control (SOC)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide signed written consent (or, in the case of illiteracy, witnessed oral consent plus patient thumbprint) prior to undertaking any trial-related procedures.
• Body weight (in light clothing without shoes) between 30 and 90 kg.
• Radiographic evidence of pulmonary tuberculosis
• Positive Xpert TB/RIF (original or Ultra) for MTB
• RIF susceptibility diagnosed by Xpert TB/RIF, with subsequent culture confirmation
• FEV1≤65% of predicted
• Eligible for treatment with a 6-month regimen comprised of INH, RIF, EMB, and PZA
• If sexually active, willing to use effective contraceptive methods for a period of 9 months (3 months post-study treatment)
• HIV-1 seronegative, or if HIV-1 seropositive, presenting to a non-India clinical site with a CD4 T cell count ≥100/µl and either receiving ART or willing to start ART during study participation
• SARS-CoV-2 PCR or antigen test negative, or if positive, either fully vaccinated against Covid-19 or with D-dimer \<1 µg/ml
• eGFR ≥30 ml/min/1.73 m2 (CKD EPI 2009)

You may not qualify if:

• Any condition for which participation in the trial, as judged by the investigator, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments
• Currently pregnant or nursing, or pregnancy planned in next 12 months
• Is critically ill, and in the judgment of the investigator has a diagnosis likely to result in death during the trial or the follow-up period.
• TB meningitis or spondylitis, or other forms of severe tuberculosis with high risk of a poor outcome as judged by the investigator.
• History of allergy or hypersensitivity to any of the trial therapies or related substances.
• History of a chronic lung condition (including COPD or asthma) requiring treatment in the previous year
• Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial.
• Prior TB treatment in the preceding 6 months, other than within the 7 days immediately prior to enrollment.
• Angina pectoris requiring treatment with nitroglycerin or other nitrates
• Cardiac arrhythmia requiring medication, or any clinically significant ECG abnormality, in the opinion of the investigator
• History of diabetes mellitus requiring treatment with metformin or resulting in hospitalization for hyper- or hypoglycaemia within the past year prior to start of screening
• Use of systemic corticosteroids within the past 28 days.
• Patients requiring treatment with medications not compatible with rifampin, such as HIV-1 protease inhibitors
• History of Pneumoconiosis.
• Subjects with any of the following abnormal laboratory values: hemoglobin \<8 g/dL, platelets \<100x109 cells/L, serum potassium \<3.5 mM/L, alanine aminotransferase (ALT) ≥2.0 x ULN, alkaline phosphatase (AP) \>5.0 x ULN, total bilirubin \>1.5 mg/dL, HbA1c \>6.5 %

Sponsors & Collaborators

• Open Source Pharma Foundation: lead
• National Institute for Research in Tuberculosis, Chennai, India: collaborator

Related Publications (5)

• Pavan Kumar N, Padmapriyadarsini C, Nancy A, Tamizhselvan M, Mohan A, Reddy D, Ganga Devi NP, Rathinam P, Jeyadeepa B, Shandil RK, Guleria R, Singh M, Babu S. Effect of Metformin on systemic chemokine responses during anti-tuberculosis chemotherapy. Tuberculosis (Edinb). 2024 Sep;148:102523. doi: 10.1016/j.tube.2024.102523. Epub 2024 Jun 1.

  PMID: 38850838 BACKGROUND

• Kumar AKH, Kadam A, Karunaianantham R, Tamizhselvan M, Padmapriyadarsini C, Mohan A, Jeyadeepa B, Radhakrishnan A, Singh UB, Bapat S, Mane A, Kumar P, Mamulwar M, Bhavani PK, Haribabu H, Rath N, Guleria R, Khan AM, Menon J; METRIF Team. Effect of Metformin on Plasma Exposure of Rifampicin, Isoniazid, and Pyrazinamide in Patients on Treatment for Pulmonary Tuberculosis. Ther Drug Monit. 2024 Jun 1;46(3):370-375. doi: 10.1097/FTD.0000000000001149. Epub 2023 Nov 28.

  PMID: 38019456 BACKGROUND

• Padmapriydarsini C, Mamulwar M, Mohan A, Shanmugam P, Gomathy NS, Mane A, Singh UB, Pavankumar N, Kadam A, Kumar H, Suresh C, Reddy D, Devi P, Ramesh PM, Sekar L, Jawahar S, Shandil RK, Singh M, Menon J, Guleria R. Randomized Trial of Metformin With Anti-Tuberculosis Drugs for Early Sputum Conversion in Adults With Pulmonary Tuberculosis. Clin Infect Dis. 2022 Aug 31;75(3):425-434. doi: 10.1093/cid/ciab964.

  PMID: 34849651 BACKGROUND

• Mapamba DA, Sabi I, Lalashowi J, Sauli E, Buza J, Olomi W, Mtafya B, Kibona M, Bakuli A, Rachow A, Velen K, Hoelscher M, Ntinginya NE, Charalambous S, Churchyard G, Wallis RS; TB SEQUEL consortium. N-acetylcysteine modulates markers of oxidation, inflammation and infection in tuberculosis. J Infect. 2025 Feb;90(2):106379. doi: 10.1016/j.jinf.2024.106379. Epub 2025 Jan 3.

  PMID: 39756697 BACKGROUND

• Wallis RS, Sabi I, Lalashowi J, Bakuli A, Mapamba D, Olomi W, Siyame E, Ngaraguza B, Chimbe O, Charalambous S, Rachow A, Ivanova O, Zurba L, Myombe B, Kunambi R, Hoelscher M, Ntinginya N, Churchyard G. Adjunctive N-Acetylcysteine and Lung Function in Pulmonary Tuberculosis. NEJM Evid. 2024 Sep;3(9):EVIDoa2300332. doi: 10.1056/EVIDoa2300332. Epub 2024 Aug 27.

  PMID: 39189858 BACKGROUND

MeSH Terms

Conditions

Tuberculosis; Recurrence

Interventions

Metformin; Acetylcysteine; Therapeutics

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Robert Wallis, MD

  OSPF and Aurum Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jaykumar Menon, JD

CONTACT

+19173020722; jaykumar.menon@ospfound.org

Nibedita Rath, PhD

CONTACT

+919900506286; nibedita.rath@ospfound.org

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants will be randomized 1:1:1 to the 3 arms.

Study Record Dates

• First Submitted: August 5, 2025
• First Posted: August 22, 2025
• Study Start: January 1, 2026
• Primary Completion (Estimated): January 1, 2031
• Study Completion (Estimated): July 1, 2031
• Last Updated: August 22, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: IPD will be available after the publication of the primary manuscript. The end date has not yet been determined.
• Access Criteria: Qualified investigators.