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

Official title

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

Overview

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.

Detailed description

Tuberculosis is a leading global cause of morbidity and mortality. Current treatments are inadequate, requiring patients closely adhere to multi-drug regimens that are long, complex, and often poorly tolerated and/or ineffective. Even if cured, a majority patients are left with bronchiectasis and fibrosis, permanent conditions that impair lung function, particularly causing loss of FEV1% (the maximal 1-second exhaled volume in relation to age, sex, and height). FEV1 loss has profound long-term health consequences. Large cohort studies have confirmed that even modest loss of FEV1, remaining within 'normal' limits, is associated with excess mortality risk. This is most pronounced in low-income countries where TB is most prevalent. This study will examine if two treatments, metformin and N-acetylcysteine (NAC), can promote the recovery of lung function in TB. There currently are no drugs approved for this indication.

Interventions

• Drug Metformin
  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
• Dietary supplement N-Acetylcysteine (NAC) Treatment
  N-acetylcysteine (NAC) 1800 mg orally twice daily plus standard TB treatment
• Combination product Standard TB treatment
  Standard TB treatment

Primary outcome measures

• FEV1 [Time frame: month 18]
• Favourable treatment outcome [Time frame: 18 months]

Secondary outcome measures (6)

• Other measures of lung function [Time frame: Through month 18]
• Microbiology [Time frame: Through month 6]
• Pharmacology [Time frame: After 1 month of TB treatment]
• Serious and non-serious adverse events [Time frame: Through month 18]
• Radiography [Time frame: 18 months]
• Immunology [Time frame: 2, 6, and 18 months]

Eligibility criteria

Inclusion criteria

• 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)

Exclusion criteria

• 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 %

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• 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
• 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; PMID 38019456
• 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/ci PMID 34849651
• 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
• 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

Identifiers

NCT: NCT07136987 · AUR1-22-465 TB-MET-NAC

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗