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

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.

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 %