Safety and Tolerability of Metformin in People With Tuberculosis (TB) and Human Immunodeficiency Virus (HIV)

Prior treatment

• Resistance to any first-line ATT drug demonstrated by susceptibility testing.
• More than 14 days ATT for the current episode of TB, prior to enrollment.
• Use of metformin within 1 year prior to enrollment.

Other illness

• Any condition for which participation in the trial, as judged by the investigator, could compromise the well-being of the participant or prevent, limit or confound protocol-specified assessments.
• History of congestive heart failure, chronic liver disease, diabetes, autoimmune disease or malignancy.
• History of sensitivity to metformin.
• Hepatitis B surface antigen positive.
• Diagnosis of active Coronavirus Disease 2019 (COVID-19) at the time of screening or high suspicion of active COVID-19 disease during screening.

Lab values

• History of diabetes mellitus or fasting blood glucose \>7.0 mmol/L on screening evaluation.
• Acute or chronic metabolic acidosis based on reported medical history or laboratory tests performed on screening.
• Peripheral blood CD4 + T cell count \<50 cells/mm\^3 on screening evaluation.
• Hemoglobin \<9 g/dL for males, and \<8 g/dL (women) for females on screening evaluation.
• Platelet count \<50,000/mm\^3 on screening evaluation.
• Absolute neutrophil count \<750 cells/mm\^3 on screening evaluation.
• Estimated glomerular filtration rate (eGFR) \<60 mL/min/1.73m\^2 calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
• Serum bicarbonate \<18 mmol/L on screening evaluation.
• Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3 times the upper limit of normal (ULN) on screening evaluation.

Other

• 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 other forms of severe TB with high risk of a poor outcome as judged by the investigator.
• Pregnant or breastfeeding.
• Taking any fluoroquinolone antibiotic.
• Consumption of \>28 units (men) OR \>21 units (women) of alcohol/week.
• Body mass index (BMI) \<17kg/m\^2 on screening evaluation.
• Enrollment in another interventional study at any time during participation in the METHOD trial.
• Imprisonment at the time of or after enrollment in the METHOD trial.

• Age 18 through 65 years.
• HIV-1 seropositive status prior to or after screening.
• Chest radiograph compatible with pulmonary TB.
• Positive sputum Xpert MTB/RIF or Xpert MTB/RIF Ultra with one cycle threshold (Ct) \<25 or subsequent culture confirmation.
• RIF susceptibility diagnosed by an approved TB diagnostic test e.g. Xpert MTB/RIF (Cepheid), Xpert MTB/RIF Ultra (Cepheid) or BD MAX (Becton-Dickinson).
• Residence within study catchment area.
• If female of childbearing potential, willing to use contraception for the duration of study participation (Criteria for childbearing potential and for acceptable contraception). If male, willing to use condoms for the duration of metformin treatment plus 3 months after stopping metformin.
• Able and willing to provide informed consent.