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

The METHOD study will examine whether adding metformin to standard antibiotic treatment for tuberculosis (TB) in people with HIV is safe and well tolerated. The study will also test if adding metformin clears the infection more quickly and with less lung damage. When enrolled, participants will have an equal chance of being in the group that takes standard TB medicines alone or in the group that also takes metformin. Participants will have a chance to be put on either: 1) standard TB medicines (isoniazid, rifampicin, ethambutol and pyrazinamide for two months, continuing isoniazid and rifampin for four more months) only; or 2) the same standard TB medicines plus metformin. Participants randomized to the metformin arm will take metformin for eleven weeks, starting one week after starting the standard TB medicines. In addition to monitoring for side effects, all participants will have studies of drug levels and lung and immune function.

The METHOD trial is a Phase II A randomized, open-label trial of metformin added to standard anti-tuberculosis treatment (ATT) and anti-retroviral therapy (ART) in TB/HIV co-infected patients. HIV-positive adults (treated or ART-naïve) newly diagnosed with sputum culture-positive, drug-sensitive pulmonary TB will be recruited to and enrolled in the study. All participants in the interventional study will take standard ATT for drug-sensitive pulmonary TB starting at enrollment. Participants in the metformin arm will begin taking metformin 1 week later and metformin will be stopped on week-12. The "omics" control group will include those (treated or ART-naïve) without evidence of active TB. The total cohort is sample size N=112, comprising 56 participants each in two parallel study arms (standard therapy or standard therapy plus metformin) with the goal of retaining 100 participants with evaluable data for analysis. The duration of the METHOD trial is 5 years. The duration of individual participation in the interventional arms of the study is 36 weeks, not including an initial period of screening over an interval of up to 14 additional days prior to study enrollment. The final clinic visit coincides with the completion of ATT at week-24. The final follow-up contact is a phone interview at week-36. Ten consenting participants from each study arm (n=20 total) will have intensive pharmacokinetic/pharmacodynamic (PK/PD) sampling. The remaining 92 participants will have sparse PK/PD sampling.

Eligibility Criteria:
Inclusion Criteria:

1. Age 18 through 65 years.
2. HIV-1 seropositive status prior to or after screening.
3. Chest radiograph compatible with pulmonary TB.
4. Positive sputum Xpert TB/RIF or Ultra with one CT \<25.
5. RIF susceptibility diagnosed by Xpert TB/RIF or Ultra.
6. Residence within study catchment area.
7. 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.
8. Able and willing to provide informed consent. Inclusion criteria 1, 2, 6, 7, and 8 also apply to the control group.

Exclusion criteria:

1. 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.
2. 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.
3. TB meningitis or other forms of severe TB with high risk of a poor outcome as judged by the investigator.
4. Pregnant or breastfeeding.
5. Resistance to any first-line ATTB drug demonstrated by susceptibility testing.
6. More than 14 days ATT for the current episode of TB, prior to enrollment.
7. Taking any fluoroquinolone antibiotic.
8. History of diabetes mellitus or fasting blood glucose \>7.0 mmol/L on screening evaluation
9. History of congestive heart failure, chronic liver disease, diabetes, autoimmune disease or malignancy.
10. Consumption of \>28 units (men) OR \>21 units (women) of alcohol/week (see Protocol Appendix; Alcohol Pre-Screening Checklist).
11. Use of metformin within 1 year prior to enrollment.
12. History of sensitivity to metformin.
13. Acute or chronic metabolic acidosis based on reported medical history or laboratory tests performed on screening.
14. Body mass index (BMI) \<17.0 kg/m2 on screening evaluation.
15. Peripheral blood CD4 T cell count \<50 cells/mm3 on screening evaluation.
16. Hemoglobin \<9 g/dL for males, and \<8 g/dL (women) for females on screening evaluation.
17. Platelet count \<50,000/mm3 on screening evaluation.
18. Absolute neutrophil count \<750 cells/mm3 on screening evaluation.
19. Estimated glomerular filtration rate (eGFR) \<60 mL/min/1.73m2 calculated by the CKD-EPI equation.
20. Serum bicarbonate \<18 mmol/L on screening evaluation.
21. AST or ALT ≥3 times the upper limit of normal (ULN) on screening evaluation.
22. Hepatitis B surface antigen positive.
23. Enrollment in another interventional study at any time during participation in the METHOD trial.
24. Imprisonment at the time of or after enrollment in the METHOD trial.
25. Diagnosis of active COVID-19 at the time of screening or high suspicion of active COVID-19 disease during screening.

Exclusion criteria 1, 2, 4, 5, 7, 8-11, 13-25 also apply to participants in the omics control group. In addition, a positive sputum Xpert TB/RI, Mtb culture or any radiographic evidence of any pulmonary infectious disease process is exclusion criteria for the omics control group.