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

• Status: Recruiting
• Trial end date: 2024-09-30
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Massachusetts, Worcester
• Collaborators: A*STAR Infectious Diseases Labs; Aurum Institute; National Institute of Allergy and Infectious Diseases (NIAID); Singapore Immunology Network; University of Cape Town
• Treatments: Ethambutol; Isoniazid; Metformin; Pyrazinamide; Rifampin

Criteria

Inclusion Criteria:

• HIV-1 seropositive status prior to or after screening.

• Chest radiograph compatible with pulmonary TB

• Positive sputum pert TB/Rifampicin (RIF) with one Ct<25 or subsequent culture confirmation

• RIF susceptibility diagnosed by GeneXpert MTB/RIF

• Residence within study catchment area

• If female of childbearing potential, willing to use contraception for the duration of study participation

• Able and willing to provide informed consent

Exclusion Criteria:

• 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.

• 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.

• Resistance to any first-line ATT drug demonstrated by susceptibility testing.

• More than 7 days ATT for the current episode of TB, prior to enrollment.

• Taking an ART regimen that contains Dolutegravir (DTG).

• Taking any fluoroquinolone antibiotic.

• Minimally advanced pulmonary TB on chest x-ray (NTRDA criteria).

• History of diabetes mellitus or fasting blood glucose ≥7.0 mmol/L on screening evaluation.

• History of congestive heart failure, chronic liver disease, autoimmune disease or malignancy.

• Consumption of >28 units (men) OR >21 units (women) of alcohol/week

• Use of metformin within 1 year prior to enrollment.

• History of sensitivity to metformin.

• Acute or chronic metabolic acidosis based on reported medical history or laboratory tests performed on screening evaluation.

• Body mass index (BMI) <17.0 kg/m2 on screening evaluation.

• Peripheral blood Cluster Differentiation 4 (CD4) T cell count <200 cells/mm3 on screening evaluation.

• Hemoglobin <10 g/dL on screening evaluation.

• Platelet count <50,000/mm3 on screening evaluation.

• Absolute neutrophil count <750 cells/mm3 on screening evaluation.

• Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 calculated by the chronic kidney disease epidemiology (CKD-EPI) equation.

• Serum bicarbonate <20 mmol/L on screening evaluation.

• Asparate aminotransferase (AST or ALT) ≥3 times the upper limit of normal (ULN) on screening evaluation.

• Anti-hepatitis B surface antigen or hepatitis C virus seropositive.

• Imprisonment at the time of or after enrollment in the METHOD trial.

• Diagnosis of active COVID-19 at time of screening or high suspicion of active Coronavirus disease of 2019 (COVID-19) disease during screening