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

NCT04930744 | Completed Phase 2 DMC FDA Drug

• 2 other identifiers: AUR1-1-1995U01AI134585
• Study Type: interventional
• Target: 112
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Tuberculosis; Pulmonary Tuberculosis; HIV Coinfection

Keywords

Metformin; Tuberculosis; Anti-Tuberculosis Treatment (ATT); Anti-Viral Therapy (ART)

Outcome Measures

Primary Outcomes (1)

• Number of participants experiencing grade 3 or higher adverse events

  The cumulative number of participants in each arm experiencing grade 3 or higher adverse events, assessed on every visit from week-1 to week-24.

  Up to 24 weeks

Secondary Outcomes (8)

• Time to sputum liquid culture conversion

  Up to 24 weeks

• Change in radiographic severity score from baseline to TB treatment completion

  24 weeks

• Change in 6-minute walk test distance from baseline to TB treatment completion

  24 weeks

• Change in 6-minute walk test distance-saturation product from baseline to TB treatment completion

  24 weeks

• Change in FVC from baseline to TB treatment completion

  24 weeks

Study Arms (2)

Standard Tuberculosis Medicines

ACTIVE COMPARATOR

Participants will have a chance to be put on standard tuberculosis medicines (Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) only. It is a combination pill pack that will be taken by mouth daily. The combination pack includes Isoniazid, Rifampicin, Ethambutol, and Pyrazinamide which they will take for 2 months. They will only take Isoniazid and Rifampicin for the last 4 months.

Drug: Isoniazid; Drug: Rifampicin; Drug: Ethambutol; Drug: Pyrazinamide

Standard Tuberculosis Medicines and Metformin

EXPERIMENTAL

Participants will have a chance to be put on standard tuberculosis medicines (Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) only. It is a combination pill pack that will be taken by mouth daily. The combination pack includes Isoniazid, Rifampicin, Ethambutol, and Pyrazinamide which they will take for 2 months. They will only take Isoniazid and Rifampicin for the last 4 months. For this arm, they will also take Metformin hydrochloride one 500 mg tablet daily starting one week after the initiation of tuberculosis medicines, then increasing to one 500 mg tablet twice daily through study week-12 for a total 11 weeks of metformin exposure.

Drug: Isoniazid; Drug: Rifampicin; Drug: Ethambutol; Drug: Pyrazinamide; Drug: Metformin hydrochoride

Interventions

Rifampicin DRUG

Rifampicin, dose prescribed by participant's physician, will be taken by mouth daily. Rifampicin is in a combination pill pack with the other standard ATT medications.

Standard Tuberculosis Medicines; Standard Tuberculosis Medicines and Metformin

Ethambutol DRUG

Ethambutol, dose prescribed by participant's physician, will be taken by mouth daily. Ethambutol is in a combination pill pack with the other standard ATT medications.

Also known as: Myambutol

Standard Tuberculosis Medicines; Standard Tuberculosis Medicines and Metformin

Pyrazinamide DRUG

Pyrazinamide, dose prescribed by participant's physician, will be taken by mouth daily. Pyrazinamide is in a combination pill pack with the other standard ATT medications.

Standard Tuberculosis Medicines; Standard Tuberculosis Medicines and Metformin

Isoniazid DRUG

Isoniazid, dose prescribed by participant's physician, will be taken by mouth daily. Isoniazid, is in a combination pill pack with the other standard ATT medications.

Standard Tuberculosis Medicines; Standard Tuberculosis Medicines and Metformin

Metformin hydrochoride DRUG

Metformin hydrochloride 500 mg tablet once daily starting one week after the initiation of TB treatment, then increasing to twice daily through study week-12 (11 weeks total metformin treatment).

Also known as: Glucophage

Standard Tuberculosis Medicines and Metformin

Eligibility Criteria

• Age: 18 Years - 65 Years
• Gender Eligibility Details: Participant eligibility is based on self-representation of gender identity.
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 pert 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.

You may not qualify if:

• 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 14 days ATT for the current episode of TB, prior to enrollment.
• Taking any fluoroquinolone antibiotic.
• History of diabetes mellitus or fasting blood glucose \>7.0 mmol/L on screening evaluation.
• History of congestive heart failure, chronic liver disease, diabetes, 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.
• Body mass index (BMI) \<17kg/m\^2 on screening evaluation.
• Peripheral blood CD4 T cell count \<50 cells/mm\^3 on screening evaluation.

Sponsors & Collaborators

• University of Massachusetts, Worcester: lead
• Aurum Institute: collaborator
• A*STAR Infectious Diseases Labs: collaborator
• Wits Health Consortium (Pty) Ltd: collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• University of Cape Town: collaborator

Study Sites (2)

Tembisa Clinical Research Centre-The Aurum Institute

Johannesburg, Gauteng, 1632, South Africa

Location

Isango Lethemba TB Research Unit

Port Elizabeth, South Africa

Location

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MeSH Terms

Conditions

Tuberculosis; Tuberculosis, Pulmonary; HIV Infections

Interventions

Isoniazid; Rifampin; Ethambutol; Pyrazinamide; Metformin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Ethylenediamines; Diamines; Polyamines; Amines; Pyrazines; Biguanides; Guanidines; Amidines

Study Officials

• Robert S Wallis, MD, FIDSA

  Aurum Institute

  STUDY CHAIR

• Hardy Kornfeld, MD

  The University of Massachusetts Chan Medical School

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Senior study leadership, Drs. Kornfeld, Wallis, Churchyard, Singhal will be blinded. Participants, study personnel and clinicians are not blinded.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Participants are assigned to one of two groups, Standard ATT or Standard ATT plus Metformin in parallel for 11 weeks starting 1 week after ATT initiation.

Study Record Dates

• First Submitted: May 26, 2021
• First Posted: June 18, 2021
• Study Start: August 26, 2021
• Primary Completion: April 29, 2025
• Study Completion: August 15, 2025
• Last Updated: March 25, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Data generated by this investigation will be made publicly available no later than six months after the initial data submission to NIH or at the time of the first publication, whichever occurs first.
• Access Criteria: Following publication of research data, may be shared upon request by contacting the study principal investigators by email.

Locations

ZA (2)