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

A Prospective, Randomized Open-Label Phase II Study of the Safety and Tolerability of Metformin in Combination With Standard Antimicrobial Treatment of Pulmonary Tuberculosis in People Co-infected With 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.

Study Overview

• Status: Completed
• Conditions: Tuberculosis; Pulmonary Tuberculosis; HIV Coinfection
• Intervention / Treatment: Drug: Isoniazid; Drug: Rifampicin; Drug: Ethambutol; Drug: Pyrazinamide; Drug: Metformin hydrochoride

Detailed Description

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 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.

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • Port Elizabeth, South Africa
    • Isango Lethemba TB Research Unit
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 1632
      • Tembisa Clinical Research Centre-The Aurum Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 MTB/RIF or pert MTB/RIF Ultra with one cycle threshold (Ct) <25 or subsequent culture confirmation.
5. 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).
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.

Exclusion criteria:

1. 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.
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 ATT 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.
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) <17kg/m^2 on screening evaluation.
15. Peripheral blood CD4 T cell count <50 cells/mm^3 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/mm^3 on screening evaluation.
19. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m^2 calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
20. Serum bicarbonate <18 mmol/L on screening evaluation.
21. Aspartate Aminotransferase (AST) or Alanine Aminotransferase (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 Coronavirus Disease 2019 (COVID-19) at the time of screening or high suspicion of active COVID-19 disease during screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard Tuberculosis Medicines; 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; 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.; Drug: Rifampicin; 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.; Drug: Ethambutol; 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.; Other Names: Myambutol; Drug: Pyrazinamide; 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.
Experimental: Standard Tuberculosis Medicines and Metformin; 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; 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.; Drug: Rifampicin; 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.; Drug: Ethambutol; 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.; Other Names: Myambutol; Drug: Pyrazinamide; 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.; Drug: Metformin hydrochoride; 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).; Other Names: Glucophage

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to sputum liquid culture conversion	Number of weeks from baseline positive sputum culture to first negative sputum culture measured at every visit by study arm.	Up to 24 weeks
Number of participants experiencing one or more adverse event of any grade	The cumulative number of participants in each arm experiencing adverse events of any grade, assessed on every visit from week-1 to week-24.	Up to 24 weeks
Change in radiographic severity score from baseline to TB treatment completion	Difference in radiographic TB severity measured at baseline and week-24 by study arm. Two blinded readers scored de-identified 1-view chest X-rays using the Timika Scale. Differences in scores were resolved by consensus.	Baseline and 24 weeks
Change in 6-minute walk test distance from baseline to TB treatment completion	Difference in 6-minute walk test distance measured in meters, assessed at baseline and week-24 by study arm.	Baseline and 24 weeks
Change in 6-minute walk test distance-saturation product from baseline to TB treatment completion	Difference in 6-minute walk test distance-saturation product measured in meters x percent, assessed at baseline and at week-24 by study arm.	Baseline and 24 weeks
Change in FVC from baseline to TB treatment completion	Difference between FVC (liters) measured at baseline and week-24 by study arm.	Baseline and 24 weeks
Change in FEV1% from baseline to TB treatment completion	Difference between FEV1 (% predicted) measured at baseline and week-24 by study arm.	Baseline and 24 weeks
Change in St. George's Respiratory Questionnaire score from baseline to TB treatment completion	Difference in St. George's Respiratory Questionnaire score at baseline and week-24 by study arm.	Baseline and 24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of metformin as measured by time to sputum conversion in Mycobacterial Growth Indicator Tube (MGIT)	Sputum liquid culture conversion will be tabulated by treatment arm	Up to 24 weeks

Collaborators and Investigators

• Sponsor: University of Massachusetts, Worcester
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Aurum Institute; University of Cape Town; Wits Health Consortium (Pty) Ltd; A*STAR Infectious Diseases Labs
• Investigators: Study Chair: Robert S Wallis, MD, FIDSA, Aurum Institute; Principal Investigator: Hardy Kornfeld, MD, The University of Massachusetts Chan Medical School

Publications and helpful links

General Publications

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• Singhal A, Jie L, Kumar P, Hong GS, Leow MK, Paleja B, Tsenova L, Kurepina N, Chen J, Zolezzi F, Kreiswirth B, Poidinger M, Chee C, Kaplan G, Wang YT, De Libero G. Metformin as adjunct antituberculosis therapy. Sci Transl Med. 2014 Nov 19;6(263):263ra159. doi: 10.1126/scitranslmed.3009885.
• Degner NR, Wang JY, Golub JE, Karakousis PC. Metformin Use Reverses the Increased Mortality Associated With Diabetes Mellitus During Tuberculosis Treatment. Clin Infect Dis. 2018 Jan 6;66(2):198-205. doi: 10.1093/cid/cix819.
• Johnson JL, Hadad DJ, Dietze R, Maciel EL, Sewali B, Gitta P, Okwera A, Mugerwa RD, Alcaneses MR, Quelapio MI, Tupasi TE, Horter L, Debanne SM, Eisenach KD, Boom WH. Shortening treatment in adults with noncavitary tuberculosis and 2-month culture conversion. Am J Respir Crit Care Med. 2009 Sep 15;180(6):558-63. doi: 10.1164/rccm.200904-0536OC. Epub 2009 Jun 19.
• Pasipanodya JG, McNabb SJ, Hilsenrath P, Bae S, Lykens K, Vecino E, Munguia G, Miller TL, Drewyer G, Weis SE. Pulmonary impairment after tuberculosis and its contribution to TB burden. BMC Public Health. 2010 May 19;10:259. doi: 10.1186/1471-2458-10-259.
• Abdool Karim SS, Churchyard GJ, Karim QA, Lawn SD. HIV infection and tuberculosis in South Africa: an urgent need to escalate the public health response. Lancet. 2009 Sep 12;374(9693):921-33. doi: 10.1016/S0140-6736(09)60916-8. Epub 2009 Aug 24.
• Lachmandas E, Eckold C, Bohme J, Koeken VACM, Marzuki MB, Blok B, Arts RJW, Chen J, Teng KWW, Ratter J, Smolders EJ, Van den Heuvel C, Stienstra R, Dockrell HM, Newell E, Netea MG, Singhal A, Cliff JM, Van Crevel R. Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects. J Infect Dis. 2019 Jun 5;220(1):139-150. doi: 10.1093/infdis/jiz064.
• Kumar NP, Moideen K, Viswanathan V, Shruthi BS, Sivakumar S, Menon PA, Kornfeld H, Babu S. Elevated levels of matrix metalloproteinases reflect severity and extent of disease in tuberculosis-diabetes co-morbidity and are predominantly reversed following standard anti-tuberculosis or metformin treatment. BMC Infect Dis. 2018 Jul 25;18(1):345. doi: 10.1186/s12879-018-3246-y.
• Sheth SH, Larson RJ. The efficacy and safety of insulin-sensitizing drugs in HIV-associated lipodystrophy syndrome: a meta-analysis of randomized trials. BMC Infect Dis. 2010 Jun 23;10:183. doi: 10.1186/1471-2334-10-183.
• Ralph AP, Kenangalem E, Waramori G, Pontororing GJ, Sandjaja, Tjitra E, Maguire GP, Kelly PM, Anstey NM. High morbidity during treatment and residual pulmonary disability in pulmonary tuberculosis: under-recognised phenomena. PLoS One. 2013 Nov 29;8(11):e80302. doi: 10.1371/journal.pone.0080302. eCollection 2013.
• Ralph AP, Ardian M, Wiguna A, Maguire GP, Becker NG, Drogumuller G, Wilks MJ, Waramori G, Tjitra E, Sandjaja, Kenagalem E, Pontororing GJ, Anstey NM, Kelly PM. A simple, valid, numerical score for grading chest x-ray severity in adult smear-positive pulmonary tuberculosis. Thorax. 2010 Oct;65(10):863-9. doi: 10.1136/thx.2010.136242.
• Chandel NS, Avizonis D, Reczek CR, Weinberg SE, Menz S, Neuhaus R, Christian S, Haegebarth A, Algire C, Pollak M. Are Metformin Doses Used in Murine Cancer Models Clinically Relevant? Cell Metab. 2016 Apr 12;23(4):569-70. doi: 10.1016/j.cmet.2016.03.010. No abstract available.
• Song IH, Zong J, Borland J, Jerva F, Wynne B, Zamek-Gliszczynski MJ, Humphreys JE, Bowers GD, Choukour M. The Effect of Dolutegravir on the Pharmacokinetics of Metformin in Healthy Subjects. J Acquir Immune Defic Syndr. 2016 Aug 1;72(4):400-7. doi: 10.1097/QAI.0000000000000983.
• Te Brake LHM, Yunivita V, Livia R, Soetedjo N, van Ewijk-Beneken Kolmer E, Koenderink JB, Burger DM, Santoso P, van Crevel R, Alisjahbana B, Aarnoutse RE, Ruslami R; TANDEM Consortium. Rifampicin Alters Metformin Plasma Exposure but Not Blood Glucose Levels in Diabetic Tuberculosis Patients. Clin Pharmacol Ther. 2019 Mar;105(3):730-737. doi: 10.1002/cpt.1232. Epub 2018 Oct 29.
• Grun B, Kiessling MK, Burhenne J, Riedel KD, Weiss J, Rauch G, Haefeli WE, Czock D. Trimethoprim-metformin interaction and its genetic modulation by OCT2 and MATE1 transporters. Br J Clin Pharmacol. 2013 Nov;76(5):787-96. doi: 10.1111/bcp.12079.
• Wulffele MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, Donker AJ, Stehouwer CD. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med. 2003 Nov;254(5):455-63. doi: 10.1046/j.1365-2796.2003.01213.x.
• Booysen HL, Woodiwiss AJ, Raymond A, Sareli P, Hsu HC, Dessein PH, Norton GR. Chronic kidney disease epidemiology collaboration-derived glomerular filtration rate performs better at detecting preclinical end-organ changes than alternative equations in black Africans. J Hypertens. 2016 Jun;34(6):1178-85. doi: 10.1097/HJH.0000000000000924.
• Wallis RS, Peppard T. Early Biomarkers and Regulatory Innovation in Multidrug-Resistant Tuberculosis. Clin Infect Dis. 2015 Oct 15;61Suppl 3:S160-3. doi: 10.1093/cid/civ612.
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• Wester CW, Eden SK, Shepherd BE, Bussmann H, Novitsky V, Samuels DC, Hendrickson SL, Winkler CA, O'Brien SJ, Essex M, D'Aquila RT, DeGruttola V, Marlink RG. Risk factors for symptomatic hyperlactatemia and lactic acidosis among combination antiretroviral therapy-treated adults in Botswana: results from a clinical trial. AIDS Res Hum Retroviruses. 2012 Aug;28(8):759-65. doi: 10.1089/AID.2011.0303. Epub 2012 Jun 1.
• Aperis G, Paliouras C, Zervos A, Arvanitis A, Alivanis P. Lactic acidosis after concomitant treatment with metformin and tenofovir in a patient with HIV infection. J Ren Care. 2011 Mar;37(1):25-9. doi: 10.1111/j.1755-6686.2011.00209.x.
• Ortiz-Brizuela E, Perez-Patrigeon S, Recillas-Gispert C, Gomez-Perez FJ. Lactic Acidosis Complicating Metformin and Non-Nucleoside Reverse Transcriptase Inhibitor Combination Therapy: A Smoldering Threat in the Post-HAART Era. Rev Invest Clin. 2015 Jul-Aug;67(4):273-4.
• Hashim H, Sahari NS, Sazlly Lim SM, Hoo FK. Fatal Tenofovir-Associateacd Lactic Acidosis: A Case Report. Iran Red Crescent Med J. 2015 Oct 24;17(10):e19546. doi: 10.5812/ircmj.19546. eCollection 2015 Oct.
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• Cho SK, Yoon JS, Lee MG, Lee DH, Lim LA, Park K, Park MS, Chung JY. Rifampin enhances the glucose-lowering effect of metformin and increases OCT1 mRNA levels in healthy participants. Clin Pharmacol Ther. 2011 Mar;89(3):416-21. doi: 10.1038/clpt.2010.266. Epub 2011 Jan 26.
• Lazarus B, Wu A, Shin JI, Sang Y, Alexander GC, Secora A, Inker LA, Coresh J, Chang AR, Grams ME. Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function: A Community-Based Cohort Study. JAMA Intern Med. 2018 Jul 1;178(7):903-910. doi: 10.1001/jamainternmed.2018.0292.
• Moyo S, Bussmann H, Mangwendeza P, Dusara P, Gaolathe T, Mine M, Musonda R, van Widenfelt E, Novitsky V, Makhema J, Marlink RG, Essex M, Wester CW. Validation of A Point-of-Care Lactate Device For Screening At-Risk Adults Receiving Combination Antiretroviral Therapy In Botswana. J Antivir Antiretrovir. 2011 Oct;3(4):45-48. doi: 10.4172/jaa.1000034. Epub 2011 Sep 20.

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2021
• Primary Completion (Actual): April 29, 2025
• Study Completion (Actual): August 15, 2025

Study Registration Dates

• First Submitted: May 26, 2021
• First Submitted That Met QC Criteria: June 10, 2021
• First Posted (Actual): June 18, 2021

Study Record Updates

• Last Update Posted (Actual): April 6, 2026
• Last Update Submitted That Met QC Criteria: March 30, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Metformin; Tuberculosis; Anti-Tuberculosis Treatment (ATT); Anti-Viral Therapy (ART)
• Additional Relevant MeSH Terms: Blood-Borne Infections; Urogenital Diseases; Genital Diseases; Immune System Diseases; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; HIV Infections; Tuberculosis; Tuberculosis, Pulmonary; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Polycyclic Compounds; Amines; Heterocyclic Compounds, 4 or More Rings; Rifamycins; Lactams, Macrocyclic; Macrocyclic Compounds; Pyrazines; Biguanides; Guanidines; Amidines; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Ethylenediamines; Diamines; Polyamines; Metformin; Rifampin; Ethambutol; Isoniazid; Pyrazinamide
• Other Study ID Numbers: AUR1-1-199; 5U01AI134585 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The plan is to share the study protocol and the informed consent form. Research data that document, support and validate research findings will be made available after the main findings from the final research data set have been accepted for publication. The trial also includes a plan to collect and store genomic DNA. Written informed consent is obtained indicating consent for their genomic and phenotypic data to be used for future research purposes and to be shared broadly in a de-identified manner. Institutional certification has been obtained. Data generated from this trial, including genomic data and associated data, will be submitted to an NIH-designated repository such as database of Genotype and Phenotype (dbGaP).
• IPD Sharing 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.
• IPD Sharing Access Criteria: Following publication of research data, may be shared upon request by contacting the study principal investigators by email.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No