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

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.

• 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.
• 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.
• Ethambutol (Drug), also known as Myambutol: 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.
• 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.
• Metformin hydrochoride (Drug), also known as Glucophage: 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).

Primary outcomes

• Number of Participants Experiencing Grade 3 or Higher Adverse Events [Up to 24 weeks]: 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.

Secondary outcomes

• Time to Sputum Liquid Culture Conversion [Up to 24 weeks]: Number of weeks from baseline positive sputum culture to first negative sputum culture measured at every visit by study arm.
• Change in Radiographic Severity Score From Baseline to TB Treatment Completion [Baseline and 24 weeks]: Difference in change 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. The minimum score is 0 and the maximum score is 140, with a score of 140 indicating higher severity. The change in score from baseline to 24 weeks is analyzed by subtracting the baseline score from the 24 week score. High negative magnitude of change indicates greater improvement.
• Change in 6-minute Walk Test Distance From Baseline to TB Treatment Completion [Baseline and 24 weeks]: Difference in change in 6-minute walk test distance measured in meters, assessed at baseline and week-24 by study arm. The 6-minute walk test measures the number of meters walked over six minutes with a higher score indicating a larger number of meters walked and a lower score indicating a smaller number of meters walked with a minimum score of 0 and a maximum score of 999. The change in 6-minute walk is calculated by subtracting the baseline walk score from the 24-week score. A higher number indicates a greater change from baseline.
• Change in 6-minute Walk Test Distance-saturation Product From Baseline to TB Treatment Completion [Baseline and 24 weeks]: Difference in change in 6-minute walk test distance-saturation product measured in meters times percent oxygen saturation, assessed at baseline and at week-24 by study arm. The 6-minute walk test distance saturation product measures the number of meters a patient walks over six minutes multiplied by the oxygen saturation at completion of the walk with a higher score indicating better outcome with a minimum score of 0 and a maximum score or 999. The change in 6-minute walk saturation product is calculated by subtracting the baseline score from the 24-week score. A higher number indicates a greater change from baseline.
• Change in FVC From Baseline to TB Treatment Completion [Baseline and 24 weeks]: Difference in change in Forced Vital Capacity (liters) measured at baseline and week-24 by study arm. The maximum FVC is 15 liters and the minimum is 0 liters. The difference from baseline to 24 weeks is calculated by subtracting the baseline FVC from the 24 week FVC. A higher number indicates a greater change from baseline.
• Change in FEV1% From Baseline to TB Treatment Completion [Baseline and 24 weeks]: Difference between Forced Expiratory Volume in 1 second (% predicted) measured at baseline and week-24 by study arm. The maximum FEV1% is 150 and the minimum is 0. The difference from baseline to 24 weeks is calculated by subtracting the baseline FEV1% from the 24 week FEV1%. A higher number indicates a greater change from baseline.
• Change in St. George's Respiratory Questionnaire Score From Baseline to TB Treatment Completion [Baseline and 24 weeks]: Difference in change in St. George's Respiratory Questionnaire score at baseline and week-24 by study arm. The St. George's Respiratory Questionnaire measures health impairment in patients with respirator disease. The potential scores range from 0 to 100 with higher scores indicating more severe impairment. The change in score from baseline to 24 weeks is analyzed by subtracting the baseline score from the 24 week score. High negative magnitude of change indicates greater improvement.
• Number of Participants Experiencing One or More Adverse Event of Any Grade [Up to 24 weeks]: The cumulative number of participants in each arm experiencing adverse events of any grade, assessed on every visit from week-1 to week-24.

Sex: All, ages: 18 Years to 65 Years

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 Xpert 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/mm\^3 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.

Participant flow

Outcome results

• Number of Participants Experiencing Grade 3 or Higher Adverse Events (Primary), Count of participants, Participants: Standard Tuberculosis Medicines 6; Standard Tuberculosis Medicines and Metformin 4 (p 0.363)
• Time to Sputum Liquid Culture Conversion (Secondary), Median, weeks: Standard Tuberculosis Medicines 5 (3 to 7); Standard Tuberculosis Medicines and Metformin 5 (2 to 7) (p 0.837)
• Change in Radiographic Severity Score From Baseline to TB Treatment Completion (Secondary), Mean, score on a scale: Standard Tuberculosis Medicines -39 (-46.89 to -31.11); Standard Tuberculosis Medicines and Metformin -33.53 (-41.59 to -25.48) (p 0.563)
• Change in 6-minute Walk Test Distance From Baseline to TB Treatment Completion (Secondary), Mean, Meters: Standard Tuberculosis Medicines 48.69 +/- 11.42; Standard Tuberculosis Medicines and Metformin 11.88 +/- 11.52 (p 0.024)
• Change in 6-minute Walk Test Distance-saturation Product From Baseline to TB Treatment Completion (Secondary), Mean, Meters * %SpO2: Standard Tuberculosis Medicines 51.66 (28.77 to 74.54); Standard Tuberculosis Medicines and Metformin 7.68 (-14.97 to 30.33) (p 0.008)
• Change in FVC From Baseline to TB Treatment Completion (Secondary), Mean, Liters: Standard Tuberculosis Medicines -0.00 (-0.09 to 0.09); Standard Tuberculosis Medicines and Metformin 0.10 (0.01 to 0.19) (p 0.288)
• Change in FEV1% From Baseline to TB Treatment Completion (Secondary), Mean, percent predicted FEV1: Standard Tuberculosis Medicines 1.89 (-0.00 to 3.79); Standard Tuberculosis Medicines and Metformin 1.21 (-0.65 to 3.08) (p 0.615)
• Change in St. George's Respiratory Questionnaire Score From Baseline to TB Treatment Completion (Secondary), Mean, units on a scale: Standard Tuberculosis Medicines -25.56 (-29.32 to -21.79); Standard Tuberculosis Medicines and Metformin -23.32 (-27.06 to -19.59) (p 0.412)
• Number of Participants Experiencing One or More Adverse Event of Any Grade (Secondary), Count of participants, Participants: Standard Tuberculosis Medicines 45; Standard Tuberculosis Medicines and Metformin 44 (p 0.986)

Adverse events

Time frame: 36 weeks

Serious adverse events by term

Other adverse events by term

31 more terms not shown.

Limitations and caveats: This study had limitations: 1. The sample size was too small to power the secondary objectives. 2. The duration of metformin treatment may have been too short to provide maximum benefit. 3. Reduced rifampicin exposure in the metformin group may have obscured an effect on sputum conversion. 4. The last lung health assessment was done at TB treatment completion; later testing might have revealed protective effects of metformin that were not seen within the study period.

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• Study Protocol and Statistical Analysis Plan (PDF, 2024-08-19)
• Informed Consent Form: Main Consent Form-Form 2 (PDF, 2024-08-19)
• Informed Consent Form: HIV Screening-Form 1 (PDF, 2024-02-22)
• Informed Consent Form: Sample Storage Consent Form (PDF, 2024-02-22)

• Robert S Wallis, MD, FIDSA, Study chair, Aurum Institute
• Hardy Kornfeld, MD, Principal investigator, The University of Massachusetts Chan Medical School

NIH grants: U01AI134585