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

Study Overview
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Brief Summary
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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.

Detailed Description
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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 7 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.

Official Title
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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 With TB and Co-infected With HIV

Conditions
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Tuberculosis, Pulmonary Tuberculosis, HIV Coinfection

Intervention / Treatment
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* Drug: Isoniazid
* Drug: Rifampicin
* Drug: Ethambutol
* Drug: Pyrazinamide
* Drug: Metformin hydrochoride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 seropositive status prior to or after screening. Chest radiograph compatible with pulmonary TB Positive sputum Xpert TB/Rifampicin (RIF) with one Ct<25 or subsequent culture confirmation RIF susceptibility diagnosed by TB/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 14 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 <150 cells/mm3 on screening evaluation. Hemoglobin <9 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 <18 mmol/L on screening evaluation. Asparate aminotransferase (AST or ALT) ≥3 times the upper limit of normal (ULN) on screening evaluation. Hepatitis B surface antigen positive 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants are assigned to one of two or more groups, Standard ATT or Standard ATT plus Metformin in parallel for 11 weeks starting 1 week after ATT initiation.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Tuberculosis Medicine<br>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<br>* 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.<br>Drug: Rifampicin<br>* 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.<br>Drug: Ethambutol<br>* 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.<br>* Other names: Myambutol;Drug: Pyrazinamide<br>* 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.<br>|
| Experimental: Standard TB Medicines and Metformin<br>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 table twice daily through study week-12 for a total 11 weeks of metformin exposure. | Drug: Isoniazid<br>* 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.<br>Drug: Rifampicin<br>* 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.<br>Drug: Ethambutol<br>* 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.<br>* Other names: Myambutol;Drug: Pyrazinamide<br>* 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.<br>Drug: Metformin hydrochoride<br>* Metformin hydrochloride 500 mg tablet once daily starting one week after the initiation of TB treatment, then increasing to study twice daily through study week-12 (11 weeks total metformin treatment).<br>* Other names: Glucophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of metformin as measured by the number of grade 3 or higher gastrointestinal (GI) adverse events | Average and median numbers of Grade 3, 4 and 5 adverse events will be tabulated by treatment arm | Up to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metformin added to standard ATT improves respiratory health as measured by radiographic score | Between arm differences of change in radiographic score will be tabulated by arm and time point. | Change in baseline radiographic score at week 24 | 
| Metformin added to standard ATT improves respiratory health as measured by 6-minute Walk Test (6MWT) as assessed by distance x 02 saturation (2° endpoint) | Between arm differences of change in 6MWT distance oxygen saturation will be tabulated by arm and time point. | Change in baseline 6MWT at week 24 | 
| Metformin added to standard ATT improves respiratory health as measured by spirometry: Forced Vital Capacity (FVC) | Between arm differences of change in spirometric values will be tabulated by arm and time point. | Change in baseline spirometric value at week 24 | 
| Metformin added to standard ATT improves respiratory health as measured by spirometry: Forced Expiratory Volume (FEV1%) (2° endpoint) | Between arm differences of change in spirometric values will be tabulated by arm and time point. | Change in baseline spirometric value at week 24 | 
| Metformin added to standard ATT improves respiratory health as measured by Saint George's Respiratory Questionnaire (SGRQ) assessed by 2° endpoint | Between arm differences of change in SGRQ score will be tabulated by arm and timepoint. | Change in baseline SGRQ at week 24 | 
| Metformin added to standard ATT improves HIV outcomes as measured by HIV viral load | Between-arm differences of HIV viral load | Up to 24 weeks | 
| Metformin added to standard ATT improves HIV outcomes as measured by CD4 | Between-arm differences in CD4 | Up to 24 weeks | 
| Metformin added to standard ATT improves HIV outcomes as measured by T cell count | Between-arm differences of T cell count | Up to 24 weeks | 
| Metformin added to standard ATT improves TB treatment outcomes | Between arm differences will be tabulated in the secondary endpoints of cure, failure, death, default, and relapse. | Up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metformin, Tuberculosis, Anti-Tuberculosis Treatment (ATT), Anti-Viral Therapy (ART)