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

Sponsor
University of Massachusetts, Worcester (Other)
Overall Status
Recruiting
CT.gov ID
NCT04930744
Collaborator
National Institute of Allergy and Infectious Diseases (NIAID) (NIH), Aurum Institute (Other), A*STAR Infectious Diseases Labs (Other), University of Cape Town (Other)
112
Enrollment
1
Location
2
Arms
44.9
Anticipated Duration (Months)
2.5
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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 "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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
112 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention 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.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)
Masking Description:
Senior study leadership, Drs. Kornfeld, Wallis, Churchyard, Singhal will be blinded. Participants, study personnel and clinicians are not blinded.
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Aug 3, 2021
Anticipated Primary Completion Date :
Jun 15, 2024
Anticipated Study Completion Date :
Apr 30, 2025

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Standard Tuberculosis Medicine

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 TB 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 table 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 study twice daily through study week-12 (11 weeks total metformin treatment).
    Other Names:
  • Glucophage

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Safety and tolerability of metformin as measured by the number of grade 3 or higher gastrointestinal (GI) adverse events [Up to 16 weeks]

      Average and median numbers of Grade 3, 4 and 5 adverse events will be tabulated by treatment arm

    Secondary Outcome Measures

    1. Metformin added to standard ATT improves respiratory health as measured by radiographic score [Change in baseline radiographic score at week 24]

      Between arm differences of change in radiographic score will be tabulated by arm and time point.

    2. 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) [Change in baseline 6MWT at week 24]

      Between arm differences of change in 6MWT distance oxygen saturation will be tabulated by arm and time point.

    3. Metformin added to standard ATT improves respiratory health as measured by spirometry: Forced Vital Capacity (FVC) [Change in baseline spirometric value at week 24]

      Between arm differences of change in spirometric values will be tabulated by arm and time point.

    4. Metformin added to standard ATT improves respiratory health as measured by spirometry: Forced Expiratory Volume (FEV1%) (2° endpoint) [Change in baseline spirometric value at week 24]

      Between arm differences of change in spirometric values will be tabulated by arm and time point.

    5. Metformin added to standard ATT improves respiratory health as measured by Saint George's Respiratory Questionnaire (SGRQ) assessed by 2° endpoint [Change in baseline SGRQ at week 24]

      Between arm differences of change in SGRQ score will be tabulated by arm and timepoint.

    6. Metformin added to standard ATT improves HIV outcomes as measured by HIV viral load [Up to 24 weeks]

      Between-arm differences of HIV viral load

    7. Metformin added to standard ATT improves HIV outcomes as measured by CD4 [Up to 24 weeks]

      Between-arm differences in CD4

    8. Metformin added to standard ATT improves HIV outcomes as measured by T cell count [Up to 24 weeks]

      Between-arm differences of T cell count

    9. Metformin added to standard ATT improves TB treatment outcomes [Up to 24 weeks]

      Between arm differences will be tabulated in the secondary endpoints of cure, failure, death, default, and relapse.

    Other Outcome Measures

    1. Efficacy of metformin as measured by time to sputum conversion in Mycobacterial Growth Indicator Tube (MGIT) [Up to 24 weeks]

      Sputum liquid culture conversion will be tabulated by treatment arm

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Tembisa Clinical Research Centre-The Aurum Institute Johannesburg Gauteng South Africa 1632

    Sponsors and Collaborators

    • University of Massachusetts, Worcester
    • National Institute of Allergy and Infectious Diseases (NIAID)
    • Aurum Institute
    • A*STAR Infectious Diseases Labs
    • University of Cape Town

    Investigators

    • Study Chair: Robert S Wallis, MD, FIDSA, Aurum Institute
    • Principal Investigator: Hardy Kornfeld, MD, The University of Massachusetts Medical School

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Hardy Kornfeld, MD, Professor, University of Massachusetts, Worcester
    ClinicalTrials.gov Identifier:
    NCT04930744
    Other Study ID Numbers:
    • AUR1-1-199
    • 1U01AI134585-01A1
    First Posted:
    Jun 18, 2021
    Last Update Posted:
    Jun 13, 2022
    Last Verified:
    Jun 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Hardy Kornfeld, MD, Professor, University of Massachusetts, Worcester
    Metformin
    Tuberculosis
    Anti-Tuberculosis Treatment (ATT)
    Anti-Viral Therapy (ART)
    Additional relevant MeSH terms:
    Tuberculosis
    Tuberculosis, Pulmonary
    Coinfection
    HIV Infections
    Metformin
    Rifampin
    Isoniazid
    Pyrazinamide
    Ethambutol

    Study Results

    No Results Posted as of Jun 13, 2022