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

Primary Purpose

Tuberculosis, Pulmonary Tuberculosis, HIV Coinfection

Status

Recruiting

Phase

Phase 2

Locations

South Africa

Study Type

Interventional

Intervention

Isoniazid

Rifampicin

Ethambutol

Pyrazinamide

Metformin hydrochoride

About this trial

This is an interventional treatment trial for Tuberculosis focused on measuring Metformin, Tuberculosis, Anti-Tuberculosis Treatment (ATT), Anti-Viral Therapy (ART)

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Tembisa Clinical Research Centre-The Aurum InstituteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Standard Tuberculosis Medicine

Standard TB Medicines and Metformin

Arm Description

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.

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.

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.

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.

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.

Metformin added to standard ATT improves HIV outcomes as measured by HIV viral load

Between-arm differences of HIV viral load

Metformin added to standard ATT improves HIV outcomes as measured by CD4

Between-arm differences in CD4

Metformin added to standard ATT improves HIV outcomes as measured by T cell count

Between-arm differences of T cell count

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.

Full Information

NCT ID

NCT04930744

First Posted

May 26, 2021

Last Updated

March 27, 2023

Sponsor

University of Massachusetts, Worcester

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT04930744

Brief Title

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

Acronym

METHOD

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Recruiting

Study Start Date

August 3, 2021 (Actual)

Primary Completion Date

October 31, 2024 (Anticipated)

Study Completion Date

October 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Massachusetts, Worcester

Collaborators

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Tuberculosis, Pulmonary Tuberculosis, HIV Coinfection

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

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)

Masking Description

Senior study leadership, Drs. Kornfeld, Wallis, Churchyard, Singhal will be blinded. Participants, study personnel and clinicians are not blinded.

Allocation

Randomized

Enrollment

112 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Standard Tuberculosis Medicine

Arm Type

Active Comparator

Arm Description

Arm Title

Standard TB Medicines and Metformin

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Isoniazid

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Rifampicin

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Ethambutol

Other Intervention Name(s)

Myambutol

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Pyrazinamide

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Metformin hydrochoride

Other Intervention Name(s)

Glucophage

Intervention Description

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).

Primary Outcome Measure Information:

Title

Safety and tolerability of metformin as measured by the number of grade 3 or higher gastrointestinal (GI) adverse events

Description

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

Time Frame

Up to 16 weeks

Secondary Outcome Measure Information:

Title

Metformin added to standard ATT improves respiratory health as measured by radiographic score

Description

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

Time Frame

Change in baseline radiographic score at week 24

Title

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)

Description

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

Time Frame

Change in baseline 6MWT at week 24

Title

Metformin added to standard ATT improves respiratory health as measured by spirometry: Forced Vital Capacity (FVC)

Description

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

Time Frame

Change in baseline spirometric value at week 24

Title

Metformin added to standard ATT improves respiratory health as measured by spirometry: Forced Expiratory Volume (FEV1%) (2° endpoint)

Description

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

Time Frame

Change in baseline spirometric value at week 24

Title

Metformin added to standard ATT improves respiratory health as measured by Saint George's Respiratory Questionnaire (SGRQ) assessed by 2° endpoint

Description

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

Time Frame

Change in baseline SGRQ at week 24

Title

Metformin added to standard ATT improves HIV outcomes as measured by HIV viral load

Description

Between-arm differences of HIV viral load

Time Frame

Up to 24 weeks

Title

Metformin added to standard ATT improves HIV outcomes as measured by CD4

Description

Between-arm differences in CD4

Time Frame

Up to 24 weeks

Title

Metformin added to standard ATT improves HIV outcomes as measured by T cell count

Description

Between-arm differences of T cell count

Time Frame

Up to 24 weeks

Title

Metformin added to standard ATT improves TB treatment outcomes

Description

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

Time Frame

Up to 24 weeks

Other Pre-specified Outcome Measures:

Title

Efficacy of metformin as measured by time to sputum conversion in Mycobacterial Growth Indicator Tube (MGIT)

Description

Sputum liquid culture conversion will be tabulated by treatment arm

Time Frame

Up to 24 weeks

10. Eligibility

Sex

All

Gender Based

Yes

Gender Eligibility Description

Participant eligibility is based on self-representation of gender identity.

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Modulakgotla Sebe, MBCHB

Phone

+27 87 135 1645

msebe@auruminstitute.org

First Name & Middle Initial & Last Name or Official Title & Degree

Lerato Mngomezulu, BNSC

Phone

+27 87 135 1560

lmgnomezulu@auruminstitute.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Robert S Wallis, MD, FIDSA

Organizational Affiliation

Aurum Institute

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Hardy Kornfeld, MD

Organizational Affiliation

The University of Massachusetts Medical School

Official's Role

Principal Investigator

Facility Information:

Facility Name

Tembisa Clinical Research Centre-The Aurum Institute

City

Johannesburg

State/Province

Gauteng

ZIP/Postal Code

1632

Country

South Africa

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Mondulakgotla A Sebe, MBCHB

Phone

+27 61 430 3117

msebe@auruminstitute.org

First Name & Middle Initial & Last Name & Degree

Lerato Mngomezulu

Phone

+27 73 817 1725

lmngomezulu@auruminstitute.org

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

The plan is to share the standard operating procedures, the study protocol, the informed consent form, and the data collection tools. 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.

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

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