TuberculosisPhase 2METHODNCT04930744
Safety and Tolerability of Metformin in People With Tuberculosis (TB) and Human Immunodeficiency Virus (HIV)
A Phase 2 study testing Isoniazid, Rifampicin and Ethambutol in people with Tuberculosis and Pulmonary Tuberculosis, run by University of Massachusetts, Worcester at 2 sites in South Africa.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Tuberculosis, Pulmonary Tuberculosis, HIV Coinfection
- What is being tested?
- Isoniazid, Rifampicin and Ethambutol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 112 participants
- Where
- 2 sitesSouth Africa
- Study dates
- 4 Mar 2022to 15 Aug 2025
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18 through 65 years.
- HIV-1 seropositive status prior to or after screening.
- Chest radiograph compatible with pulmonary TB.
- Positive sputum Xpert MTB/RIF or Xpert MTB/RIF Ultra with one cycle threshold (Ct) <25 or subsequent culture confirmation.
- 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).
- Residence within study catchment area.
- 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.
- Able and willing to provide informed consent.
Who cannot join
- 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.
Show all 25Show fewer
- Taking any fluoroquinolone antibiotic.
- History of diabetes mellitus or fasting blood glucose >7.0 mmol/L on screening evaluation.
- History of congestive heart failure, chronic liver disease, diabetes, 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.
- Body mass index (BMI) <17kg/m^2 on screening evaluation.
- Peripheral blood CD4 + T cell count <50 cells/mm^3 on screening evaluation.
- Hemoglobin <9 g/dL for males, and <8 g/dL (women) for females on screening evaluation.
- Platelet count <50,000/mm^3 on screening evaluation.
- Absolute neutrophil count <750 cells/mm^3 on screening evaluation.
- Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m^2 calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
- Serum bicarbonate <18 mmol/L on screening evaluation.
- Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3 times the upper limit of normal (ULN) on screening evaluation.
- Hepatitis B surface antigen positive.
- Enrollment in another interventional study at any time during participation in the METHOD trial.
- Imprisonment at the time of or after enrollment in the METHOD trial.
- Diagnosis of active Coronavirus Disease 2019 (COVID-19) at the time of screening or high suspicion of active COVID-19 disease during screening.
Trial locations and contacts
2 sites in 1 country.
South Africa2 sites
Tembisa Clinical Research Centre-The Aurum Institute
Johannesburg, Gauteng, 1632
Isango Lethemba TB Research Unit
Port Elizabeth
About this study
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 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.
Read the 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.
- Conditions
- Tuberculosis, Pulmonary Tuberculosis, HIV Coinfection
- Being tested
- Isoniazid, Rifampicin, Ethambutol, Pyrazinamide, Metformin hydrochoride
- Keywords
- Metformin, Tuberculosis, Anti-Tuberculosis Treatment (ATT), Anti-Viral Therapy (ART)
- Medical subject headings
- Tuberculosis, Tuberculosis, Pulmonary, HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IsoniazidDrug
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.
RifampicinDrug
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.
EthambutolDrug
Also called 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.
PyrazinamideDrug
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 hydrochorideDrug
Also called 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).
| Study group | Role | What they receive |
|---|---|---|
| Standard Tuberculosis Medicines | Active comparator | Participants are randomized to receive standard tuberculosis medicines (Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) in a combination pill pack taken by mouth daily for 2 months. This is followed by Isoniazid and Rifampicin for 4 months. Receives: Drug: Isoniazid; Drug: Rifampicin; Drug: Ethambutol; Drug: Pyrazinamide |
| Standard Tuberculosis Medicines and Metformin | Experimental | Participants are randomized to receive standard tuberculosis medicines (Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) only, in a combination pill pack taken by mouth daily for 2 months. This is followed by Isoniazid and Rifampicin for 4 months. They also take Metformin hydrochloride, one 500 mg tablet, daily starting one week after the initiation of tuberculosis medicines, increasing to one 500 mg tablet twice daily through study week-12 for a total of 11 weeks of metformin exposure. Receives: Drug: Isoniazid; Drug: Rifampicin; Drug: Ethambutol; Drug: Pyrazinamide; Drug: Metformin hydrochoride |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Up to 24 weeks
Secondary outcomes (8)
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.
Measured: Up to 24 weeks
Change in Radiographic Severity Score From Baseline to TB Treatment Completion
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.
Measured: Baseline and 24 weeks
Change in 6-minute Walk Test Distance From Baseline to TB Treatment Completion
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.
Measured: Baseline and 24 weeks
Change in 6-minute Walk Test Distance-saturation Product From Baseline to TB Treatment Completion
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.
Measured: Baseline and 24 weeks
Change in FVC From Baseline to TB Treatment Completion
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.
Measured: Baseline and 24 weeks
Change in FEV1% From Baseline to TB Treatment Completion
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.
Measured: Baseline and 24 weeks
Change in St. George's Respiratory Questionnaire Score From Baseline to TB Treatment Completion
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.
Measured: Baseline and 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.
Measured: Up to 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jun 2021
- Study start4 Mar 2022
- Primary completion29 Apr 2025
- Study completion15 Aug 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (37)Papers the sponsor has linked to this study.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- More trials run by University of Massachusetts, WorcesterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Participants are assigned to one of two groups, Standard ATT or Standard ATT plus Metformin in parallel for 11 weeks starting 1 week after ATT initiation.
- Masking
- None (open label)
- Enrolment
- 112 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Massachusetts, Worcester
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID), Aurum Institute, A*STAR Infectious Diseases Labs, University of Cape Town, Wits Health Consortium (Pty) Ltd
- Responsible party
- Principal investigator, Hardy Kornfeld, MD, University of Massachusetts, Worcester
- Investigators
- Robert S Wallis, MD, FIDSA, Study chair, Aurum InstituteHardy Kornfeld, MD, Principal investigator, The University of Massachusetts Chan Medical School
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04930744
- Sponsor's protocol ID
- AUR1-1-199
- Other IDs
- 5U01AI134585
- Acronym
- METHOD
- Status last verified
- Jul 2026
- First submitted
- 26 May 2021
- Last updated
- 6 Aug 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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).
Publications
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.
PubMed 19542476Pasipanodya 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.
PubMed 20482835Abdool 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.
PubMed 19709731Singhal 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.
PubMed 25411472Lachmandas 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.
PubMed 30753544Degner 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.
PubMed 29325084Kumar 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.
PubMed 30045688Padmapriyadarsini C, Bhavani PK, Natrajan M, Ponnuraja C, Kumar H, Gomathy SN, Guleria R, Jawahar SM, Singh M, Balganesh T, Swaminathan S. Evaluation of metformin in combination with rifampicin containing antituberculosis therapy in patients with new, smear-positive pulmonary tuberculosis (METRIF): study protocol for a randomised clinical trial. BMJ Open. 2019 Mar 1;9(3):e024363. doi: 10.1136/bmjopen-2018-024363.
PubMed 30826761Sheth 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.
PubMed 20573187Ralph 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.
PubMed 24312209Ralph 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.
PubMed 20861290Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010 Apr 14;2010(4):CD002967. doi: 10.1002/14651858.CD002967.pub4.
PubMed 20393934Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE, Timmins P, Williams KM. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011 Feb;50(2):81-98. doi: 10.2165/11534750-000000000-00000.
PubMed 21241070Chandel 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.
PubMed 27076070Song 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.
PubMed 26974526
Study at a glance
From the registry record, last updated by the sponsor on 6 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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 Co-infected With HIV
- ClinicalTrials.gov ID
- NCT04930744
- Acronym / sponsor ID
- METHOD / AUR1-1-199
- Conditions
- Tuberculosis, Pulmonary Tuberculosis, HIV Coinfection
- Keywords
- Metformin, Tuberculosis, Anti-Tuberculosis Treatment (ATT), Anti-Viral Therapy (ART)
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 112 participants (actual)
- Lead sponsor
- University of Massachusetts, WorcesterUniversity, hospital or other
- Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID), Aurum Institute, A*STAR Infectious Diseases Labs, University of Cape Town, Wits Health Consortium (Pty) Ltd
- Study start
- 4 Mar 2022 (actual)
- Primary completion
- 29 Apr 2025 (actual)
- Study completion
- 15 Aug 2025 (actual)
- First posted
- 18 Jun 2021 (actual)
- Results
- Posted 6 Aug 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Participants are assigned to one of two groups, Standard ATT or Standard ATT plus Metformin in parallel for 11 weeks starting 1 week after ATT initiation.
| Arm | Type | Receives |
|---|---|---|
| Standard Tuberculosis Medicines | Active comparator | Drug: Isoniazid, Drug: Rifampicin, Drug: Ethambutol, Drug: PyrazinamideParticipants are randomized to receive standard tuberculosis medicines (Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) in a combination pill pack taken by mouth daily for 2 months. This is followed by Isoniazid and Rifampicin for 4 months. |
| Standard Tuberculosis Medicines and Metformin | Experimental | Drug: Isoniazid, Drug: Rifampicin, Drug: Ethambutol, Drug: Pyrazinamide, Drug: Metformin hydrochorideParticipants are randomized to receive standard tuberculosis medicines (Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) only, in a combination pill pack taken by mouth daily for 2 months. This is followed by Isoniazid and Rifampicin for 4 months. They also take Metformin hydrochloride, one 500 mg tablet, daily starting one week after the initiation of tuberculosis medicines, increasing to one 500 mg tablet twice daily through study week-12 for a total of 11 weeks of metformin exposure. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Age 18 through 65 years.
- HIV-1 seropositive status prior to or after screening.
- Chest radiograph compatible with pulmonary TB.
- Positive sputum Xpert MTB/RIF or Xpert MTB/RIF Ultra with one cycle threshold (Ct) <25 or subsequent culture confirmation.
- 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).
Key exclusion criteria (25 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IsoniazidIsoniazid, 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 | Standard Tuberculosis Medicines, Standard Tuberculosis Medicines and Metformin |
| RifampicinRifampicin, 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 | Standard Tuberculosis Medicines, Standard Tuberculosis Medicines and Metformin |
| EthambutolAlso: MyambutolEthambutol, 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. | Drug | Standard Tuberculosis Medicines, Standard Tuberculosis Medicines and Metformin |
| PyrazinamidePyrazinamide, 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 | Standard Tuberculosis Medicines, Standard Tuberculosis Medicines and Metformin |
| Metformin hydrochorideAlso: GlucophageMetformin 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). | Drug | Standard Tuberculosis Medicines and Metformin |
Primary outcome
Number of Participants Experiencing Grade 3 or Higher Adverse Events
Time frame: 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.
8 secondary outcomes
Time to Sputum Liquid Culture Conversion
Time frame: Up to 24 weeks
Change in Radiographic Severity Score From Baseline to TB Treatment Completion
Time frame: Baseline and 24 weeks
Change in 6-minute Walk Test Distance From Baseline to TB Treatment Completion
Time frame: Baseline and 24 weeks
Change in 6-minute Walk Test Distance-saturation Product From Baseline to TB Treatment Completion
Time frame: Baseline and 24 weeks
Change in FVC From Baseline to TB Treatment Completion
Time frame: Baseline and 24 weeks
Change in FEV1% From Baseline to TB Treatment Completion
Time frame: Baseline and 24 weeks
Change in St. George's Respiratory Questionnaire Score From Baseline to TB Treatment Completion
Time frame: Baseline and 24 weeks
Number of Participants Experiencing One or More Adverse Event of Any Grade
Time frame: Up to 24 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Aug 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 19542476Johnson 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.
- Background: PubMed 20482835Pasipanodya 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.
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- Individual participant dataSharing planned: Yes. 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).
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert S Wallis, MD, FIDSA study chair
Aurum Institute
Hardy Kornfeld, MD principal investigator
The University of Massachusetts Chan Medical School
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Isoniazid, Rifampicin and Ethambutol in people with Tuberculosis and Pulmonary Tuberculosis, run by University of Massachusetts, Worcester at 2 sites in South Africa.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 6 Aug 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants Experiencing Grade 3 or Higher Adverse Events (time frame: Up to 24 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04930744, which also lists 37 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Aug 2026.