History of Changes for Study: NCT04510194

MET-COVID -- Outpatient Metformin Use for COVID-19

Latest version (submitted April 22, 2024) on ClinicalTrials.gov

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Study Record Versions

Version	Submitted Date	Changes
1	August 10, 2020	None (earliest Version on record)
2	August 24, 2020	Eligibility and Study Status
3	October 30, 2020	Outcome Measures, Study Status, Eligibility, Arms and Interventions, Study Design and Study Description
4	November 23, 2020	Outcome Measures, Arms and Interventions, Study Description, Study Status, Study Identification, References, Eligibility and Study Design
5	January 12, 2021	Recruitment Status, Study Status, Study Identification, Contacts/Locations and Oversight
6	January 15, 2021	Contacts/Locations and Study Status
7	February 17, 2021	Outcome Measures, Study Status, Arms and Interventions, Study Design, Study Description, Study Identification, Contacts/Locations, Eligibility and Sponsor/Collaborators
8	May 3, 2021	Arms and Interventions, Study Description, Study Status, Eligibility and Study Design
9	May 17, 2021	Contacts/Locations, Study Status, Eligibility, Study Identification, Outcome Measures and Arms and Interventions
10	May 21, 2021	References and Study Status
11	June 1, 2021	Study Status and Arms and Interventions
12	July 30, 2021	Contacts/Locations and Study Status
13	September 13, 2021	Study Status and Study Identification
14	September 30, 2021	Outcome Measures, Study Design, Study Identification, Study Description and Study Status
15	November 16, 2021	Study Status
16	January 20, 2022	Outcome Measures, Study Status, Study Design, Document Section, Eligibility, Arms and Interventions and Study Description
17	March 2, 2022	Recruitment Status, Study Status, Contacts/Locations and Outcome Measures
18	August 5, 2022	Study Status
19	April 18, 2023	Quality Control Review has not concluded Returned: May 11, 2023 Document Section, Study Status, Outcome Measures, Study Design
20	May 24, 2023	Quality Control Review has not concluded Returned: June 15, 2023 Adverse Events, Baseline Characteristics, Study Status, Outcome Measures, Participant Flow and Study Design
21	June 21, 2023	Study Status, Adverse Events and Outcome Measures
22	April 22, 2024	Recruitment Status and Study Status

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Study NCT04510194
Submitted Date: January 12, 2021 (v5)

Study Identification


Unique Protocol ID:	GIM-2020-29324
Brief Title:	MET-COVID -- Outpatient Metformin Use for COVID-19
Official Title:	MET-COVID Trial - Metformin for Outpatient Treatment and Post-exposure Prophylaxis (PEP) of COVID-19
Secondary IDs:

Study Status


Record Verification:	January 2021
Overall Status:	Recruiting
Study Start:	January 1, 2021
Primary Completion:	September 2021 [Anticipated]
Study Completion:	September 2021 [Anticipated]

First Submitted:	August 7, 2020
First Submitted that Met QC Criteria:	August 10, 2020
First Posted:	August 12, 2020 [Actual]

Last Update Submitted that Met QC Criteria:	January 12, 2021
Last Update Posted:	January 15, 2021 [Actual]

Study Description

Brief Summary:

The purpose of this trial is to conduct a Stage 1 Substudy powered to detect a difference in continuous laboratory outcomes:

Test if metformin treatment in non-hospitalized adults with SARS-CoV-2 can improve laboratory outcomes associated with Covid-19 severity
Test if metformin treatment in non-hospitalized adults with SARS-CoV-2 infection can prevent emergency department utilization for Covid-19.
Test if metformin treatment in non-hospitalized adults with SARS-CoV-2 disease can prevent Covid-19 disease progression.

Detailed Description:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly spreading viral infection causing COVID-19 disease. There currently is no preventive or outpatient treatment therapy for Covid-19. Six observational studies have found decreased severity of Covid-19 disease among persons with metformin use before diagnosis with Covid-19:

Cariou et al, Diabetologia, adults with diabetes (DM) in France: OR mortality 0.59 (0.42, 0.84)
Crouse et al, medrxiv.org adults with DM at Univ of Alabama Birmingham: OR mortality 0.33 (0.13-0.84)
Bramante et al, Lancet Healthy Longevity, females with DM or obesity, claims data from 50 US5 states: OR mortality 0.759 (0.601, 0.960) by propensity matching; OR 0.785 (0.650, 0.951) by Cox model.
Lou et al, Am J Trop Med, adults with diabetes in China, OR for survival: 4.36 (1.22-15.59)
Bramante et al. Under review, in adults with non-alcoholic fatty liver disease and +SARS-CoV-2, OR for admission: 0.42 (0.18-1.01, p=0.05).
Bramante et al. Under review, in adults with Covid-19, OR for admission 0.46 (0.27-0.80), p<0.01; mortality, OR 0.49 (0.26-0.94); and metformin was associated with lower IL-6 (non-significant) lower neutrophil/lymphocyte ratio and CPR, and equivalent lactate and bicarbonate as non-metformin.

Kow, J Med Virol conducted a meta analysis, with an overall odds ratio for mortality of 0.62 (0.43-0.89).

Gordon et al found decreased SARS-CoV-2 and increased cell viability with metformin in vitro. (Gordon et al, Nature). While anti-viral activity may be contributing to the observational associations of reduced severity of Covid-19, metformin has a proven history of beneficial immune-modulatory effects, including on CRP, IL-6 and TNF-alpha, neutrophil extracellular traps, and improved T cell immunity. Outpatient metformin use has now been associated with lower IL-6, CRP, and neutrophil-lymphocyte ratio in persons with Covid-19.

While vaccine development for SARS-CoV-2 has been promising, there may be reduced willingness among the public to receive a vaccine developed so quickly. This is a substudy with laboratory outcomes (70 patients will be enrolled). The intervention is metformin, a biguanide, administered in its immediate release formation, 1,500mg daily.

Study Design


Study Type:	Interventional
Primary Purpose:	Treatment
Study Phase:	Phase 2/Phase 3
Interventional Study Model:	Parallel Assignment
	The fully powered trial is a parallel enrolling treatment and post-exposure prophylaxis trial.
Number of Arms:	4
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation:	Randomized
Enrollment:	70 [Anticipated]

Arms and Interventions

Arms	Assigned Interventions
Experimental: PEP Cohort - Treatment Group Participants in the PEP cohort of the trial are those who do not test positive for SARS-COV-2 infection at the time of screening but had a close exposure to SARS-CoV-2 infected person (defined by current CDC definition of close contact). Participants in this arm and group will receive metformin.	Drug: Metformin Metformin; immediate release formation; 1,500mg daily Other Names: glucophage
Placebo Comparator: PEP Cohort - Placebo Group Participants in the PEP cohort of the trial are those who do not test positive for SARS-COV-2 infection at the time of screening but had a close exposure to SARS-CoV-2 infected person (defined by current CDC definition of close contact). Participants in this arm and group will receive placebo.	Drug: Placebo placebo; size-matched to study drug
Experimental: Treatment Arm - Treatment Group Participants in the treatment arm of the trial are those who test positive for SARS-COV-2 infection at the time of screening. Participants in this arm and group will receive the metformin.	Drug: Metformin Metformin; immediate release formation; 1,500mg daily Other Names: glucophage
Placebo Comparator: Treatment Arm - Placebo Group Participants in the treatment arm of the trial are those who test positive for SARS-COV-2 infection at the time of screening. Participants in this arm and group will receive the placebo.	Drug: Placebo placebo; size-matched to study drug

Outcome Measures


Primary Outcome Measures:
1.	Change in C-Reactive Protein [ Time Frame: 10 days ] This is one of the primary outcomes for the stage 1 trial. Outcome is reported as the change in serum concentrations of c-reactive protein (mg/L) from baseline to 5 days and baseline to 10 days.
2.	Change in Albumin [ Time Frame: 10 days ] This is one of the primary outcomes for the stage 1 trial. Outcome is reported as the change in serum concentrations of albumin (g/dL) from baseline to 5 days and baseline to 10 days.
3.	Change in Viral load [ Time Frame: 10 days ] This is one of the primary outcomes for the stage 1 trial. Outcome is reported as the change in serum viral load (copies per ml of blood) from baseline to 5 days and baseline to 10 days.
Secondary Outcome Measures:
1.	Emergency Department Utilization [ Time Frame: 14 days, 28 days ] For Covid-19 Symptoms (as defined by current CDC definition of Covid-19 symptoms).
2.	Incidence of Possible COVID-19 Symptoms [ Time Frame: 14 days, 28 days ] Assessed with Symptom Scale Recommended by FDA for Industry 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.
3.	WHO Disease Progression Scale [ Time Frame: 14 days, 28 days. ] Incidence of hospitalization for Covid-19 Incidence of oxygen therapy needed Incidence of mechanical ventilation Incidence of death

Eligibility


Minimum Age:	30 Years
Maximum Age:	85 Years
Sex:	All
Gender Based:
Accepts Healthy Volunteers:	Yes
Criteria:	Inclusion Criteria, Stage 1 Treatment Trial: Positive laboratory test for active SARS-CoV-2 viral infection based on local laboratory standard (i.e. +PCR) within 3 days of randomization; negative antibody test not required. Age >=30 years and < 85 years GFR>45ml/min within 2 weeks of enrollment Patient has medical record visible within the EHR of participating sites BMI >= 25kg/m2 by self-report height/weight or >= 23kg/m2 in patients who self-identify in S. Asian or Latinx background.59-61 Willing and able to comply with study procedures Has an address and electronic device for communication Exclusion Criteria, Stage 1 Treatment Trial: Symptom onset greater than 7 days before randomization (symptoms not required for inclusion). Currently taking metformin Electronic medical record history of kidney disease, i.e.: Estimated Glomerular Filtration Rate (eGFR) of < 45ml/min/1.73 m2 Other kidney disease that in the opinion of the investigator would affect clearance Electronic medical record history of severe liver disease Other liver disease that in the opinion of the investigator, would affect metformin clearance Documented AST or ALT > 3 times the upper limit of normal within 3 months of randomization (if available in electronic medical record) EHR of NYHA Stage 3 or 4 heart failure Inability to obtain informed consent Enrollment in another blinded RCT for COVID Alcohol use disorder Patients taking these medications: cimetidine, hydroxychloroquine, insulin, sulfonylurea, dolutegravir, patiromer, ranolazine, tafenoquine Hospitalized, for COVID-19 or other reasons.

Contacts/Locations


Central Contact Person:	Carolyn Bramante, MD Telephone: 612-624-5624 Email: Covid19trial@umn.edu
Study Officials:	Carolyn Bramante, MD Principal Investigator University of Minnesota
Locations:	United States, Minnesota
	University of Minnesota [Recruiting] Minneapolis, Minnesota, United States, 55455 Contact:Contact: Carolyn Bramante, MD, MPH

References


Citations:	Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL, Tummino TA, Huttenhain R, Kaake RM, Richards AL, Tutuncuoglu B, Foussard H, Batra J, Haas K, Modak M, Kim M, Haas P, Polacco BJ, Braberg H, Fabius JM, Eckhardt M, Soucheray M, Bennett MJ, Cakir M, McGregor MJ, Li Q, Meyer B, Roesch F, Vallet T, Mac Kain A, Miorin L, Moreno E, Naing ZZC, Zhou Y, Peng S, Shi Y, Zhang Z, Shen W, Kirby IT, Melnyk JE, Chorba JS, Lou K, Dai SA, Barrio-Hernandez I, Memon D, Hernandez-Armenta C, Lyu J, Mathy CJP, Perica T, Pilla KB, Ganesan SJ, Saltzberg DJ, Rakesh R, Liu X, Rosenthal SB, Calviello L, Venkataramanan S, Liboy-Lugo J, Lin Y, Huang XP, Liu Y, Wankowicz SA, Bohn M, Safari M, Ugur FS, Koh C, Savar NS, Tran QD, Shengjuler D, Fletcher SJ, O'Neal MC, Cai Y, Chang JCJ, Broadhurst DJ, Klippsten S, Sharp PP, Wenzell NA, Kuzuoglu-Ozturk D, Wang HY, Trenker R, Young JM, Cavero DA, Hiatt J, Roth TL, Rathore U, Subramanian A, Noack J, Hubert M, Stroud RM, Frankel AD, Rosenberg OS, Verba KA, Agard DA, Ott M, Emerman M, Jura N, von Zastrow M, Verdin E, Ashworth A, Schwartz O, d'Enfert C, Mukherjee S, Jacobson M, Malik HS, Fujimori DG, Ideker T, Craik CS, Floor SN, Fraser JS, Gross JD, Sali A, Roth BL, Ruggero D, Taunton J, Kortemme T, Beltrao P, Vignuzzi M, Garcia-Sastre A, Shokat KM, Shoichet BK, Krogan NJ. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020 Jul;583(7816):459-468. doi: 10.1038/s41586-020-2286-9. Epub 2020 Apr 30. PubMed 32353859
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