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Outpatient Treatment of COVID-19 With Metformin

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ClinicalTrials.gov Identifier: NCT04510194
Recruitment Status : Recruiting
First Posted : August 12, 2020
Last Update Posted : February 21, 2021
Sponsor:
Collaborators:
UnitedHealth Group
Northwestern University
Hennepin County Medical Center, Minneapolis
University of Colorado, Denver
Olive View-UCLA Education & Research Institute
Information provided by (Responsible Party):
University of Minnesota

Brief Summary:

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

  1. Test if metformin treatment in non-hospitalized adults with SARS-CoV-2 infection can prevent hypoxia and emergency department utilization for Covid-19.
  2. Test if metformin treatment in non-hospitalized adults with SARS-CoV-2 disease can prevent Covid-19 disease progression.
  3. Test if metformin treatment in non-hospitalized adults with SARS-CoV-2 can improve viral load and CRP(self-collected, laboratory subsidy)

Condition or disease Intervention/treatment Phase
Covid19 SARS-CoV Infection Drug: Metformin Drug: Placebo Phase 2 Phase 3

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 definitive preventive or early 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:

  1. Cariou et al, Diabetologia, adults with diabetes (DM) in France: OR mortality 0.59 (0.42, 0.84)
  2. Crouse et al, medrxiv.org adults with DM at Univ of Alabama Birmingham: OR mortality 0.33 (0.13-0.84)
  3. 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.
  4. Lou et al, Am J Trop Med, adults with diabetes in China, OR for survival: 4.36 (1.22-15.59)
  5. 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).
  6. 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 750 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Funding has been obtained for Stage 1 (70 patients) of this fully-powered Phase 3 trial (750 patients total).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Only the investigational pharmacy and one statistician have access to patient treatment allocation.
Primary Purpose: Treatment
Official Title: COVIDOUT: Outpatient Treatment of COVID-19 With Metformin (Former Title: MET-COVID)
Actual Study Start Date : January 1, 2021
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : August 2021


Arm Intervention/treatment
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 Name: 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; appearance and size-matched to study drug




Primary Outcome Measures :
  1. Decreased oxygenation [ Time Frame: 14 days ]
    SpO2 =< 93% on home monitoring.

  2. Emergency Department Utilization [ Time Frame: 14 days ]
    Emergency department utilization for Covid-19 Symptoms (as defined by current CDC definition of Covid-19 symptoms or by treating clinical team).


Secondary Outcome Measures :
  1. Maximum symptom severity [ Time Frame: 14 days and day 28 ]
    Maximum numeric score (defined by adding the symptom score for each individual symptom) on the "Daily Symptom Scale Recommended by FDA for Industry."

  2. Clinical Progression Scale [ Time Frame: 14 days and day 28. ]
    Maximum Clinical Support Needed on the Following Scale: 1) O2 saturation >93% with supplemental oxygen requirement; 2) ED visit for any COVID symptom; 3) Hospitalization for any COVID symptom; 4) Hospitalized requiring ventilator support; 5) The above + ventilator support for at least 3 days; 6) Requiring extracorporeal membrane oxygenation (ECMO); 7) Death.

  3. Time to meaningful recovery [ Time Frame: 14 days and day 28 ]
    Symptom improvement of > 2 points or Clinical progression improved by one category and sustained for at least 36 hours

  4. Laboratory Outcome Subsidy [ Time Frame: Day 1, 5, 10 ]
    Self-collect anterior nasal swab will be done on the first 70 patients (viral load). Change in Viral Load between Baseline and Follow-up with be compared between treatment arms.

  5. Laboratory Outcome Subsidy [ Time Frame: Day 1, 5, 10 ]
    Self-collect finger stick blood will be done on the first 70 patients (CRP). Change in CRP between Baseline and Follow-up with be compared between treatment arms.

  6. Laboratory Outcome Subsidy [ Time Frame: Day 1, 5, 10 ]
    Self-collect finger stick blood will be done on the first 70 patients (Albumin). Change in Albumin between Baseline and Follow-up with be compared between treatment arms.

  7. Laboratory Outcome Subsidy [ Time Frame: Days 1, 5, 10 ]
    Optional self-collect stool samples.16S rRNA sequencing and shotgun sequencing will be used to assess the impact of metformin-based treatment options for Covid on improving the ratio of beneficial to inflammatory bacteria in the gastrointestinal tract, and the role of the microbiome in health and disease outcomes.



Information from the National Library of Medicine

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Ages Eligible for Study:   30 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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 or after 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04510194


Contacts
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Contact: Carolyn Bramante, MD 612-624-5624 metstudy@umn.edu

Locations
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United States, Minnesota
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Carolyn Bramante, MD, MPH       covidout@umn.edu   
Sponsors and Collaborators
University of Minnesota
UnitedHealth Group
Northwestern University
Hennepin County Medical Center, Minneapolis
University of Colorado, Denver
Olive View-UCLA Education & Research Institute
Investigators
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Principal Investigator: Carolyn Bramante, MD University of Minnesota
Publications:
Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL, Tummino TA, Hüttenhain 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, García-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.

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Responsible Party: University of Minnesota
ClinicalTrials.gov Identifier: NCT04510194    
Other Study ID Numbers: GIM-2020-29324
First Posted: August 12, 2020    Key Record Dates
Last Update Posted: February 21, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Coronavirus Infections
Severe Acute Respiratory Syndrome
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs