COVID-OUT: Early Outpatient Treatment for SARS-CoV-2 Infection (COVID-19)

NCT04510194 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: GIM-2020-29324
• Study Type: interventional
• Target: 1,323
• Locations: 1 country
• Sites: 7

Brief Summary

1. 1.The purpose of this trial is to conduct a 2x3 factorial randomized trials, which efficiently allows the parallel conduct of three randomized trials to understand whether metformin, ivermectin, or fluvoxamine, is superior to placebo for preventing Covid-19 disease progression in non-hospitalized adults with SARS- CoV-2 infection.
2. 2.To understand if the active treatment arms are superior to placebo in improving viral load, serologic markers associated with Covid-19, and gut microbiome in non-hospitalized adults with SARS-CoV-2 infection.
3. 3.To understand if any of the active treatment arms prevent long-covid syndrome, PASC (post-acute sequelae of SARS-CoV-2 infection).

Conditions

Covid19; SARS-CoV Infection

Outcome Measures

Primary Outcomes (1)

• Clinical Progression to Severe Covid

  Clinical progression, defined as Emergency department visit for any COVID-19 related symptom (including hospitalization or death) or decrease in O2 saturation (\<=93% on room air, or need for supplemental oxygen to maintain an O2 saturation \<=93%)

  14 Days

Secondary Outcomes (7)

• Clinical Progression to Severe Covid

  14 days

• Progression

  28 days

• Maximum Symptom Severity

  14 days

• Clinical Deterioration: Hospital and Vent >3days

  28 days

• Laboratory Outcome Study

  Day5-Day10

Study Arms (6)

Metformin + Placebo

EXPERIMENTAL

This is the randomization group that received active metformin + either fluvoxamine placebo or ivermectin placebo.

Drug: Metformin; Drug: Placebo

Placebo

EXPERIMENTAL

This is the randomization group that received metformin placebo + either fluvoxamine placebo or ivermectin placebo.

Drug: Placebo

Ivermectin + Metformin Placebo

EXPERIMENTAL

This is the randomization group that received active ivermectin + metformin placebo.

Drug: Placebo; Drug: Ivermectin

Fluvoxamine + Metformin Placebo

EXPERIMENTAL

This is the randomization group that received active fluvoxamine + metformin placebo.

Drug: Placebo; Drug: Fluvoxamine

Metformin + Fluvoxamine

EXPERIMENTAL

This is the randomization group that received active metformin + active fluvoxamine.

Drug: Metformin; Drug: Fluvoxamine

Metformin + Ivermectin

EXPERIMENTAL

This is the randomization group that received active metformin + active ivermectin.

Drug: Metformin; Drug: Ivermectin

Interventions

Metformin DRUG

Metformin; immediate release formation; 500mg on Day 1; 500mg BID on Day 2 through Day 5; 500mg in AM and 1,000mg in PM on Day 6 through Day 14.

Also known as: glucophage

Metformin + Fluvoxamine; Metformin + Ivermectin; Metformin + Placebo

Placebo DRUG

placebo; appearance and size are exact matching to the three study drugs.

Fluvoxamine + Metformin Placebo; Ivermectin + Metformin Placebo; Metformin + Placebo; Placebo

Fluvoxamine DRUG

An antidepressant, administered 50mg per day on Day 1; then 50mg twice-daily for Day 2 through Day 14

Also known as: Luvox

Fluvoxamine + Metformin Placebo; Metformin + Fluvoxamine

Ivermectin DRUG

An anti-parasitic medication administered as 390mcg/kg to 470mcg/kg per day for 3 days

Also known as: Stromectol

Ivermectin + Metformin Placebo; Metformin + Ivermectin

Eligibility Criteria

• Age: 30 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Positive laboratory test for active SARS-CoV-2 viral infection based on local laboratory standard (i.e. +PCR) within 3 days of randomization.
• No known history of confirmed SARS-CoV-2 infection
• BMI \>= 25kg/m2 by self-report height/weight or \>= 23kg/m2 in patients who self-identify in South Asian or Latinx background.
• Willing and able to comply with study procedures (i.e. swallow pills)
• Has an address and electronic device for communication
• GFR\>45ml/min within 2 weeks for patients \>75 years old, or with history of heart, kidney, or liver failure.

You may not qualify if:

• Hospitalized, for COVID-19 or other reasons.
• Immune compromised state (solid organ transplant, bone marrow transplant, AIDS, on high dose steroids)
• Hepatic impairment (Child-Pugh B and C) or other condition that, in the opinion of the investigator, would affect safety
• Inability to obtain informed consent
• Enrollment in another blinded Randomized Controlled Trial for COVID-19
• Already received an effective (FDA approved/EUA\*) therapy for COVID-19 (currently monoclonal antibody treatment)
• Alcohol use disorder
• Other unstable medical condition or combination of home medications that in the view of the PI make it unsafe for the individual to participate
• History of severe kidney disease i.e.:
• Stage 4 or 5 CKD, or Estimated Glomerular Filtration Rate (eGFR) of \< 45ml/min/1.73 m2
• Other kidney disease that in the opinion of the investigator would affect clearance
• Unstable heart failure (Stage 3 or 4 heart failure)
• Allergic reaction to metformin, fluvoxamine, or ivermectin in the past
• Bipolar disease: individuals who report they have bipolar disorder or are taking medication for bipolar disorder (lithium, valproate, high-dose antipsychotic), unless the investigator concludes that the risk for mania is unlikely
• Current loa loa or onchocerciasis infection

Sponsors & Collaborators

• University of Minnesota: lead
• UnitedHealth Group: collaborator
• Northwestern University: collaborator
• Hennepin County Medical Center, Minneapolis: collaborator
• University of Colorado, Denver: collaborator
• Olive View-UCLA Education & Research Institute: collaborator

Study Sites (7)

Olive View UCLA Medical Center

Sylmar, California, 91342, United States

Location

University of Colorado Denver; Department of Medicine; Anschutz Health and Wellness Center

Aurora, Colorado, 80045, United States

Location

New West Physicians

Golden, Colorado, 80401, United States

Location

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

American Health Network of Indiana

Greenfield, Indiana, 46140, United States

Location

Hennepin County Medical Center

Minneapolis, Minnesota, 55415, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Related Publications (8)

• 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.

  PMID: 32353859 BACKGROUND

• Castle, B.T., C. Dock, M. Hemmat, S. Kline, C. Tignanelli, R. Rajasingham, D. Masopust, P. Provenzano, R. Langlois, T. Schacker, A. Haase, and D.J. Odde, Biophysical modeling of the SARS-CoV-2 viral cycle reveals ideal antiviral targets. bioRxiv, 2020. https://www.biorxiv.org/content/10.1101/2020.05.22.111237v2.

  BACKGROUND

• Hartman KM, Patel B, Rao V, Hagen AA, Saveraid HG, Fricton R, Lee S, Snyder AT, Pullen MF, Boulware DR, Liebovitz DM, Belani HK, Niklas JM, Murray TA, Cohen K, Thompson JL, Erickson SM, Bramante CT. A Comparison of Recruitment Methods for a Remote, Nationwide Clinical Trial for COVID-19 Treatment. Open Forum Infect Dis. 2024 Apr 29;11(7):ofae224. doi: 10.1093/ofid/ofae224. eCollection 2024 Jul.

  PMID: 38947738 DERIVED

• Bramante CT, Beckman KB, Mehta T, Karger AB, Odde DJ, Tignanelli CJ, Buse JB, Johnson DM, Watson RHB, Daniel JJ, Liebovitz DM, Nicklas JM, Cohen K, Puskarich MA, Belani HK, Siegel LK, Klatt NR, Anderson B, Hartman KM, Rao V, Hagen AA, Patel B, Fenno SL, Avula N, Reddy NV, Erickson SM, Fricton RD, Lee S, Griffiths G, Pullen MF, Thompson JL, Sherwood NE, Murray TA, Rose MR, Boulware DR, Huling JD; COVID-OUT Study Team. Favorable Antiviral Effect of Metformin on SARS-CoV-2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of COVID-19. Clin Infect Dis. 2024 Aug 16;79(2):354-363. doi: 10.1093/cid/ciae159.

  PMID: 38690892 DERIVED

• Bramante CT, Buse JB, Liebovitz DM, Nicklas JM, Puskarich MA, Cohen K, Belani HK, Anderson BJ, Huling JD, Tignanelli CJ, Thompson JL, Pullen M, Wirtz EL, Siegel LK, Proper JL, Odde DJ, Klatt NR, Sherwood NE, Lindberg SM, Karger AB, Beckman KB, Erickson SM, Fenno SL, Hartman KM, Rose MR, Mehta T, Patel B, Griffiths G, Bhat NS, Murray TA, Boulware DR; COVID-OUT Study Team. Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial. Lancet Infect Dis. 2023 Oct;23(10):1119-1129. doi: 10.1016/S1473-3099(23)00299-2. Epub 2023 Jun 8.

  PMID: 37302406 DERIVED

• Boulware DR, Murray TA, Proper JL, Tignanelli CJ, Buse JB, Liebovitz DM, Nicklas JM, Cohen K, Puskarich MA, Belani HK, Siegel LK, Klatt NR, Odde DJ, Karger AB, Ingraham NE, Hartman KM, Rao V, Hagen AA, Patel B, Fenno SL, Avula N, Reddy NV, Erickson SM, Lindberg S, Fricton R, Lee S, Zaman A, Saveraid HG, Tordsen WJ, Pullen MF, Sherwood NE, Huling JD, Bramante CT; COVID-OUT study team. Impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccination and Booster on Coronavirus Disease 2019 (COVID-19) Symptom Severity Over Time in the COVID-OUT Trial. Clin Infect Dis. 2023 Feb 8;76(3):e1-e9. doi: 10.1093/cid/ciac772.

  PMID: 36124697 DERIVED

• Bramante CT, Huling JD, Tignanelli CJ, Buse JB, Liebovitz DM, Nicklas JM, Cohen K, Puskarich MA, Belani HK, Proper JL, Siegel LK, Klatt NR, Odde DJ, Luke DG, Anderson B, Karger AB, Ingraham NE, Hartman KM, Rao V, Hagen AA, Patel B, Fenno SL, Avula N, Reddy NV, Erickson SM, Lindberg S, Fricton R, Lee S, Zaman A, Saveraid HG, Tordsen WJ, Pullen MF, Biros M, Sherwood NE, Thompson JL, Boulware DR, Murray TA; COVID-OUT Trial Team. Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19. N Engl J Med. 2022 Aug 18;387(7):599-610. doi: 10.1056/NEJMoa2201662.

  PMID: 36070710 DERIVED

• Dodds MG, Doyle EB, Reiersen AM, Brown F, Rayner CR. Fluvoxamine for the treatment of COVID-19. Lancet Glob Health. 2022 Mar;10(3):e332. doi: 10.1016/S2214-109X(22)00006-7. No abstract available.

  PMID: 35180412 DERIVED

MeSH Terms

Conditions

COVID-19; Severe Acute Respiratory Syndrome

Interventions

Metformin; Fluvoxamine; Ivermectin

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Oximes; Hydroxylamines; Amines; Macrolides; Polyketides; Lactones

Results Point of Contact

• Title: Carolyn Bramante
• Organization: University of Minnesota

jcharles@umn.edu

612-624-0468

Study Officials

• Carolyn Bramante, MD

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Only the investigational pharmacy and unblinded statistician have access to patient treatment allocation. All participants receive two types of pills to maintain masking.
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 7, 2020
• First Posted: August 12, 2020
• Study Start: January 1, 2021
• Primary Completion: December 14, 2022
• Study Completion: December 14, 2022
• Last Updated: April 24, 2026
• Results First Posted: July 13, 2023

Record last verified: 2026-04

Locations

US (7)