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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04510194
Recruitment Status : Recruiting
First Posted : August 12, 2020
Last Update Posted : November 18, 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 understand whether:

  1. Metformin vs fluvoxamine vs ivermectin vs metformin+fluvoxamine vs metformin+ivermectin is superior to placebo in non-hospitalized adults with SARS-CoV-2 disease for preventing Covid-19 disease progression.
  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. To understand if any of the active treatment arms prevent long-covid syndrome, PASC (post-acute sequelae of SARS-CoV-2 infection).

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1160 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
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: COVID-OUT: Early Outpatient Treatment for SARS-CoV-2 Infection (COVID-19)
Actual Study Start Date : January 1, 2021
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021


Arm Intervention/treatment
Experimental: Treatment Arm - Metformin Only 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 alone.
Drug: Metformin
Metformin; immediate release formation; 1,500mg daily for 14 days
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

Experimental: Treatment Arm - Ivermectin Only 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 ivermectin alone.
Drug: Ivermectin
An antiparasitic medication administered as 390mcg/kg for weight category <104 kg, and 470mcg/kg for weight category >104 kg for 3 days
Other Name: Stromectol

Experimental: Treatment Arm - Fluvoxamine Only 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 fluvoxamine alone.
Drug: Fluvoxamine
An antidepressant, administered in twice-daily dosing, 50 mg twice per day for 14 days
Other Name: Luvox

Experimental: Treatment Arm - Metformin and Fluvoxamine 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 metformin and fluvoxamine.
Drug: Metformin
Metformin; immediate release formation; 1,500mg daily for 14 days
Other Name: glucophage

Drug: Fluvoxamine
An antidepressant, administered in twice-daily dosing, 50 mg twice per day for 14 days
Other Name: Luvox

Experimental: Treatment Arm - Metformin and Ivermectin 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 metformin and ivermectin.
Drug: Metformin
Metformin; immediate release formation; 1,500mg daily for 14 days
Other Name: glucophage

Drug: Ivermectin
An antiparasitic medication administered as 390mcg/kg for weight category <104 kg, and 470mcg/kg for weight category >104 kg for 3 days
Other Name: Stromectol




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 - Viral Load [ 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 - CRP [ 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 - Albumin [ 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 - Microbiome [ 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.

  8. Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) Questionnaire [ Time Frame: 6 and 12 months ]
    PASC assessment will be conducted monthly after enrollment for 6 months to 12 months with the Questionnaire to characterize long COVID. Outcome is reported as the percent of participants who report PASC any symptoms.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   30 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • Hospitalized, for COVID-19 or other reasons.
  • Symptom onset greater than 7 days before randomization (symptoms not required for inclusion).
  • 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.:

    1. Stage 4 or 5 CKD, or Estimated Glomerular Filtration Rate (eGFR) of < 45ml/min/1.73 m2
    2. 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
  • Typhoid, BCG, or cholera vaccination within the 14-days or 3 days after

Medication Exclusions:

  • Cimetidine, hydroxychloroquine, insulin, sulfonylurea, dolutegravir, patiromer, ranolazine, tafenoquine.
  • Rasagiline, selegiline, or monoamine oxidase inhibitors, linezolid, methadone
  • Duloxetine, methylene blue
  • Tizanidine, ramelteon, sodium picosulfate
  • Alosetron, agomelatine, bromopride, dapoxetine, tamsimelteon, thioridazine, urokinase, pimozide

The following medications may not need to be excluded when dose for that individual is considered alongside the low dose of fluvoxamine being used and other medications being used. The PI or site PI may review and decide if the patient should be excluded from the fluvoxamine arms:

  1. Taking SSRIs, SNRIs, or tricyclic antidepressants, unless these are at a low dose such that a study investigator concludes that a clinically significant interaction with fluvoxamine (ie either serotonin syndrome or TCA overdose) is unlikely (examples: participant takes escitalopram but only at 10mg daily; that dose plus 100mg fluvoxamine would be insufficient to cause serotonin syndrome; or, participant takes amitriptyline but only at 25mg nightly; even if fluvoxamine inhibits its metabolism, it would be an insufficient dose to cause QTc prolongation or problematic side effects). Risk Class C, monitor therapy.
  2. Individuals who take alprazolam or diazepam and are unwilling to cut the medication by 20% (rationale: fluvoxamine modestly inhibits the metabolism of these drugs). Risk Class C, monitor therapy
  3. Participants taking theophylline, clozapine, or olanzapine (drugs with a narrow therapeutic index that are primarily metabolized by CYP 1A2, which is inhibited by fluvoxamine) will be reviewed with a study investigator and excluded unless the investigator concludes that the risk to the participant is low (this would be unlikely; example: participant takes clozapine only as needed and is willing to avoid it for the 14 days of the study).
  4. Patients will be advised that there is a small risk that the following substances will be affected by fluvoxamine, but that significant effects are not likely at the low dose being used: caffeine, nicotine, melatonin. Risk Class C, monitor therapy
  5. Taking warfarin-also known as Coumadin, NSAIDs, and Aspirin (rationale: increased risk of bleeding), phenytoin (rationale: fluvoxamine inhibits its metabolism), clopidogrel (rationale: fluvoxamine inhibits its metabolism from pro-drug to active drug which raises risk of cardiovascular events), and St John's wort (rationale: fluvoxamine + St John's wort are considered contraindicated because of the risk of serotonin syndrome) Risk C, monitor therapy.

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: Website covidout.com 651-661-9560 covidout@umn.edu

Locations
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United States, California
Olive View UCLA Medical Center Recruiting
Sylmar, California, United States, 91342
Contact: Hrishi Belani, MD         
Principal Investigator: Hrishi Belani, MD         
United States, Colorado
Anschutz Health and Wellness Center Recruiting
Aurora, Colorado, United States, 80045
Contact: Jacinda Nicklas, MD         
Principal Investigator: Jacinda Nicklas, MD         
New West Physicians Recruiting
Golden, Colorado, United States, 80401
Contact: Ken Cohen, MD         
Principal Investigator: Ken Cohen, MD         
United States, Illinois
Northwestern University Feinberg School of Medicine Recruiting
Chicago, Illinois, United States, 60611
Contact: David Liebovitz, MD         
Principal Investigator: David Liebovitz, MD         
United States, Indiana
American Health Network of Indiana Recruiting
Greenfield, Indiana, United States, 46140
Contact: Andrew Daluga, MD         
Principal Investigator: Andrew Daluga, MD         
United States, Minnesota
Hennepin County Medical Center Recruiting
Minneapolis, Minnesota, United States, 55415
Contact: Mike Puskarich, MD         
Principal Investigator: Mike Puskarich, MD         
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Carolyn Bramante, MD, MPH       covidout@umn.edu   
Sub-Investigator: David Boulware, MD         
Sub-Investigator: Christopher Tignanelli, MD         
Sub-Investigator: David Odde, MD         
Sub-Investigator: Nick Ingraham, MD         
Sub-Investigator: Michelle Biros, MD         
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.
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.

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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: November 18, 2021
Last Verified: November 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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Infections
Communicable Diseases
COVID-19
Severe Acute Respiratory Syndrome
Disease Attributes
Pathologic Processes
Respiratory Tract Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Metformin
Ivermectin
Fluvoxamine
Hypoglycemic Agents
Physiological Effects of Drugs
Antiparasitic Agents
Anti-Infective Agents
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators