We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04510194
Recruitment Status : Active, not recruiting
First Posted : August 12, 2020
Last Update Posted : August 8, 2022
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

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. Study study assess 3 existing generic medications: metformin, fluvoxamine, and ivermectin.

Metformin: in-silico, in-vitro, ex-vivo tissue assays suggest that metformin inhibits viral replication of SARS-CoV-2 virus (Castle et al; Gordon et al; and Schaller et al). Several retrospective cohort analyses have suggested an association between taking metformin prior to SARS-CoV-2 infection and less severe outcomes. 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 (Lou et al, Diabetes Care 2020).

Fluvoxamine: appears to have anti-inflammatory effects in SARS-CoV-2 infection. There is evidence that SARS-CoV-2 infection causes ER stress and activates pathways of unfolded protein response. Sigma-1 receptor (S1R) is an ER chaperone protein that regulates cytokine production through interaction with IRE1. Fluvoxamine is a selective serotonin reuptake inhibitor that is a powerful S1R agonist. Fluvoxamine has previously been shown to protect mice from septic shock and reduce the inflammatory response. There is potential for fluvoxamine as an immunomodulatory treatment for SARS-Cov-2. Fluvoxamine in CACO2 cells infected with SARS-Cov-2 had a reduction in production of a subset of cytokines including IL-6, IL-8, CXCL1, and CXCL10.53 A randomized controlled clinical trial of 152 patients showed that patients who received fluvoxamine were less likely to experience clinical deterioration, or serious adverse events due to SARS-Cov-2 when compared to placebo (0% vs. 8%). A follow-up real-world observational cohort had similar findings of 0% (0/65) hospitalization with fluvoxamine vs. 12% (6/48) with observation.

Ivermectin has also shown anti-inflammatory effects that would reduce the harmful cytokine cascade noted in severe Covid-19 disease. A recent trial assessing a multi-therapy including 12mg one-time dose of ivermectin found a 75% reduction in hospitalizations. Another small double-blinded RCT showed significant increased chance of viral clearance after a 5-day course of ivermectin. Another March 2021 RCT reported no effect on diminishing symptoms, but was under-powered for assessing reductions in hospitalization. An RCT with ivermectin must be done in the US, as endemic strongyloidiasis in other countries may confound results.

Statistical Considerations:

An independent data safety monitoring board will assess safety approximately twice per month; and will assess futility and efficacy at least twice throughout the study. If one of the arms reaches pre-specified boundaries for futility or efficacy, the DSMB will recommend closing of that arm(s). The detailed statistical analysis plan will be developed by the blinded statistician and co-investigators and per the protocol will be submitted to the DSMB.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1350 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Only the investigational pharmacy and unblinded 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
Actual Primary Completion Date : February 14, 2022
Estimated Study Completion Date : February 14, 2023


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; 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.
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 are exact matching to the three study drugs.

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 anti-parasitic medication administered as 390mcg/kg to 470mcg/kg per day 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 50mg per day on Day 1; then 50mg twice-daily for Day 2 through Day 14
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; 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.
Other Name: glucophage

Drug: Fluvoxamine
An antidepressant, administered 50mg per day on Day 1; then 50mg twice-daily for Day 2 through Day 14
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; 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.
Other Name: glucophage

Drug: Ivermectin
An anti-parasitic medication administered as 390mcg/kg to 470mcg/kg per day for 3 days
Other Name: Stromectol




Primary Outcome Measures :
  1. Clinical Progression [ Time Frame: 14 days ]
    1) 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%).


Secondary Outcome Measures :
  1. Maximum symptom severity [ Time Frame: 14 days ]
    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: day 28. ]
    0) No COVID-19 symptoms 1) Outpatient symptomatic but without hypoxia (>93% O2 saturation) 2) Outpatient with O2 saturation <93% on room air (or receiving supplemental oxygen to maintain >93%) 3) Emergency Department visit for any COVID symptom; 4) Hospitalization for any COVID symptom; 5) ICU requiring ventilator support; 6) ICU requiring ventilator support for at least 3 days or ECMO; 7) Death.

  3. Time to meaningful recovery [ Time Frame: 14 days and day 28 ]
    Symptom improvement or Clinical progression improved.

  4. Laboratory Outcome Subsidy - Viral Load [ Time Frame: Day 1, 5, 10 ]
    Self-collection of anterior nasal swab samples is optional for participants. 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 ]
    Collection of blood samples by mobile phlebotomy is optional for participants and determined by availability of mobile phlebotomy. Change in inflammatory and coagulopathic markers will be compared from baseline to follow-up between treatment arms.

  6. Laboratory Outcome Subsidy - Microbiome [ Time Frame: Days 1, 5, 10 ]
    Self-collection of stool samples is optional for participants.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.

  7. Portion of participants with Post-Acute Sequelae of SARS-CoV-2 infection (PASC) [ Time Frame: 6 and 12 months ]
    PASC assessment will be conducted monthly after enrollment for approximately 9 months with the Questionnaire to characterize long COVID.



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.


Layout table for eligibility information
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.

    • Additional COVID-19 treatments to exclude will be decided by a panel of at least 3 Co-Investigators on this study. The additional treatments to exclude will be documented and submitted to the IRB but may be implemented before formal IRB approval is complete. We take this approach because of the rapidly changing treatment landscape of COVID-19. Participation in the study does not prevent them from receiving such treatments after enrollment.

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


Locations
Layout table for location information
United States, California
Olive View UCLA Medical Center
Sylmar, California, United States, 91342
United States, Colorado
University of Colorado Denver; Department of Medicine; Anschutz Health and Wellness Center
Aurora, Colorado, United States, 80045
New West Physicians
Golden, Colorado, United States, 80401
United States, Illinois
Northwestern University Feinberg School of Medicine
Chicago, Illinois, United States, 60611
United States, Indiana
American Health Network of Indiana
Greenfield, Indiana, United States, 46140
United States, Minnesota
Hennepin County Medical Center
Minneapolis, Minnesota, United States, 55415
University of Minnesota
Minneapolis, Minnesota, United States, 55455
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
Layout table for investigator information
Principal Investigator: Carolyn Bramante, MD University of Minnesota
  Study Documents (Full-Text)

Documents provided by University of Minnesota:
Study Protocol  [PDF] December 8, 2021

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
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: August 8, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
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