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

NCT ID: NCT04510194

Last Updated: 2024-05-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1323 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-01-01
• Study Completion Date: 2022-02-14

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).

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.

Conditions

Covid19; SARS-CoV Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Metformin

Intervention Type: 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.

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Ivermectin

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Fluvoxamine

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Metformin

Intervention Type: 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.

Fluvoxamine

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Metformin

Intervention Type: 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.

Ivermectin

Intervention Type: DRUG

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

Interventions

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.

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

Fluvoxamine

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

Intervention Type: DRUG

Ivermectin

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

Intervention Type: DRUG

Other Intervention Names

glucophage; Luvox; Stromectol

Eligibility 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.

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

UnitedHealth Group

INDUSTRY

Sponsor Role: collaborator

Northwestern University

OTHER

Sponsor Role: collaborator

Hennepin County Medical Center, Minneapolis

OTHER

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: collaborator

Olive View-UCLA Education & Research Institute

OTHER

Sponsor Role: collaborator

University of Minnesota

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Carolyn Bramante, MD

Role: PRINCIPAL_INVESTIGATOR

University of Minnesota

Locations

Olive View UCLA Medical Center

Sylmar, California, United States

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

Aurora, Colorado, United States

New West Physicians

Golden, Colorado, United States

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States

American Health Network of Indiana

Greenfield, Indiana, United States

Hennepin County Medical Center

Minneapolis, Minnesota, United States

University of Minnesota

Minneapolis, Minnesota, United States

Countries

United States

References

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Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

GIM-2020-29324

Identifier Type: -

Identifier Source: org_study_id