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

Sponsor
University of Minnesota (Other)
Overall Status
Recruiting
CT.gov ID
NCT04510194
Collaborator
UnitedHealth Group (Industry), Northwestern University (Other), Hennepin County Medical Center, Minneapolis (Other), University of Colorado, Denver (Other), Olive View-UCLA Education & Research Institute (Other)
1,160
Enrollment
7
Locations
6
Arms
11
Anticipated Duration (Months)
165.7
Patients Per Site
15.1
Patients Per Site Per Month

Study Details

Study Description

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 DiseaseIntervention/TreatmentPhase
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.

In addition to metformin, fluvoxamine appears to have important anti-viral and 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. S1R modulation has demonstrated significant changes to coronavirus replication, and atypical antipsychotics with S1R activity have displayed protective effects against clinical deterioration. 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.

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. The intervention is metformin, a biguanide, administered in its immediate release formation, 1,500mg daily.

Study Design

Study Type:
Interventional
Anticipated 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 :
Jan 1, 2021
Anticipated Primary Completion Date :
Oct 1, 2021
Anticipated Study Completion Date :
Dec 1, 2021

Arms and Interventions

ArmIntervention/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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • glucophage
  • Drug: Fluvoxamine
    An antidepressant, administered in twice-daily dosing, 50 mg twice per day for 14 days
    Other Names:
  • 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 Names:
  • 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 Names:
  • Stromectol
  • Outcome Measures

    Primary Outcome Measures

    1. Decreased oxygenation [14 days]

      SpO2 =< 93% on home monitoring.

    2. Emergency Department Utilization [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 [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 [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 [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 [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 [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 [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 [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 [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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    30 Years to 85 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Olive View UCLA Medical CenterSylmarCaliforniaUnited States91342
    2Anschutz Health and Wellness CenterAuroraColoradoUnited States80045
    3New West PhysiciansGoldenColoradoUnited States80401
    4Northwestern University Feinberg School of MedicineChicagoIllinoisUnited States60611
    5American Health Network of IndianaGreenfieldIndianaUnited States46140
    6Hennepin County Medical CenterMinneapolisMinnesotaUnited States55415
    7University of MinnesotaMinneapolisMinnesotaUnited States55455

    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

    • Principal Investigator: Carolyn Bramante, MD, University of Minnesota

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    University of Minnesota
    ClinicalTrials.gov Identifier:
    NCT04510194
    Other Study ID Numbers:
    • GIM-2020-29324
    First Posted:
    Aug 12, 2020
    Last Update Posted:
    Oct 8, 2021
    Last Verified:
    Sep 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Oct 8, 2021