COVID-OUT: Early Outpatient Treatment for SARS-CoV-2 Infection (COVID-19)
Condition: Covid19; SARS-CoV Infection
MeSH terms: Infections; Communicable Diseases; COVID-19; Severe Acute Respiratory Syndrome
Intervention: Metformin; Placebo; Fluvoxamine; Ivermectin
Intervention description: 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.; placebo; appearance and size are exact matching to the three study drugs.; An antidepressant, administered 50mg per day on Day 1; then 50mg twice-daily for Day 2 through Day 14; An anti-parasitic medication administered as 390mcg/kg to 470mcg/kg per day for 3 days
Intervention MeSH terms: Metformin; Ivermectin; Fluvoxamine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
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.
Enrollment: 1323.0
Sex: All
Minimum age: 30 Years
Maximum age: 85 Years
Healthy volunteers: No

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).
    

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.