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).
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.
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: Placebo
placebo; appearance and size are exact matching to the three study drugs.
Drug: Fluvoxamine
An antidepressant, administered 50mg per day on Day 1; then 50mg twice-daily for Day 2 through Day 14
Other Name: Luvox
Drug: Ivermectin
An anti-parasitic medication administered as 390mcg/kg to 470mcg/kg per day for 3 days
Other Name: Stromectol
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.
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
Carolyn Bramante, MD, Principal Investigator
University of Minnesota