1. The purpose of this trial is to conduct a 2x3 factorial randomized trials, which efficiently allows the parallel conduct of three randomized trials to understand whether metformin, ivermectin, or fluvoxamine, is superior to placebo for preventing Covid-19 disease progression in non-hospitalized adults with SARS- CoV-2 infection. 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
1,323
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
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
Clinical Progression to Severe Covid
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%)
Time frame: 14 Days
Clinical Progression to Severe Covid
Emergency department visit for any COVID-19 related symptom (including hospitalization or death), active relative to placebo
Time frame: 14 days
Progression
Count of participants with clinical progression to Hospitalization, Death
Time frame: 28 days
Maximum Symptom Severity
Defined by adding the symptom score for each individual symptom on the "Daily Symptom Scale Recommended by FDA For Industry." Each symptom on the scale had an answer option ranging from 0 to 3. They corresponded to 0= no symptom; 1=mild symptom; 2=moderate symptom; 3=severe symptom. The range for the total score is 0 to 42 (14 symptoms x 3). The data presented here are the unadjusted mean (SD) for the total symptom score on Day 14.
Time frame: 14 days
Clinical Deterioration: Hospital and Vent >3days
Progression to Hospitalization or Ventilation by Day 28
Time frame: 28 days
Laboratory Outcome Study
Count of participants with no detectable viral load on Day 10.
Time frame: Day5-Day10
All-cause Study Medicine Discontinuation
Study drug discontinuation (total interrupted - total restarted), per treatment allocation. Per treatment allocation means that these counts are not per randomized comparison.
Time frame: 14 days
Long Covid
Proportion of participants with long-covid syndrome, PASC (post-acute sequelae of SARS-CoV-2 infection)
Time frame: Day 300
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