NCT04510194

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

• Status: Completed
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 1,323 (actual)
• Sponsor: University of Minnesota · Academic / Other
• Sex: All
• Age: 30 Years – 85 Years
• Healthy volunteers: Not accepted

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

Interventions

Type	Name	Description
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.
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
DRUG	Ivermectin	An anti-parasitic medication administered as 390mcg/kg to 470mcg/kg per day for 3 days

Timeline

• Start date: 2021-01-01
• Primary completion: 2022-02-14
• Completion: 2022-02-14
• First posted: 2020-08-12
• Last updated: 2024-05-16
• Results posted: 2023-07-13

Locations

7 sites across 1 country: United States

Regulatory

• FDA-regulated drug study