Outpatient Treatment of SARS-CoV-2 With Ivermectin, Fluvoxamine, and Metformin (COVID-19)

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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 am...

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: Cariou et al, Diabetologia, adults with diabetes (DM) in France: OR mortality 0.59 (0.42, 0.84) Crouse et al, medrxiv.org adults with DM at Univ of Alabama Birmingham: OR mortality 0.33 (0.13-0.84) 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. Lou et al, Am J Trop Med, adults with diabetes in China, OR for survival: 4.36 (1.22-15.59) 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). 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.

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