1. Metformin, ivermectin, and fluvoxamine do not prevent hypoxemia, emergency department visits, hospitalization, or death in coronavirus disease 2019 (COVID-19) patients.

2. Patients in the treatment groups did not experience a significant reduction in overall symptoms or COVID-19-related symptoms compared to placebo.

Evidence Rating Level: 1 (Excellent)

Study Rundown: The COVID-19 pandemic has resulted in significant morbidity and mortality globally since it began in 2019. Yet, there are currently very limited options for COVID-19 outpatient treatments. Based on their biophysical profiles, it has been hypothesized that metformin, ivermectin, and fluvoxamine could be deleterious to different elements of viral replication and inflammatory responses which contribute to COVID-19 severity. In the present trial, these therapeutic agents were compared to a placebo control in COVID-19 patients. Overall, there was no significant effect on hypoxemia, emergency department visits, hospitalization, or death by any of the three trial medications. This lack of effect was consistently observed in all subgroup analyses, as well. On self-reported symptom scales, none of the trial drugs reduced symptoms faster than the placebo control. A pertinent study limitation is the narrow study population, which was limited to those between 30 and 85 years old as well as those who were obese or overweight. The strength of this study was that it examined both subjective and objective measures of disease severity and impact.

Click to read the study in NEJM

Relevant Reading: Resurgence of SARS-CoV-2 infection in a highly vaccinated health system workforce

In-Depth [randomized control trial]: The present phase three, double-blinded, randomized controlled trial examined the effectiveness of three therapeutic agents (metformin, ivermectin, and fluvoxamine) in preventing serious or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Eligibility criteria included individuals aged 30 to 85 years, a body-mass index in the overweight or obese category, confirmed SARS-CoV-2 infection within the past three days, and symptoms within seven days of study randomization. Outcomes included hypoxemia, emergency department visits, hospitalization, or death. Additionally, self-reported generalized symptom and COVID-19-specific symptom scales were administered. Individuals were randomized into one of six groups, which were combinations of two of the trial drugs as well as a placebo control. A total of 1,323 patients were enrolled in the study and subsequently included in the primary analysis. The adjusted odds ratio for a primary event was 0.84 (95% Confidence Interval [CI], 0.66 to 1.09; p=0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; p=0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; p=0.75). Hospitalization or death occurred in eight of 596 patients (1.3%) in the metformin group and 19 of 601 patients (3.2%) in the control group. None of the trial medications had an effect on self-reported symptoms related to COVID-19 or otherwise. No medication-related serious adverse events occurred during the study. In summary, the present study suggests that metformin, ivermectin, and fluvoxamine are not effective therapeutic agents for treating COVID-19.

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