Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up

Abstract

Background: Long Covid is an emerging chronic illness potentially affecting millions, sometimes preventing the ability to work or participate in normal daily activities. COVID-OUT was an investigator-initiated, multi-site, phase 3, randomized, quadruple-blinded placebo-controlled clinical trial (NCT04510194). The design simultaneously assessed three oral medications (metformin, ivermectin, fluvoxamine) using two by three parallel treatment factorial assignment to efficiently share placebo controls and assessed Long Covid outcomes for 10 months to understand whether early outpatient treatment of SARS-CoV-2 with metformin, ivermectin, or fluvoxamine prevents Long Covid.

Methods: This was a decentralized, remotely delivered trial in the US of 1,125 adults age 30 to 85 with overweight or obesity, fewer than 7 days of symptoms, and enrolled within three days of a documented SARS-CoV-2 infection. Immediate release metformin titrated over 6 days to 1,500mg per day 14 days total; ivermectin 430mcg/kg/day for 3 days; fluvoxamine, 50mg on day one then 50mg twice daily through 14 days. Medical-provider diagnosis of Long Covid, reported by participant by day 300 after randomization was a pre-specified secondary outcome; the primary outcome of the trial was severe Covid by day 14.

Result: The median age was 45 years (IQR 37 to 54), 56% female of whom 7% were pregnant. Two percent identified as Native American; 3.7% as Asian; 7.4% as Black/African American; 82.8% as white; and 12.7% as Hispanic/Latino. The median BMI was 29.8 kg/m² (IQR 27 to 34); 51% had a BMI >30kg/m². Overall, 8.4% reported having received a diagnosis of Long Covid from a medical provider: 6.3% in the metformin group and 10.6% in the metformin control; 8.0% in the ivermectin group and 8.1% in the ivermectin control; and 10.1% in the fluvoxamine group and 7.5% in the fluvoxamine control. The Hazard Ratio (HR) for Long Covid in the metformin group versus control was 0.58 (95% CI 0.38 to 0.88); 0.99 (95% CI 0.592 to 1.643) in the ivermectin group; and 1.36 in the fluvoxamine group (95% CI 0.785 to 2.385).

Conclusions: There was a 42% relative decrease in the incidence of Long Covid in the metformin group compared to its blinded control in a secondary outcome of this randomized phase 3 trial.

Figure 1.

Overview of factorial design groups. Participants were randomized to equal allocation to one of the 6 arms above. They were compared to concurrently randomized controls from the groups outlined above. Every participant in the trial received a pill that looked like metformin – either active metformin or exact matching metformin placebo.

Figure 2.. Cumulative incidence of “Long Covid,” post-acute sequelae of SARS-CoV-2 infection (PASC), diagnosed by a medical provider over 10 months after randomization.

Panel A is metformin; Panel B is all 6 arms in the trial; Panel C is ivermectin; Panel D is fluvoxamine. In this factorial design trial, each participant received two types of pills. Every participant received a pill that looked like metformin -- either metformin or an exact-matching metformin placebo. The second pill was active fluvoxamine or ivermectin, or their exact matching placebo.

Figure 3.. Assessment of heterogeneity of Metformin treatment effect for preventing the development of Long Covid compared to blinded control.

In this factorial design trial, each participant received two types of pills. Every participant received a pill that looked like metformin -- either metformin or an exact-matching metformin placebo. The second pill was active fluvoxamine or ivermectin, or exact matching placebo for fluvoxamine or ivermectin. Fluvoxamine enrollment halted on January 7, 2022 by the independent data and safety monitoring board. Overall trial enrollment completed on January 28, 2022 when reaching the target sample size.