ABSTRACT
Background: Metformin has in vitro activity against SARS-CoV-2. In a published phase 3, quadruple-blinded, placebo-controlled randomized trial of outpatient COVID-19 therapy, metformin resulted in a 42% reduction in ER visits/hospitalizations/deaths by day 14, 58% reduction in hospitalizations/ death by day 28, and 42% reduction in Long Covid through 10 months. This analysis presents the results of viral load sampling performed during that clinical trial. Method(s): Covid-Out trial (NCT04510194) enrolled adults aged 30 to 85 within 3 days of a documented SARS-CoV-2 infection and < 7 days after symptom onset. The trial randomized 1323 participants to metformin (1000mg/day days 2-5;1500mg/day days 6 to 14), ivermectin, fluvoxamine, and/or exact-matching placebo in a 2x3 factorial trial design. Nasal swabs for viral load were an optional component, self-collected from the anterior nares on day 1, 5, and 10. Viral loads were measured via RT-qPCR using N1 and N2 targets in the SARSCoV- 2 nucleocapsid protein, with relative Ct values converted to absolute copy number via calibration to droplet digital PCR. A linear Tobit regression model was used to assess change over time while accounting for left censoring due to the viral load limit of detection. Results were adjusted for other treatment allocations within the factorial design, vaccination status, and baseline viral load. Repeated measures were accounted for using clustered standard errors within participants. Result(s): Samples were available from n = 945, 871, and 775 participants on days 1, 5, and 10, respectively. The mean change from baseline to followup was -0.64 log10 copies/mL (95%CI, -1.16 to -0.13) for metformin versus placebo, which equates to a 4.4-fold greater decrease. The mean change in SARS-CoV-2 from baseline to day 5 was -0.48 log10 copies/mL, and was -0.81 log10 copies/mL from baseline to day 10. The anti-viral effect increased with increased metformin dosing days 6-14. The antiviral effect was larger in those unvaccinated (mean -0.95 log copies/mL) than vaccinated (mean -0.39 log copies/mL). There was no change in viral load vs. placebo for ivermectin or fluvoxamine. Conclusion(s): Metformin lowered SARS-CoV-2 viral load in this quadrupleblinded, randomized clinical trial. The temporal relationship to dose titration suggests a dose-dependent effect. The magnitude of antiviral effect was similar to nirmatrelvir at day 5, greater than nirmatrelvir at day 10. Metformin is safe, widely available, and has few contraindications.
ABSTRACT
BACKGROUND: Traditionally, randomized clinical trials have relied on physical research centers to support subject recruitment and participation. The COVID-19 pandemic has highlighted the need to interact with subjects who are unable to physically visit research centers. By leveraging remote technology, such clinical trials may reach subjects in isolation and broaden geographical reach. We describe a fully remote, multisite randomized controlled clinical trial of outpatient COVID-19 treatments using a technologyenabled, decentralized approach. METHODS: We conducted a remote double-blind, randomized placebocontrolled trial (COVID-OUT). We identified subjects through medical records, patient advocacy groups, testing facilities, and multiformat advertising. They were recruited via brochure, electronic message, telephone outreach, and self-referral. Research staff across sites used the Research Electronic Data Capture (REDCap) system to manage local and central enrollment and were reallocated dynamically based on trial needs. Subjects were screened by phone, consented and randomized electronically and delivered study medication by courier or same-day mail. They were followed via their preferred communication method (phone, video, text, or email) to determine the study endpoints. RESULTS: 1195 non-hospitalized adults aged 30-85 years with laboratory confirmed infection with SARS-CoV-2 were enrolled into the COVID-OUT trial through January 6, 2022 over a span of 7 months. Initially starting as a 2- arm trial with 7 sites, the study expanded to a 6-arm trial with recruitment at 8 sites. To date, 9600 subjects have been screened with an enrollment rate of 12% from 822 zip codes. 25 research coordinators are involved across 8 sites, and the rate of study completion is 90%. CONCLUSIONS: Decentralized remote studies offer an efficient, low-touch way of performing research in the COVID-19 era. Our decentralized study design enables research with infectious, isolated subjects in widespread geographies, while maintaining safety of subjects, the research team, and public atlarge. Coordination across sites via RED Cap enabled programmatic efficiencies, including the ability to redistribute staffing support across enrollment sites for study drug distribution, follow-up calls, recruitment, and event reporting. We decreased overall costs by less need for physical research space. The decentralized infrastructure enabled nimble adaptations of the protocol, including increasing follow-up periods to assess long-COVID symptoms and adding study arms for additional outpatient treatments. Given the widespread availability of mobile phones and remote communication, decentralized trials show promise for improving reach and efficiency in both pandemic and nonpandemic times.