The trial compared the effect of ivermectin, fluvoxamine and metformin in a randomized double-blind placebo-controlled trial. Scientists have found that metformin, a commonly prescribed diabetes drug, reduces the odds of emergency department visits, hospitalizations or death due to COVID-19 by more than 40 percent. and over 50 percent if prescribed early in symptom onset. The study, published Aug. 18 in the New England Journal of Medicine, also found no positive effect from treatment with either ivermectin or low-dose fluvoxamine. The research was conducted by the University of Minnesota School of Medicine and School of Public Health. “We are pleased to contribute to the body of knowledge about COVID-19 treatments in general, with treatments that are widely available,” said Carolyn Bramante, MD, principal investigator of the study. Bramante is an assistant professor of internal medicine and pediatrics at the U of M School of Medicine. “Our trial shows that metformin can reduce the likelihood that you will need to go to the emergency room or be hospitalized for COVID-19.” Bramante noted that this was a secondary outcome of the trial. The main outcome included whether someone had low oxygen on a home oxygen monitor. None of the drugs in the trial prevented the primary outcome. The COVID-OUT trial was the first in the country to study whether metformin, a type 2 diabetes drug. low-dose fluvoxamine, an antidepressant. and ivermectin, an antiparasitic, or their combinations could serve as potential treatments to prevent emergency department visits or hospitalizations, as well as long-term Covid. Dr. Carolyn Bramante from the University of Minnesota answers questions about COVID OUT. Credit: University of Minnesota Medical School The study design was simple and straightforward. Patients were randomly assigned to receive one of the three drugs alone, placebo, or a combination of metformin and fluvoxamine or metformin and ivermectin. Although the study was placebo-controlled with exact matching of placebo pills, Dr. Bramante says 83% of volunteers received drugs supported by the existing data because of the six-arm design. Each volunteer received 2 types of pills to keep treatment assignment hidden, for 3 to 14 days of treatment. Each participant tracked their symptoms and after 14 days, completed a survey. The 1,323 trial participants were limited to adults with a body mass index (BMI) greater than or equal to 25 kg/m2, which is classified as overweight – for example, someone who was at least five feet six inches tall and weighed more than 155 pounds. To be eligible for the study, participants voluntarily enrolled within three days of receiving a positive COVID-19 test. It was among the first randomized clinical trials for COVID-19 to include pregnant women. The study included both those who were vaccinated against COVID-19 and those who were not. This is the first published trial where the majority of participants were vaccinated. The clinical trial began in January 2021 after scientists at the U of M School of Medicine found, through computer modeling and observational studies, that outpatient metformin use appeared to reduce the likelihood of death from or hospitalization for COVID-19. Their research, in collaboration with UnitedHealth Group, was published in the Journal of Medical Virology and The Lancet Healthy Longevity. Test-tube studies also found that metformin inhibited the Covid-19 virus in laboratory settings. These findings, along with additional prospective studies supporting the use of higher-dose fluvoxamine and ivermectin, provided the evidence to include all three drugs as well as combination arms. “Observational studies and in vitro experiments can’t be conclusive, but they add to the evidence,” said Bramante, who is also an internist and pediatrician at M Health Fairview. “To complete this study, we enrolled volunteers nationwide through six institutions in the US, including Minneapolis.” Reference: “Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19” by Carolyn T. Bramante, MD, MPH, Jared D. Huling, Ph.D., Christopher J. Tignanelli, MD, John B. Buse, MD , Ph.D., David M. Liebovitz, MD, Jacinda M. Nicklas, MD, MPH, Kenneth Cohen, MD, Michael A. Puskarich, MD, Hrishikesh K. Belani, MD, MPH, Jennifer L. Proper, BS, Lianne K. Siegel, Ph.D., Nichole R. Klatt, Ph.D., David J. Odde, Ph.D., Darlette G. Luke, Pharm.D., Blake Anderson, MD, Amy B. Karger, MD, Ph.D., Nicholas E. Ingraham, MD, Katrina M. Hartman, BA, Via Rao, MS, Aubrey A. Hagen, BA, Barkha Patel, MS, Sarah L. Fenno, MPH, Nandini Avula, BS, Neha V. Reddy, BS, Spencer M. Erickson, BA, Sarah Lindberg, MPH, Regina Fricton, BA, Samuel Lee, BS, Adnin Zaman, MD, Hanna G. Saveraid, Walker J. Tordsen, BA, Matthew F. Pullen , MD, Michelle Biros, MD, Nancy E. Sherwood, Ph.D., Jennifer L. Thompson, MD, David R. Boulware, MD, MPH, and Thomas A. Murray, Ph.D. for the COVID-OUT trial arm, August 18, 2022, New England Journal of Medicine.DOI: 10.1056/NEJMoa2201662 Participating clinical trial sites included M Health Fairview and Hennepin Healthcare in Minneapolis, Northwestern University in Chicago, Olive View – UCLA Education & Research Institute in Los Angeles, Optum in Colorado and Indiana, and the University of Colorado Denver . Co-investigators on the study include Jared Huling, PhD. Thomas Murray, PhD; Hrishikesh Belani, MD; Michelle Biros, MD; David Boulware, MD; David Leibovitz, MD; Jacinda Nicklas, MD; David Odde, PhD; Matt Pullen, MD; Mike Puskarich, MD; John Buse, MD, PhD; Jennifer Thompson, MD; and Christopher Tignanelli, MD. The trial received financial support from the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants and UnitedHealth Group. In addition, this research was supported by National Institutes of Health National Center for Advancing Translational Sciences grants UL1TR002494 and KL2TR002492 and National Digestive, Diabetes, and Kidney Diseases Institute K23 DK124654. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences of the National Institutes of Health.
