COVID OUT clinical trial suggests metformin effective at reducing odds of serious outcomes for COVID-19 patients seeking early treatment
Trial compared effect of ivermectin, fluvoxamine, and metformin in randomized double-blinded placebo- controlled trial
Peer-Reviewed PublicationVIDEO: DR. CAROLYN BRAMANTE FROM THE UNIVERSITY OF MINNESOTA ANSWERS QUESTIONS ABOUT COVID OUT. view more
CREDIT: UNIVERSITY OF MINNESOTA MEDICAL SCHOOL
Published in the New England Journal of Medicine, researchers — led by the University of Minnesota Medical School and School of Public Health — have found that metformin, a commonly prescribed diabetes medication, lowers the odds of emergency department visits, hospitalizations, or death due to COVID-19 by over 40 percent; and over 50 percent if prescribed early in onset of symptoms. The study also found no positive effect from treatment with either ivermectin or low-dose fluvoxamine.
“We are pleased to contribute to the body of knowledge around COVID-19 therapies in general, with treatments that are widely available,” said Carolyn Bramante, MD, principal investigator of the study and an assistant professor of internal medicine and pediatrics at the U of M Medical School. “Our trial suggests that metformin may reduce the likelihood of needing to go to the emergency room or be hospitalized for COVID-19.”
Bramante noted that this was a secondary outcome of the trial; the primary outcome included whether someone had low oxygen on a home oxygen monitor, and none of the medications in the trial prevented the primary outcome.
The COVID-OUT trial was the nation’s first to study whether metformin, a medication for type 2 diabetes; low-dose fluvoxamine, an antidepressant; and ivermectin, an antiparasitic, or their combinations could serve as possible treatments to prevent ER visits or hospitalization, as well as Long-COVID.
The study design was simple — patients were randomly assigned to receive one of the three drugs individually, placebo, or a combination of metformin and fluvoxamine or metformin and ivermectin. Although the study was placebo-controlled with exact-matching placebo pills, Dr. Bramante says 83% of volunteers received medications supported by existing data because of the six-arm design. Each participant received 2 types of pills to keep their treatment assignment masked, for 3 to 14 days of treatment. Each volunteer tracked their symptoms, and after 14 days, they completed a survey.
The 1323 participants in the trial were limited to adults with a body mass index greater than or equal to 25 kg/m2, which qualifies as overweight – for instance, someone who was at least five feet and six inches tall and weighed more than 155 pounds. To qualify for the study, volunteers enrolled within three days after receiving a positive COVID-19 test. It was among the first randomized clinical trials for COVID-19 to include pregnant women.
The study included those who were vaccinated and those who were not. This is the first published trial where the majority of participants were vaccinated.
“Although we know COVID-19 vaccines are highly effective, we know that some new strains of the virus may evade immunity and vaccines may not be available worldwide. So we felt we should study safe, available and inexpensive outpatient treatment options as soon as possible,” said Bramante. “Understanding whether outpatient treatments could ensure more people survive the illness if they contract it and have fewer long-term symptoms is an important piece of the pandemic response.”
The clinical trial launched in January 2021 after U of M Medical School researchers identified, through computer modeling and observational studies, that outpatient metformin use appeared to decrease the likelihood of mortality from, or being hospitalized for COVID-19. Their research, in partnership with UnitedHealth Group, was published in the Journal of Medical Virology and in The Lancet Healthy Longevity. Test-tube studies also found that metformin inhibited the Covid-19 virus in lab settings. These findings, along with additional prospective studies supporting the use of higher-dose fluvoxamine and ivermectin, provided the evidence to include all three medications as well as combination arms.
“Observational studies and in vitro experiments cannot be conclusive but do contribute to bodies of evidence,” said Bramante, who is also an internist and pediatrician with M Health Fairview. “To complete this study, we enrolled volunteers nationwide through six institutions in the U.S., including in Minneapolis.”
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 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 monetary support from the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group.
In addition, this research was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, grants UL1TR002494 and KL2TR002492, and the National Institute of Digestive, Diabetes, and Kidney diseases K23 DK124654. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences.
JOURNAL
New England Journal of Medicine
METHOD OF RESEARCH
Randomized controlled/clinical trial
SUBJECT OF RESEARCH
People
ARTICLE TITLE
Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19
Metformin drastically reduces COVID hospitalization, study shows
Widely available drug reduced emergency room visits, hospitalization, and death by COVID-19 by more than half if started within 4 days of symptoms
Peer-Reviewed PublicationThe widely available diabetes drug metformin reduced serious outcomes by more than half if started within 4 days of COVID symptoms in a large, randomized, double blind controlled trial, the University of Minnesota announced today. The results were published Aug. 18 in the New England Journal of Medicine.
The study was primarily funded by three philanthropic foundations: Parsemus Foundation, Rainwater Charitable Foundation, and Fast Grants.
“This was really intriguing to us early on when we learned that people who take metformin were catching COVID less and being hospitalized less,” said Elaine Lissner, founder and trustee of small California nonprofit Parsemus Foundation, which works on low-cost solutions neglected by the pharmaceutical industry. “But you don’t know whether it’s just coincidence until you start at the beginning, with a rigorous randomized trial.”
“When we learned that researchers at the University of Minnesota were already trying to raise funds to test it, we jumped at the opportunity.”
A little-known past
Metformin, also known as Glucophage, has an added benefit: a little-known past in the 1950s as an anti-viral called “Fluamine.” In more recent research, it also seems to affect mTOR inflammation pathways. Since COVID involves viral inflammation, lead researcher Dr. Carolyn Bramante and team thought the combination of anti-inflammatory plus antiviral action was intriguing enough to put to the test.
The study almost didn’t happen, though. At the time, most government and pharmaceutical funds were going to vaccine research, or the search for profitable new drugs.
“We took a chance and gave what we could, enough to get the first few study sites started and generate preliminary data to strengthen the case for other funders,” said Linda Brent, executive director of the Parsemus Foundation. “But the study never would have made it if it weren’t for the dedicated larger funders who believed in it right away and came on board with critical support.”
Three medications studied
For added rigor, the large University of Minnesota study compared three medications that were considered promising at the time—fluvoxamine, an antidepressant that had shown strong results in previous studies; ivermectin, the object of much interest and passion; and metformin — and provided valuable answers, even about the drugs that were not the clear winner.
“You can argue about details, but in the end, this was kind of ‘three strikes and you’re out’ for ivermectin,” said Lissner. “But ivermectin deserved this kind of careful study, head-to-head with other medications, to finally get solid answers. You have to give everything a fair test.”
“And I think a lot of us were pretty disappointed that the fluvoxamine results were not conclusive. We did learn that the dose the study used, which was a third to half as much as used in previous studies in an attempt to avoid side effects, was not enough to make a significant difference. I don’t think the door is closed on fluvoxamine at higher doses, though.”
“But in the end,” added Lissner, “you have to accept what the science tells you, no matter which you were rooting for. And it’s probably better this way. Metformin is an incredibly common drug, taken by millions of people all over the world. There’s no stigma like with an antidepressant, and it’s a lot easier to take than the other two.”
In 2019, metformin was the fourth-most commonly prescribed medication in the United States, with more than 85 million prescriptions written for over 17 million patients. FDA guidelines indicate that it should not be taken by people with advanced kidney disease, and should be taken with food, or in extended-release formulation, to avoid stomach upset. Side effects are minor and include loose stools. Metformin is also considered safe for use in pregnant women.
The study included 1323 participants most at risk of serious outcomes—adults over 30 and with BMI over 25 kg/m2—to get lifesaving results more quickly. Future studies could include lower-risk participants. However, studies of metformin for other indications, such as the national TAME trial by the American Federation for Aging Research, remain unfunded.
“I think there are lessons for all of us in making sure our global clinical trial systems are more robust and ready to jump in on globally critical studies like this in the future,” emphasized Lissner. “It shouldn’t be little foundations like us funding studies of global importance. In the meantime, I hope all the hard work and late nights pay off, and clinicians around the world take notice: metformin, an exceedingly inexpensive drug they prescribe every day, if given to high-risk people with COVID right away, can reduce serious outcomes by more than half.”
Details about the study results were published online August 18 in the New England Journal of Medicine and can be found in the University of Minnesota’s COVID-OUT study press release.
About the Parsemus Foundation (San Francisco): The Parsemus Foundation works to create meaningful improvements in human and animal health and welfare by advancing innovative and neglected medical research. The foundation’s focus is on supporting proof-of-concept studies and then pursuing press coverage of the results, so that the advances change treatment practice rather than disappearing into the scientific literature. As a small, agile nonprofit organization, the Parsemus Foundation was able to pivot from its regularly funded programs to a new focus on COVID-19 treatment during the pandemic. More information on the Parsemus Foundation and the work presented here can be found at: https://www.parsemus.org/humanhealth/covid-19/
JOURNAL
New England Journal of Medicine
METHOD OF RESEARCH
Randomized controlled/clinical trial
SUBJECT OF RESEARCH
People
ARTICLE TITLE
Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19
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