Patients treated by physicians who are faculty members at the University of Colorado School of Medicine were part of a multi-site clinical trial that may result in better prevention of severe forms of COVID-19.
The CU School of Medicine was one of five sites for a recent randomized trial of three medications — metformin, ivermectin, and fluvoxamine — for nonhospitalized adults with COVID-19. The study, which launched in January 2021, included those who were vaccinated and those who were not. Unlike many other clinical trials for COVID-19, it also included people who were pregnant. It was published August 18 in the New England Journal of Medicine.
At CU, the trial was overseen by Jacinda Nicklas, MD, MPH/MSPH, associate professor of internal medicine. Endocrine fellow Adnin Zaman and medical students Nikita Deng and Riannon Atwater also helped with the research.
From one to three drugs
The trial began with just metformin — a generic drug used to treat diabetes — after physicians noticed that patients who were taking metformin seemed to fare better when they were diagnosed and even hospitalized with COVID-19. Ivermectin and fluvoxamine were added later when the researchers realized they were being touted as effective treatments for COVID-19.
“These are all generic, inexpensive drugs, so that was partly why we wanted to study them,” Nicklas says. “Around the world, not everyone can afford the more expensive drugs that we're using in the U.S.”
The researchers enrolled patients who were classified as overweight and obese and thus more likely to be hospitalized for COVID-19. Patients were enrolled within three days after a confirmed diagnosis of infection and less than seven days after the onset of symptoms. The study looked to see if any of the medications prevented low oxygen saturation (below 93%), emergency department visits, hospitalization, or death.
Ivermectin and fluvoxamine had no effect on any of the conditions, but metformin, while it did not seem to affect oxygen saturation levels, did have a protective effect when it came to ED visits, hospitalizations, and death. In the study, the medication lowered the odds of emergency department visits, hospitalizations, or death due to COVID-19 by over 40%; over 50% if prescribed early in onset of symptoms.
“Metformin was the only one of the three drugs that lowered the odds of that composite outcome when we took out the pulse oximetry,” Nicklas says. “In the paper, the focus is showing which treatments are ineffective, like ivermectin, which many studies now have shown is not effective for COVID. But I think it leaves open the door for metformin. Certainly, it's not definitive and needs to be studied it further, but the data are suggestive that there may be something there.”
The researchers’ next steps are to look further at metformin — which has previously been shown to have antiviral properties and has shown some in vitro activity against SARS and other RNA viruses — as a potential treatment to prevent severe COVID-19.
Looking into long COVID
Study participants continue to report on their symptoms and outcomes to inform the researchers as they continue to look at metformin or any of the other medications that may have an impact on “long COVID,” symptoms such as fatigue, fever, and shortness of breath that linger beyond an initial COVID-19 infection.
“We don't have the results yet, but we are looking to see if any of these medications actually changes the trajectory of long COVID or the incidence of long COVID,” Nicklas says. “All the patients are still answering surveys every month about their ongoing symptoms.”
Patients step up for a remote trial
For Nicklas, one of the most interesting aspects of the research study was that it was conducted completely remotely — a first for her in her career.
“As you might imagine, we didn't want to have contact with people who had active COVID disease, particularly early in the pandemic,” Nicklas says. “So we conducted the entire study remotely, including sending a box to their house with everything they needed for data collection. They had surveys to keep track of their symptoms, and we had them do viral swabs that we would have FedEx pick up. It was great to see we can actually do a study that way.”
Nicklas says she also was inspired by the patients who stepped up to be part of the trial early in the pandemic, looking to contribute to research that could help others.
“That's one of the great benefits of being a patient where your physicians are also conducting research,” she says. “I'm one of the primary care physicians at the internal medicine clinic, and I was able to recommend this trial to patients who were qualified. Many of them did it just to help figure out how to help people who had COVID.”