The University of Minnesota is conducting the nation's first randomized trial of a controversial anti-parasite drug that has a fervent U.S. following and is being used on the black market against COVID-19 across the globe.

Ivermectin is being added to an ongoing trial in which U researchers hope to find a rare outpatient therapy that can prevent infection with the coronavirus that causes COVID-19 from resulting in hospitalization, long-term complications or death.

The research comes amid declining pandemic activity in Minnesota, where vaccinations have helped to cut the daily number of infections by half over the past two weeks and dropped the number of COVID-19 hospitalizations below 400 for the first time since late March. However, U researchers said treatments are needed in parts of the world where vaccine access is lacking and in pockets of the U.S. and Minnesota where refusal to get shots could result in localized outbreaks.

"Not everybody has access to the vaccine, whereas these medications are existing generics, already FDA-approved, that are available in most pharmacies around the world," said Dr. Carolyn Bramante, a U internal medicine specialist leading the national trial. "If we find evidence of benefit, [the drugs] could be used immediately anywhere."

U research already has shown possible benefits of metformin, usually used to manage diabetes, in reducing COVID-19 illness and death in women. But now researchers will compare its effectiveness against ivermectin as well as fluvoxamine, an antidepressant. The U started recruiting up to 1,100 patients 30 or older last week to receive one of the drugs, alone or in combination with metformin, or a non-medicating placebo for comparison.

Effectiveness will primarily be measured by whether patients suffer hypoxia — severe oxygen deficiency.

Proven medications against COVID-19 have been lacking, especially those that could be used on an outpatient basis to prevent severe illness. The U was among the first to test hydroxychloroquine — an antiviral championed last year by former President Donald Trump and his supporters — only to conclude that it didn't substantially prevent infection or symptom onset.

Ivermectin has been advocated by a handful of U.S. medical groups and believers, and by some in India, South Africa and other countries in the absence of vaccine. No large clinical trials have proved effectiveness, though, and manufacturer Merck issued a statement in February discouraging its clinical use against COVID-19. The FDA also discourages use of the drug outside of a study.

Bramante said ivermectin has anti-inflammatory benefits that need closer study to see if it inhibits the overreaction to infection by the immune system that can cause severe COVID-19 symptoms.

The Rainwater Charitable Foundation that provided $1 million for the U trial had interest in studying ivermectin and sponsored a similar trial in Brazil.

"Serious physicians who help care for people with COVID-19 around the world need high-quality data to make decisions," said Dr. David Boulware, a U infectious disease expert who is advising the trial and led the hydroxychloroquine studies. He added that he would be "ecstatic" if ivermectin works, but that the results one way or another will be meaningful.

Minnesota's 396 COVID-19 hospitalizations on Thursday represented a substantial drop from 699 on April 14 — but the total remains well above the low mark this year of 210 on March 6. The seven-day average of daily infections dropped from 1,409 on May 7 to 679 on Friday.

Mayo Clinic modeling suggests the latest COVID-19 wave would have been far worse if not for the state's vaccination efforts. Minnesota reported on Friday that more than 2.8 million people have received at least a first dose and more than 2.4 million have completed the one- or two-dose series.

The vaccine progress means that 62.7% of Minnesotans 16 and older have received shots, bringing the state closer to its 70% goal by July 1. The state's data for the first time Friday included shots that Minnesotans received in Iowa. Minnesota already has reported shots administered in Wisconsin and North Dakota, but not in other states unless recipients reported them to local providers or the state's immunization tracking system.

Vaccination coverage remains spotty, though, raising the potential for localized outbreaks that will benefit from better treatments. The first-dose vaccination rate varies from 72% in Hennepin County to 37% in Benton County.

Metformin and fluvoxamine were identified by U modeling that started last spring by assuming that this coronavirus would behave like the one that caused the 2003 SARS pandemic. The model appears "seven for seven" in predicting drugs such as remdesivir that work, or drugs such as hydroxychloroquine that don't work, said David Odde, a U biomedical engineer who led the modeling.

The modeling made no recommendation on ivermectin, because it was focused on specific moments in the life cycle of the virus that are affected by other drugs, Odde said.

The U trial is challenging, because clinicians suspect that the drugs work best when provided as early as possible. Recruits must have had positive test results within three days, and the goal is to ship overnight study medications to them so they will start taking them within seven days.

Promoters of ivermectin seized on social media posts about perceived weaknesses in the trial, with some fearing that it wouldn't provide medications quickly enough to prove the actual effectiveness of the drug. Others said they wouldn't enroll given only a 1 in 3 chance of receiving ivermectin — and a 17% chance of receiving a placebo.

Bramante said supporters of ivermectin should want to participate if they suffer infections, because it is the only U.S. randomized clinical trial seeking to prove that it works.

"Even if they don't get it," she said, "they're really contributing to the science around ivermectin."

Jeremy Olson • 612-673-7744