An anti-malaria drug that doctors hoped would work against COVID-19, and that President Donald Trump championed and said he took himself, has failed to show substantial benefit in a second University of Minnesota trial.

U researchers compared 491 people with early symptoms of COVID-19 — with one group taking hydroxychloroquine for five days and the other taking a non-medicating placebo — and found no measurable differences in their outcomes.

Death rates of 0.4% were identical in the groups. Hospitalizations and persistent symptoms over 14 days were slightly more common in the placebo group, but not by a significant margin. Mostly mild side effects such as nausea were reported by 43% of patients taking the drug vs. 22% taking placebos.

The results were hardly what U researchers hoped for in March when they launched one of the world’s first clinical trials of any drug for COVID-19, an infectious disease caused by a novel coronavirus.

“This is definitely not what we thought was going to happen,” said Dr. David Boulware, a leader of the trial and a U infectious disease physician.

No known treatments for COVID-19 existed at the time — and few have been proven even now — but Boulware and colleagues were optimistic because hydroxychloroquine was cheap and widely available and affected the very same ACE-2 receptors that the virus attacks on cells.

The study adds to a volume of evidence that discourages the use of hydroxychloroquine to treat COVID-19 — including the first trial result that the U published in the New England Journal of Medicine last month that showed that the drug offered no protection for people who likely had been exposed to the virus and were at risk for infection.

The results leave the world thin on proven treatments for COVID-19, which to date has been confirmed in Minnesota in 44,347 cases and 1,526 deaths. That includes 611 cases and eight deaths reported Thursday by the Health Department.

A large U.S. trial showed that an antiviral, remdesivir, offered some benefits for hospitalized patients with severe symptoms. The large British RECOVERY trial also showed a reduction in deaths for patients who took the steroid dexamethasone — which HCMC in Minneapolis had already been using aggressively in off-label treatment of hospitalized COVID-19 patients.

Aside from drug therapies, Minnesota doctors said they have improved survival rates for severe COVID-19 cases through better respiratory support and judgments about when and how to use ventilators to help patients breathe.

Minnesota hospital outcomes data showed death rates above 40% in April and May for patients needing placement on ventilators or heart-lung bypass machines. That rate dropped to 31% in June.

‘Just didn’t work’

Hospitalizations for COVID-19 reached their lowest numbers in Minnesota since mid-April — with 249 patients hospitalized on Thursday and 103 receiving intensive care.

But state health officials are concerned that an uptick in cases among young adults could soon spread the virus to older and more vulnerable adults, which could in turn lead to more hospitalizations and deaths. Cases among people 29 and younger have more than doubled in Minnesota since June 1, outpacing overall case growth.

The second U trial suggests that hydroxychloroquine won’t be part of the solution, but whether it will be phased out entirely from COVID-19 treatment is unclear. One wild card is whether Trump continues to use his influential Twitter feed to promote the drug despite the study results.

Boulware said political divisions over the unproven benefits of the drug made his team’s research harder — because Trump’s advocacy was being countered by some doctors warning that hydroxychloroquine might present risks.

Both perspectives slowed national online recruiting for the U clinical trial — because opponents believed it was too risky to take the drug while supporters believed it was so effective that they didn’t want to risk ending up in the placebo arm of the study.

“It turns out that neither perspective is true,” Boulware said. “It is a safe medicine, but it just didn’t work.”

The U has yet to publish results from a third trial in which hydroxychloroquine was used to prevent COVID-19 in people who had yet to be exposed to the virus or show any symptoms of infection.

Boulware said there was hope that zinc would boost the effectiveness of the drug, but neither of the U’s first two studies showed any improved benefit for patients who took that supplement.

A sad end?

The latest U trial showed a slight benefit among people with early COVID-19 symptoms who were older, but too few people were in the study in this age group to be statistically significant, Boulware said. The online method of recruiting volunteers from 40 states and three Canadian provinces produced a younger study group.

Roughly 60% of the study group was health care workers. A lack of COVID-19 diagnostic testing at the time meant some enrolled patients were presumed to have the infectious disease based on their symptoms and exposure to known cases.

The National Institutes of Health canceled two hydroxychloroquine studies in May — one because the drug wasn’t showing any benefit and the other because of a lack of enrollment. And the U.S. Food and Drug Administration last month revoked an emergency use authorization supporting the use of hydroxychloroquine to treat COVID-19.

The British RECOVERY group issued an early version of study results on Wednesday, showing no difference in deaths among hospitalized COVID-19 patients who received hydroxychloroquine vs. standard care. Length of hospitalizations and the use of ventilators increased in the group taking the medication.

On the other hand, an observational study of 2,500 hospitalized patients at the Henry Ford Health System in Detroit found a 50% lower death risk in those who took hydroxychloroquine. Trump’s last tweet about the drug on July 7 lauded this study.

The U trials were unique and among the world’s first for a COVID-19 drug to be blinded and placebo-controlled — meaning that patients didn’t know whether or not they were taking the medication.

The latest U trial results in the Annals of Internal Medicine were accompanied by an editorial, which stated that the debate on hydroxychloroquine should be over after the British results are finalized.

“If the peer-reviewed findings confirm the preliminary reports of no benefit in sicker patients in the National Institutes of Health and RECOVERY trials, the saga of hydroxychloroquine and COVID-19 will likely reach its sad end,” wrote Dr. Neil Schluger of New York Medical College.