One of the hottest debates in the coronavirus pandemic is whether the malaria drugs promoted as possible treatments by President Donald Trump really work. But Americans don’t seem overly eager to help answer the question.

Enrollment in several clinical trials of chloroquine and hydroxychloroquine — including two by the University of Washington — has been anemic so far. Fewer than 260 volunteers, out of a target of 2,000, have signed up for a $9.5 million UW study being conducted in Seattle and six other sites across the country. Another multi-site project coordinated by the UW has only about 30 patients enrolled.

Researchers say enrollment in the trials plummeted after preliminary reports of possible heart arrhythmias associated with the drugs, followed by a U.S. Food and Drug Administration warning that they should be administered only in hospitals or clinical trials.

“Once that news came out, our enrollment fell almost down to zero,” said UW epidemiologist Dr. Ruanne Barnabas, who’s leading a study to find out if hydroxychloroquine can prevent infection in people like health-care workers who have been exposed to the virus.

Barnabas and other researchers say the potential risks of the drugs have been exaggerated in the heated political controversy ignited when Trump first began promoting them. Critics of the president blasted him for touting unproven medications, while his supporters have accused scientists of cover-ups and conspiracies.

Some people poisoned themselves by taking high doses of the drugs or related chemicals, thinking they would provide protection from the novel coronavirus.

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Now, the randomized, controlled trials necessary to settle the debate are threatened.

“We need an adequate number of people to enroll to know what the effectiveness is with confidence,” Barnabas said.

A group of researchers at Columbia University say they are pulling the plug on a similar clinical trial, partly as a result of flagging enrollment.

“The problem with all the exposure that hydroxychloroquine has received is that at first, everybody wanted to take it… and now nobody wants to take it,” said Dr. Jon Giles, leader of the Columbia project. “It’s gone from one extreme that’s bad for science to another extreme, which is also not good for science.”

The FDA warning in late April came after reports of potentially dangerous disruptions in heart rhythms in hospitalized patients in Brazil receiving high doses of hydroxychloroquine. Another analysis of patients at U.S. Veterans Affairs hospitals suggested death rates were higher among patients treated with the drug, but there was no control group or adjustment for severity of illness.

For people with no underlying heart or kidney problems, there is no evidence the drug — at the doses used in the clinical trials — poses serious risks of cardiac problems, said Dr. William O’Neill, who is overseeing a trial at the Henry Ford Health System in Detroit.

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“We have decades of experience with this drug,” he said. “It’s one of the few drugs approved for use during pregnancy and for lactating women.”

Enrollment has also slowed in O’Neill’s study, which is focused on testing hydroxychloroquine’s ability to protect people who work in high-risk settings, like hospitals, nursing homes and prisons, from infection. The project was funded by the Bill & Melinda Gates Foundation, which is interested in inexpensive drugs that might be used to fight COVID-19, the disease caused by the novel coronavirus, in developing countries.

O’Neill’s team has given hydroxychloroquine to about 1,700 people so far, with no serious side effects, he said.

Potential study volunteers may also have been discouraged by preliminary reports of little apparent benefit in some situations. An observational study of 1,400 hospitalized patients published in the New England Journal of Medicine this week found that those who got the drug were no less likely to need a breathing tube or die than those who did not. The study was not a randomized controlled trial.

Most of the evidence for the drugs’ effectiveness come from laboratory studies showing inhibition of the virus.  In a small, randomized trial in China, patients who got hydroxychloroquine recovered more quickly.

“Hydroxychloroquine is still completely viable mechanistically as something that might work, and it’s a lot cheaper than Remdesivir,” an antiviral medication recently approved for treating COVID-19, said Giles.

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But with the initial wave of the epidemic beginning to subside in many places, some studies may have missed the opportunity to enroll enough patients, he added.

Part of the problem is the chaotic nature of the research response, with multiple studies being launched and little coordination, said Alex John London, director of the Center for Ethics and Policy at Carnegie Mellon University. ClinicalTrials.gov currently lists nearly 50 hydroxychloroquine trials in the U.S. alone, and more than 170 worldwide.

The “circus atmosphere” around the drug has made it much harder to communicate nuances about possible risks and benefits, which is vital for all clinical trials, he added.

“It’s frustrating and sad and dangerous to see scientific questions about the risk and benefit and efficacy of medications be turned into a partisan question,” London said. “Because these drugs are going to work — or not work — on Republicans and Democrats alike.”

Dr. Christine Johnston, an infectious disease specialist at the UW, said she and her team have found many prospective volunteers are interested and want to help, but are confused and wary about the drugs and their possible side effects.

Johnston’s trial is aimed at finding out if chloroquine, hydroxychloroquine and the antibiotic azithromycin, singly or in combination, can prevent pneumonia and other serious complications in people who have the virus, but aren’t sick enough to be hospitalized. People with conditions that might make them vulnerable to cardiac problems are excluded, and all participants are monitored regularly for any health issues.

“I think people are getting a lot of misinformation,” Johnston said. “They’ve either heard that it’s a great drug that’s going to cure everything, or that it’s a bad drug and it’s not safe, when neither of those things is likely to be true. But we need to do the study to be able to answer those questions.”

More information on the two UW trials is available at www.covid19treatmentstudy.org and www.covid19pepstudy.org.

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