Safety concerns hamper study of hydroxychloroquine to prevent COVID-19 in front-line health workers

As a national study ramps up at University of Florida Health and other sites around the country to test whether hydroxychloroquine, or HCQ, can protect healthy front-line essential workers from contracting COVID-19, safety concerns about the antimalarial drug have become one of the biggest barriers to recruiting study volunteers.

The Healthcare Worker Exposure and Outcomes, or HERO, initiative’s HERO-HCQ trial is one of more than 30 controlled clinical trials now underway nationwide to evaluate the use of HCQ to prevent or treat COVID-19.

Laboratory studies have shown that HCQ has antiviral activity against the SARS-CoV-2 coronavirus, the virus that causes COVID-19. The HERO-HCQ trial is investigating the drug’s ability to prevent infection among essential workers in health care settings who are at higher than average risk of exposure to the coronavirus.

“We need to know whether hydroxychloroquine is safe and effective for the prevention of COVID-19,” said Susanna Naggie, M.D., principal investigator for the multisite HERO-HCQ Trial and vice dean for clinical research at the Duke University School of Medicine in Durham, North Carolina. “Randomized controlled trials are the only way to get this information.”

But researchers at UF say recruiting is slow, and they worry that increased media coverage of several high-profile studies on hydroxychloroquine recently may be taking a toll.

“There’s a lot of confusion about HCQ right now, which is understandable,” said Elizabeth A. Shenkman, Ph.D., a professor and chair of the UF College of Medicine’s department of health outcomes and biomedical informatics. She is also the principal investigator for the OneFlorida Clinical Research Consortium, which includes the HERO sites in Florida.

Shenkman said she has every confidence in the safety of the drug for the people enrolling in the HERO-HCQ study, in the safety protocols of the study, and in the need for randomized controlled trials like this one.

“In the midst of a global health pandemic, when we have no vaccines or approved therapies available to protect us, it’s never been more important to look to science for answers,’’ she said.

Shenkman and others involved in the HERO-HCQ study pointed out that the project is examining prevention, not treatment, and focusing on a different group of people than those in the recent studies reported in the media.

“Those studies were looking at HCQ as a treatment for COVID-19, and most of them involved treating the sickest patients hospitalized with COVID-19,” Naggie said. “That population is quite different than the population of well front-line workers that HERO-HCQ is enrolling.”

Several of the published studies found that the malaria drug chloroquine or its derivative, hydroxychloroquine, did not benefit hospitalized patients with COVID-19. The largest of these studies involved an analysis of patient data from 621 hospitals worldwide, published on May 22 in the Lancet. That study concluded that the drugs, when used alone or together with other medications for the treatment of COVID-19 in 14,888 hospitalized patients, was associated with an increased risk of abnormal heart rhythms and decreased survival, compared with 81,444 hospitalized COVID-19 patients who did not receive these drugs.

Soon after it was published, however, a group of more than 140 research scientists and physicians challenged the validity of the results in an open letter to the study authors. The group pointed out that the study’s authors didn’t take into account several factors that could have influenced the results, such as the severity of illness in the patients who received HCQ. They also questioned the quality of the data from patient records used to conduct the study.

Naggie pointed out that while these large treatment studies suggest that chloroquine and HCQ may not be appropriate for treating hospitalized patients with COVID-19, “it’s possible that the benefit of HCQ is in preventing or treating early disease.”

She added that the recent studies on hospitalized patients with COVID-19 “should not eclipse the longstanding outpatient safety record of the drug.

“HCQ is one the most widely used drugs, with a safety record dating back more than 50 years. Millions of prescriptions are written every year for the treatment of malaria, lupus and rheumatoid arthritis,” she said.

Early reports from a similar study at the University of Minnesota looking at whether HCQ can prevent coronavirus infection in healthy front-line workers have been encouraging regarding safety. Based on the public updates, there were no safety issues that led the researchers to stop the study early, Naggie said. Study participants received either the standard dose of HCQ used to treat malaria or a vitamin placebo.

The most common problems with HCQ in the standard dosages prescribed for people being treated for malaria, lupus and rheumatoid arthritis are upset stomach, skin rash and damage to the retina of the eye among long-term users.

“We feel quite confident about the safety profile of this drug in a well health care worker population who have no contraindications to hydroxychloroquine,” said Naggie.

To ensure the safety of participants in the HERO-HCQ study, the trial is being conducted with oversight by the U.S. Food and Drug Administration, Naggie said. The study also has a Data Safety and Monitoring Board that reviews study data regularly. Throughout the study, a physician-led research team oversees and monitors participants at each of the study sites.

Before enrolling in the study, all potential participants will be screened for a history of health problems that could increase their risk of experiencing side effects, including certain heart conditions or severe heart disease, skin sensitivity, retinopathy, or the use of other medications that may interact with HCQ. They’ll also sign an informed consent.

The American College of Rheumatology does not recommend that outpatients with autoimmune disease undergo EKG screening before using the drug and the HERO-HCQ trial does not require EKG testing for study participants. However, essential workers at UF Health who enroll in the study may request a baseline EKG as part of the screening process.

To participate in the HERO-HCQ study, health care workers must first enroll in the national HERO Registry. The registry, organized and operated by Duke University, hopes to enroll hundreds of thousands of health care workers nationwide, with the goal of better understanding and addressing the issues they face on the front lines of the pandemic. Anyone 18 years of age or older who works in a health care setting, including nurses, respiratory therapists, physicians, emergency responders, food service workers, environmental service workers, interpreters and transporters, may join the registry.

Members of the registry will be asked to complete surveys and invited to share their experiences. They will also have the option of participating in clinical trials like HERO-HCQ. Visit the HERO research website to learn more about the study or to join the registry.