Science Matters: Why Study Hydroxychloroquine?

By Susanna Naggie, MD, Vice Dean for Clinical Research at Duke University School of Medicine and Principal Investigator for the HERO-HCQ Trial

From politicians to pre-prints and published observational studies, recent weeks have challenged research on hydroxychloroquine. In this dynamic and confusing landscape, we are sharing our rationale for studying hydroxychloroquine in the HERO-HCQ Trial — a randomized clinical trial of approximately 15,000 healthcare workers. It will test whether hydroxychloroquine can prevent COVID-19 infection in healthcare workers.

Why HERO-HCQ?

In the laboratory, hydroxychloroquine has shown activity against the virus that causes COVID-19. We do not yet know if this activity translates into benefit in humans. It is possible that the benefit of hydroxychloroquine is in preventing or treating early disease. We need information on whether hydroxychloroquine is safe and effective for prevention of COVID-19. Randomized controlled trials are the only way to get the information we need.

Is Hydroxychloroquine Safe?

While the news about hydroxychloroquine fluctuates daily, in the outpatient setting the drug has decades of data behind it from use for autoimmune diseases like rheumatoid arthritis and lupus. There can be serious side effects, mostly with long-term exposure, that we have carefully considered and monitor. The recent reports of hydroxychloroquine have been in the inpatient setting in patients with COVID-19, which is quite different than the population that HERO-HCQ is enrolling. Furthermore, these reports should not eclipse the longstanding outpatient safety record of the drug, with 5 million prescriptions written annually.  The large treatment studies published in this area are observational with significant confounding due to selection bias and the severity of illness in the patients who received hydroxychloroquine.

Does Hydroxychloroquine Cause Abnormal Heart Rhythms?

Abnormal heart rhythms are not common when people use hydroxychloroquine in the outpatient setting. Of the millions of prescriptions written annually for autoimmune conditions, heart problems are not a significant concern. The American College of Rheumatology does not recommend EKG testing prior to starting hydroxychloroquine for outpatients with autoimmune conditions. This is why the HERO-HCQ trial does not require EKG testing or monitoring

Recent studies have found that some inpatients with COVID-19 had heart rhythm disorders while taking hydroxychloroquine, particularly when used with other medications that have the same effect. To ensure safety for participants, the HERO-HCQ trial will not allow healthcare workers at risk of heart rhythm disorders or who are taking medications that can also cause heart arrhythmias to participate.

What can other trials tell us?

There have not yet been reports of hydroxychloroquine used for prevention of COVID-19. All reports to date have been in treating people with existing COVID-19.

There are two trials from the University of Minnesota investigating the safety and efficacy of post-exposure prophylaxis in people with high-risk exposures and early treatment in people with mild COVID-19, which have completed enrollment and will soon report out results via the peer reviewed literature. Based on the public updates, there were no safety issues that led the DSMB to stop either study early. In addition, this group has an ongoing pre-exposure prophylaxis trial in healthcare workers that is ongoing.

The RECOVERY Trial is a very large treatment trial, which has over 10,000 participants randomized to multiple treatment options. Based on concerns raised in the observational studies, the RECOVERY Data Safety and Monitoring Board (DSMB) completed an emergency review of unblinded study data and concluded that the study should continue as planned. More information is publicly available on their website (here and here). 

Is the HERO-HCQ trial safe?

Yes. The FDA and others continuously monitor this trial and others in this space. The overall conclusion from the NIH, FDA, and research community, is that hydroxychloroquine should not be used in routine clinical practice. Instead, it should be tested within well-designed clinical trials with appropriate safety oversight including from DSMBs and the FDA.

The HERO-HCQ protocol excludes any participant at high risk for side effects associated with hydroxychloroquine, including those at high risk for certain heart conditions, severe skin reactions, retinopathy, severe heart disease, or who are taking medications that can interact with hydroxychloroquine. The HERO-HCQ trial has a DSMB that reviews study data regularly to identify safety events and ensure that severe unexpected events are identified and reported to the FDA. In addition, the HERO program and trial leadership are in regular communication with other hydroxychloroquine trial investigators and teams. 

For more information, read this flyer and watch this video. Follow the HERO Research Program on Twitter and Facebook for the latest trial news and updates.