The National Institutes of Health (NIH) has launched a much-anticipated Phase IIb clinical trial to evaluate whether the malaria drug hydroxychloroquine in combination with the antibiotic azithromycin can prevent hospitalization and death from COVID-19, the disease caused by the novel coronavirus 2019 or SARS-CoV-2.
Anecdotal reports out of China and subsequent small studies elsewhere suggest hydroxychloroquine alone or in combination with azithromycin may help reduce COVID-19 respiratory infections, lessening the disease’s severity. But other studies have found no improvement and, in fact, report that patients receiving both drugs together were more likely to experience cardiac arrest than those who received one or neither of the therapies.
As a result, the FDA cautions that hydroxychloroquine for COVID-19 be limited to clinical trials or for treating certain hospitalized patients under emergency use authorization so clinicians can closely monitor patients for adverse effects.
There are numerous clinical trials planned or underway to assess hydroxychloroquine as a safe, effective treatment of adults hospitalized with COVID-19. The new NIH trial is the largest and highest profile to date: a randomized, double-blind interventional trial that will recruit 2,000 participants at 30 sites across the United States.
Heading the study is Davey Smith, MD, a translational research virologist, head of Infectious Diseases and Global Public Health at University of California San Diego School of Medicine and co-director of the San Diego Center for AIDS Research.
Question: This particular approach to treating COVID-19 using hydroxychloroquine in combination with azithromycin has garnered significant interest and attention, though empirical evidence supporting its effectiveness is scant. What makes this approach so appealing and this trial so important?
Smith: There is some pre-clinical and clinical data showing that this regimen works, but it has not been tested in a rigorous way. When I say in a rigorous way, I mean a randomized, double blinded, placebo-controlled trial, the gold standard for this kind of investigation. This is how we really know if a drug works or doesn’t, and that’s is the purpose of this trial.Our goal is to find a treatment that can work early and keep people from needing hospitalization.
Question: How is this trial different from earlier studies or investigations?
Smith: Other trials were not conducted in a way that allowed for observers and reviewers to conclude with certainty that the approach works or does not. Questions or aspects were left unanswered or incomplete. Doubts remained. This study is designed to definitively say one way or the other whether hydroxychloroquine and azithromycin are safe and effective against COVID-19 — at least for some patients, especially those who are not yet sick enough to be in the hospital.
Question: How do the drugs work?
Smith: By increasing the pH of certain cellular components called endosomes, which the novel coronavirus uses to infect cells. Endosomes are compartments inside a cell’s membrane that serve as a place where materials pulled into the cell can be sorted and directed to destinations inside the cell and materials inside can be transported and moved outside the cell. If the pH is too high in these endosomes, the virus gets stuck and cannot finish infecting the cell.
Question: How will the trial operate? What are the criteria for participation?
Smith: The trial is for adults with documented, active SARS-CoV-2 infections, with symptoms of either fever, cough or shortness of breath. If a person is eligible and can participate, they will be randomized to either the study drugs (hydroxychloroquine and azithromycin) or to a placebo, and treated. They will then be followed to see if the medications help prevent the person from requiring hospitalization or dying.
Question: Hydroxychloroquine and azithromycin are both approved drugs for other conditions, and are generally considered safe. But there are cases where patients using the former have experienced heart rhythm problems, sometimes fatally. Are the drugs safe?
Smith: Like all medications, these drugs can have side effects and some of these effects can include toxicity that may cause abnormal heart rhythms. While these rhythm disturbances are very rare, they can be dangerous so we do not know if, when we use these drugs to treat COVID-19, we might actually be doing more harm than good. Thus, it’s important to test the drugs against a placebo. To limit the chances of these drugs causing heart problems and to increase participant safety, this study will only include people who otherwise would be at very low risk for heart rhythm toxicity. We will also use low medication doses not usually associated with this toxicity. All that being said, I want to be very clear that people should not take these medications on their own for COVID. Doing so is best in the setting of a trial, like this one, or at least under the supervision of a physician.
Question: How long do you expect the trial to run? Do you expect difficulty finding participants, given concerns and controversy regarding this approach? When might initial results be known?
Smith: We expect the study to run a few months. I do not know if we will have difficulty finding eligible participants. There is still a lot of COVID-19 in the community and we do not currently have a medication that works for people who are not hospitalized.
For more information about the trial, visit ClinicalTrials.gov and search identifier NCT04358068. Adults interested in participating in the study can email firstname.lastname@example.org. In San Diego, please email Steven Hendrickx at email@example.com.