Enlarge / US President Donald Trump (L), flanked by US Vice President Mike Pence, speaks during the daily briefing on the novel coronavirus, which causes COVID-19, in the Brady Briefing Room at the White House on April 9, 2020, in Washington, DC.
The US National Institutes of Health on Thursday began a clinical trial to treat adult COVID-19 patients with hydroxychloroquine, a malaria drug that President Trump has repeatedly promoted during the pandemic despite a lack of evidence for its effectiveness against the new coronavirus.
The trial is one of dozens underway to test the drug, which is currently used to treat malaria and rheumatoid conditions, such as rheumatoid arthritis and lupus. At this point it only has mixed, anecdotal evidence to support its use against COVID-19.
But that hasn’t stopped President Trump from repeatedly promoting it as a promising treatment and calling for its use. In tweets last month, Trump said that a combination treatment of hydroxychloroquine and the antibiotic azithromycin “have a real chance to be one of the biggest game changers in the history of medicine.” He followed the declaration saying he hoped they will “be put in use IMMEDIATELY.”
In a press conference Saturday, April 4, Trump continued: “I’ll say it again: What do you have to lose? Take it. I really think they should take it… I think people should—if it were me—in fact, I might do it anyway. I may take it. OK? I may take it. And I’ll have to ask my doctors about that, but I may take it.”
There is no clear evidence that hydroxychloroquine—and the closely related drug chloroquine—are effective at treating COVID-19. But there is clear evidence on risks of the drugs, which include everything from headaches, vomiting, and rashes to loss of vision (retinopathy), seizures, hypoglycemia, heart arrhythmias, and deadly heart damage. They may also pose more risks in patients with underlying health conditions, such as diabetes and liver disease.
It’s also unclear how hydroxychloroquine and chloroquine might hypothetically help fight off a COVID-19 infection. Early experiments with both chloroquine and hydroxychloroquine suggested the drugs blocked the new coronavirus— SARS-CoV-2—from infecting monkey cells grown in petri dishes. The data hints at anti-viral activity, but such data is extremely preliminary in determining whether a drug would be effective against a virus infecting a whole human.
There’s also hope that hydroxychloroquine and chloroquine could be useful at dampening out-of-control immune responses. In some critically ill patients with COVID-19, berserk immune responses are thought to cause devastating damage to lungs and other organs. And there’s some reason to think that the drugs could help with this, given their immune-quenching effects seen in patients with rheumatoid conditions, which are marked by inflammation. Some studies have suggested that the drugs work by thwarting the actions of certain receptors on human cells that trigger cascades of pro-inflammatory responses. But it’s still not entirely clear how exactly the drugs interact with the immune system—or whether it would be relevant to treating COVID-19.
The potential usefulness of these drugs against COVID-19 is now under investigation in numerous clinical trials, including the NIH’s trial that is up and running as of this week.
The NIH’s trial is a blinded, randomized, placebo-controlled experiment aiming to enroll 500 adult patients with COVID-19 who have been hospitalized or are receiving emergency care and are expected to be admitted to a hospital. Researchers will give people randomized to the treatment group two doses of hydroxychloroquine per day for five days. They’ll then track the patients’ outcomes, looking at hospitalization status moving forward, need for oxygen or invasive mechanical ventilation, and death.
The first patients were enrolled this week at Vanderbilt University Medical Center in Nashville. It is one of dozens of medical centers in a network organized by the NIH’s National Heart, Lung, and Blood Institute (NHLBI).
Given the unbridled excitement surrounding hydroxychloroquine—bolstered by President Trump—the researchers involved in the trial feel the pressure to get results as quickly as possible.
“Many US hospitals are currently using hydroxychloroquine as first-line therapy for hospitalized patients with COVID-19 despite extremely limited clinical data supporting its effectiveness,” Dr. Wesley Self, an emergency medicine physician at Vanderbilt University Medical Center who’s leading the trial, said in a statement. “Thus, data on hydroxychloroquine for the treatment of COVID-19 are urgently needed to inform clinical practice.”
Amid Trump’s push for hydroxychloroquine, the Food and Drug Administration issued an Emergency Use Authorization late last month that allows doctors to treat patients with COVID-19. The unusual move spurred extensive backlash from former FDA officials, as reported by Science magazine.
Moreover, Trump’s enthusiasm for the drug also reportedly led him to push the Centers for Disease Control and Prevention on the issue. The agency subsequently published an unprecedented guidance informing doctors how to prescribe chloroquine and hydroxychloroquine for COVID-19, based on anecdotal data.
With widespread use comes widespread risks of side effects, according to Dr. Peter Lurie, a physician and former FDA executive under Obama and Trump, who spoke with Science. “What is quite certain: When you get large numbers of people exposed to [hydroxychloroquine], there will be important adverse effects. That can be acceptable in the setting of known benefits, but it’s more difficult to accept when there isn’t now and might never be evidence of benefit” he said. Lurie now heads the advocacy group Center for Science in the Public Interest.
Experts also worry that the availability of the drugs could undermine clinical trials trying to get that evidence. Availability of the drug could perhaps discourage patients from wanting to participate in trials in which they may be randomly assigned to get a placebo instead of what they may see as a promising treatment that’s already accessible.
Moreover, there’s growing concern that the surge in interest in these drugs are causing life-threatening shortages for patients with rheumatoid conditions, such as lupus, who rely on them for proven benefits.
Along with all the concern, backlash and pushback have been mounting. In a March 31 opinion piece, researchers urged their colleagues to protect patients with rheumatoid conditions and avoid misusing hydroxychloroquine and chloroquine. They added, “Public figures should refrain from promoting unproven therapies to the public and instead provide clear messages around the uncertainties we face in testing and using experimental treatments during the current pandemic, including the risk for serious adverse events.”
Earlier this week, Reuters reported that the CDC removed the unusual guidance for physicians treating COVID-19 patients. The CDC website now correctly states, “There are no drugs or other therapeutics approved by the US Food and Drug Administration to prevent or treat COVID-19.”
Likewise, criticism has continued to build against a very small, flawed French trial that claimed to provide evidence that a combination of hydroxychloroquine and azithromycin could treat COVID-19—a trial promoted by Trump. Among other problems, the trial jettisoned data on participants who got worse on the treatment, including three admitted to intensive care, one who stopped the trial due to adverse effects, and one who died.
In an initial statement April 3, the medical society behind the journal that published the study said that the society “shares concerns” about the article, which “does not meet the Society’s expected standard.” The society later updated the statement to note that the study is going through additional review and raised the possibility that it might retract the study altogether after the review was complete.
Meanwhile, the NIH trial and dozens of others are trying to get solid data on the use of hydroxychloroquine and chloroquine for COVID-19. Among them is an international trial orchestrated by the World Health Organization, called the Solidarity trial, to test the drugs, as well as three other candidate treatments.