The spread of unproven treatments lends to inconclusive results, frustrating both researchers and desperate patients.
At some point in late March, Roger Alvarez, a pulmonologist and critical care specialist at the University of Miami Health System, noticed that some of his patients with low oxygen levels continued to decline, even after being placed on ventilators. This gave him an idea: Rather than putting these patients directly on ventilators, what if they were treated with inhaled nitric oxide first? The gas increases blood flow by relaxing and widening blood vessels in the lungs, and it is regularly used to treat a number of conditions, including acute respiratory distress syndrome.
As it happened, Alvarez had been studying the efficacy of a new, purse-sized nitric oxide delivery device—“I had the devices sitting in my research space,” he recalls—so after securing a nod from the manufacturer and approval from the U.S. Food and Drug Administration to use the device on a single patient, he and his colleagues began designing a formal study of patient volunteers so they could have clear, unequivocal evidence that nitric oxide improved outcomes for coronavirus patients on ventilators.
Of course, to do this right—to really know that the gas was the crucial factor—one of his fellow doctors advised that they should exclude COVID-19 patients who were already using other experimental coronavirus therapies, including the anti-malarial and lupus drug hydroxychloroquine (brand name Plaquenil), and tocilizumab, a common arthritis medication.
But this, Alvarez already knew, would be a challenge. “I very plainly told him, I agree with you from a science standpoint,” Alvarez says, “but I can tell you that if you did that right now in Miami, you would have no patients in your trial.” That’s because the vast majority of patients ill enough to need ventilators were already taking one or both of these drugs.
Ultimately, the team decided that if they wanted to study inhaled nitric oxide, they would have to include these patients, even though it could muddy the results. And that’s a problem that many researchers—particularly those mounting smaller studies aimed at exploring new COVID-19 treatments—might soon be facing.
Major hospitals across the country had long ago adopted hydroxychloroquine as a first-line treatment for COVID-19 when, in more recent weeks, U.S. President Donald Trump began endorsing it—without hard evidence—as effective and safe. A small but influential French study—one that many critics say was poorly designed—has helped to further stoke hydroxychloroquine prescriptions. And all of this, some physicians who run clinical trials say, could complicate and delay efforts to scrutinize whether any new treatment is really helping, or even harming, COVID-19 patients.
“The science has to be as good as possible,” says Andre Kalil, an infectious disease doctor at the University of Nebraska, “because that’s the way that we’re going to find therapies and save lives.”
“We have learned through decades of medicine that … the pill can worsen outcomes just as easily as it could help.”
– Roger Alvarez, critical care specialist at the University of Miami
Clinical trials of various COVID-19 treatments are, of course, ongoing—and the FDA has ramped up its capacity to approve new studies. But researchers are grappling with an overarching concern that with so much off-label, ad hoc, and informal experimentation underway in the battle to contain the pandemic, the baseline conditions needed for decisive studies of COVID-19 interventions are becoming more challenging to achieve. They also worry that if the public comes to believe that the evidence on hydroxychloroquine is settled, few patients will want to participate in clinical trials at all. They’ll just want the hydroxychloroquine—and there is already evidence that this is happening.
Alvarez says he gets it. “If the [French] study can
be interpreted in a good light and it’s the only one that can, then individual physicians all around the world are hanging onto that because we want to help,” he said. “We’re scared of what we’re seeing. I think any physician would tell you that this is scary and we’re grasping at straws to help people.”
And yet, he and other scientists say, all that grasping might actually be inhibiting the country’s ability to figure out the most effective ways to treat COVID-19.