There’s been a lot of heat but not much light on whether the antimalarial drug helps coronavirus patients. That’s because we still need a big clinical trial.
ON MARCH 9, members of a team of infectious disease researchers based at the University of Minnesota found themselves with four free days. An HIV conference they were supposed to attend had been called off on account of the global pandemic, which gave the group an unusual moment of breathing space. “This was right when community spread was beginning to happen, and we realized it was going to be a problem,” says David Boulware, a physician and leader of the group. “We wanted to focus on prevention and early treatment. At the time, no one was really doing that.”
Even then, research interest was circling around the decades-old antimalarial drugs chloroquine and its cousin, hydroxychloroquine. Silicon Valley hadn’t yet turned its disrupt-o-vision on the drugs, but they killed the SARS-CoV-2 virus in the lab, and a small, preliminary study in China seemed to suggest they worked in actual people too. Because physicians were already allowed to prescribe the drugs—for malaria and immune disorders like rheumatoid arthritis and lupus—they were starting to use it, Hail Mary–style, on Covid-19 patients in the hospital. It was, in short, worth a look. But not, in Boulware’s mind, for people so sick they were already hospitalized. “Late-stage severe disease, there’s a lot of things going on with the virus and the immune system. We realized six weeks ago hydroxychloroquine probably didn’t work then,” he says. But what about if it was prescribed early, to prevent people from getting the disease, or from getting very sick if they did?
The team put together a plan for a double-blind, randomized, controlled trial—hydroxychloroquine versus a placebo. The US Food and Drug Administration gave them an Investigational New Drug approval to use the stuff in this new way. Just eight days after coming up with the idea, Boulware and his team enrolled the first subject into the trial, which is asking if the drug can help people in the early stages of Covid-19 infection and protect at-risk people such as health care workers and people taking care of infected family members.
And then things got more complicated. The day before that first subject signed up, on March 16, SpaceX CEO Elon Musk tweeted about the drug, sparking interest among the crowd that wants to extend its life with metformin and blood from young people. Three days later, President Donald Trump said during a Covid-19 press briefing that he thought the drugs “could be something very, very incredible,” sparking a run on pharmacies. Whether someone believed the drugs worked against Covid-19 came to be a symbol of how they felt about the president. And all that happened without any real, solid scientific results.
As of now, no one really knows if hydroxychloroquine and chloroquine help fight Covid-19. And an information war is hindering the struggle to find out.
It’s not implausible that chloroquine could be helpful. As early as 2005, research showed that—in a laboratory mix of African green monkey cells, at least—it inhibits the virus that causes Severe Acute Respiratory Syndrome, SARS, a coronavirus related to the one that causes Covid-19. The drug kept cells from becoming infected and helped them fight off infection as well—a preventative and a therapy. Researchers even worked out its mechanism. A coronavirus anchors onto a cell via a specific docking port, a receptor called angiotensin-converting enzyme 2. Chloroquine seems to keep this ACE2 docking port from opening and also make the interior of cells less acidic, and so less friendly to the virus once it gets inside.
Sounds good, right? So much so, in fact, that as The Washington Post reported, Oracle CEO Larry Ellison lobbied President Trump to build a national system for monitoring the drug. A family doctor in New York named Vladimir Zelenko started getting national attention for a series of videos he made touting the success of a protocol of his own devising against Covid-19, combining hydroxychloroquine, azithromycin, and zinc. Fox News picked up on the president’s early cheerleading, and started talking about the drugs as well. By the end of March, the president was tweeting that hydroxychloroquine in combination with the antibiotic azithromycin could be “a game changer.”
The US Department of Health and Human Services started adding millions of doses of hydroxychloroquine to the Strategic National Stockpile of drugs for eventual distribution to states. The FDA issued an Emergency Use Authorization telling physicians they could prescribe the drug to people hospitalized for Covid-19. (Many already were; it’s relatively cheap, already in the pharmacopeia, and they didn’t have anything else.) Demand for hydroxychloroquine spiked to such an extent that people who depend on it to treat their rheumatoid arthritis or lupus started to worry that they wouldn’t be able to get it.
The evidence wasn’t as hot as the market. Unorthodox research methods and a seeming rush to publication, or even prepublication, muddied the situation. Early studies from an infectious disease researcher named Didier Raoult, director of the Research Unit in Infectious and Tropical Emergent Diseases in Marseille, seemed promising, albeit un-peer reviewed. On March 20, Raoult’s group published a second trial as a preprint and then in a peer-reviewed journal: a non-randomized, open-label trial. Instead of following the gold-standard protocol for testing drugs against diseases, the researchers simply gave Covid-19 patients the drugs and then monitored their viral counts, comparing them to Covid-19 patients elsewhere who didn’t get the drug. No placebo, no double-blinding. (Raoult has said in interviews that he doesn’t think randomization is necessary in infectious-disease drug research.)
The larger research community and scientific watchdogs quickly tore into Raoult’s methodology. The data seemed sketchy to them—not every patient who died was accounted for, and the comparisons among the groups weren’t rigorous. Some of the math behind the statistical analysis didn’t work out. And the paper itself seemed to cruise through ethical gatekeeping and peer review too quickly. The publishers of the journal, the International Society of Antimicrobial Chemotherapy and Elsevier, would eventually issue a joint statement expressing “concern” with the research. “The French stuff was low quality in terms of evidence of whether this thing works or not,” says Walid Gellad, head of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh.
Of course, Raoult wasn’t the only scientist on the case. Chinese researchers had been studying chloroquine since early on in their experience with the pandemic. But few published results, it seems. According to one, a randomized controlled trial with 30 subjects in the early stages of Covid-19 infections published in the Journal of ZheJiang University, roughly the same number of people improved whether they were on the drug or not. Those who had taken hydroxychloroquine showed moderate benefits in terms of lung damage seen on a CT scan. “There was a small trial in China that showed it did have an effect—a randomized trial showing an effect in some measures, when given early,” Gellad says.
Meanwhile, other clinical trials are spinning up. The World Health Organization’s Solidarity trial of Covid-19 treatments and the United Kingdom’s Recovery trial both include tests of hydroxychloroquine. Around the world, nearly 150 are either underway or set to begin soon.
As that global race to investigate the drug began, though, it hit what looked like speed bumps. In late April, a preprint—no peer review—detailed results for 368 people treated for Covid-19 in Veterans Affairs hospitals with hydroxychloroquine, hydroxychloroquine and azithromycin, or none of the above. The drug didn’t reduce the risk of being put on a ventilator, and it slightly increased the chances people would eventually die of the disease. Suggestive, and not in a good way.
And then the results of a Brazilian trial of chloroquine in people hospitalized with severe Covid-19 seemed to sap even more momentum. A safety committee actually stopped that randomized, double-blind study early. Nearly 40 percent of the people receiving a very high dose of chloroquine had died, and many showed a heart problem called QT interval prolongation, a known side effect of the drug and one potentially made worse when it’s used in combination with azithromycin.
On April 24, the FDA issued a new statement—a Drug Safety Communication—warning that physicians shouldn’t prescribe the drugs to people outside a hospital or trial. The FDA had also received more “adverse event” reports on the drugs, primarily related to heart problems. “While we are unable to offer more specifics on the small number of cases we have reviewed at this time, we will continue to investigate the risks associated with the use of hydroxychloroquine and chloroquine for COVID-19 and will share any additional information or analysis publicly as we’re able,” the statement read.
Sounds bad, right? Except … again, the research wasn’t clear. The VA study was retrospective, and small. That Brazilian study was only of very sick people, exactly the group that big studies like Boulware’s and the international trials planned to exclude on the grounds that they’re probably too sick to help. (Or, perhaps more importantly, it would be too hard for researchers to disaggregate the effects of the drugs from everything else going on in those people’s bodies.) And that high dose of the drug? It was really high—600 mg twice a day for people in the high-dose arm of the trial, and on the low-dose arm 450 mg twice a day on the first day and then once thereafter. That’s compared to a recommended 400 mg twice a day for one day and then once thereafter in US protocols. “What’s being used in the US is much more like the low-dose arm, and there are no issues,” Gellad says. “The high-dose arm had people with other risk factors. It doesn’t tell us much about the way it’s going to be used in the US.”
As for the FDA’s caution? “I think what’s happened is there’s been a lot of promotion of this drug as a cure-all by politicians and by the media. And, parenthetically, at the same time there’s been a lot of unnecessary vilification of the drugs,” Gellad says. “The reality is, there’s a ton of uncertainty … My guess is the FDA wanted to pull back on the idea that the government was promoting the use of this drug, not pushing this therapy but being very responsible, using it in clinical trials.”
The FDA wanted to remind primary care physicians that while they were allowed to prescribe these drugs off-label, they had real side effects—and that some people who don’t have Covid-19 infections really need them for other reasons. “We understand that health care professionals are looking for every possible treatment option for their patients, and we want to ensure we’re providing them with the appropriate information needed for them to make the best medical decisions,” FDA commissioner Stephen Hahn said via press release. “While clinical trials are ongoing to determine the safety and effectiveness of these drugs for Covid-19, there are known side effects of these medications that should be considered.”
The agency also didn’t want to step on ongoing research. Yet the ongoing back-and-forth about safety and efficacy has done exactly that. As soon as the drug hit the Strategic National Stockpile and started making its way to state hoards and the medicine cabinets of the worried well, “our enrollment started to tank,” Boulware says. Remember, being in a randomized controlled trial means you have a good chance of being in the placebo group—of not getting the drug. Trials aren’t meant to treat people; they’re meant to advance science. With so much positive spin, Boulware says, people figured: “Hey, it clearly works. Why would you be in a randomized controlled trial?” A clinical trial might not help each person, but it does help everyone; without them, no one can know if the drugs actually work.
Boulware’s group has 1,200 people enrolled already, but they need 180 more. And he’s having a hell of a time getting them signed up. So far, Boulware says, no one in the study has had any safety issues remotely like what the Brazilians experienced—probably because of the lower dose.
Yet the fights over hydroxychloroquine continue, on the internet and in real life. If the drug works, some partisans argue, it’s wrong to delay its widespread use by waiting for results; if it doesn’t, it’s wrong to even try it on people. “The social media perspective is: About half of people think it’s an unethical trial because it clearly works, and the other half thinks it’s clearly dangerous and we shouldn’t do it,” Boulware says. “We’re just trying to get the answer. Having a solid study design and having the actual answer is really important for both the country and the world, and that’s our goal.”
Meanwhile, though, it’s important to remember that nobody actually knows that answer. The Silicon Valley adherents insisting that the problem with the negative results thus far is that researchers tested the wrong kind of people, or used the wrong dose, or didn’t use zinc—they don’t have the data that can say whether any of that is true. The people saying that hydroxychloroquine is clearly unsafe, or that it can’t possibly work? They don’t have that data, either. Nobody does. The studies aren’t finished. “It’s going to be May 1, and we still don’t know if it works. It’s a giant failure,” Gellad says. “We should have had an answer. All you need is a randomized controlled placebo trial with 1,000 patients, and we’d know.”
The president’s unjustified early enthusiasm for hydroxychloroquine (and his equally unjustified apparent abandonment of the idea) didn’t translate into a centralized, rapid-response study to determine the actual truth. The National Institutes of Health didn’t spin one up until the first week of April, a month after Boulware launched his. “Ideally, you would think, this is a national emergency and there would be coordination centrally, at the federal government level,” Boulware says. “The UK put together a nationwide trial for treatment. We weren’t able to do that.”
But if we were? Imagine the satisfaction of knowing a true fact—of being able to help sick people, or knowing that hydroxychloroquine doesn’t help and being able to move on. Imagine, if you can, being able to decisively win a fight on Twitter.