Montefiore in the News

Adam Rogers Science | 06.24.2020 04:53 PM

In just three months, one British research team identified the first life-saving drug of the pandemic (and helped cancel hydroxychloroquine).

The Recovery trial’s multi-armed adaptive design and its fast-twitch release of results into the world have opened up an unusual pathway of absorption into the body of accepted scientific knowledge.Photograph: Mariusz Burcz/Alamy

Last week, a British research team announced that a cheap, safe, widely available drug called dexamethasone makes a huge difference in saving the lives of people severely ill with Covid-19. Perhaps no one was more surprised than the people on the research team. That group, the United Kingdom’s Randomised Evaluation of Covid-19 Therapy (Recovery) Trial, took just three months to go from spinning up a brand-new kind of drug trial to changing global medical practice.

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In the sluggish, procedurally mired world of therapeutics research, that’s pedal-to-the-metal. “I was expecting results at the end of June, early July,” says Martin Landray, a physician and researcher in the University of Oxford’s Nuffield Department of Population Health and one of the heads of Recovery. Instead, three weeks ago he had

data so compelling that it was obvious the moment they ended recruitment of subjects—and compelling enough to take the unusual step of announcing it via press release.

The Recovery trial has an “adaptive” design, built to evaluate a half-dozen different drugs at once, with methods and goals announced in advance. Each of the drugs has some logic for why it might work against Covid-19; the trial takes its volunteers from people in the UK’s National Health Service, randomizing them to get one of the drugs or none. A Data Monitoring Committee reviews results as they come in, allowing the trial to drop the ones that don’t work, or even add new ones. As soon as Recovery met its goal of 2,000 people taking the corticosteroid drug dexamethasone, that committee called Landray and told him he should take a look at the numbers. For people so sick they needed supplemental oxygen, dexamethasone reduced deaths by a fifth. For people on mechanical ventilators, it reduced deaths by a third. These figures were eye-popping—Landray didn’t totally believe them at first. His team spent the next two weeks, as he says, trying to break the statistics, to see if there was some mistake or confounding factor. They couldn’t find one.

That’s game-changing. Except for some mildly promising results from the exotic and expensive Ebola drug remdesivir, no therapeutic has shown any real effect against the virus. Dexamethasone, on the other hand, is a cheap, common steroid safe enough to be standard for kids with croup. (Its side effects are generally mild things like insomnia or appetite changes.) “Making this available to the world is a big thing, and the last thing I want to do is make a statement, because it was the first treatment that improved survival for a global pandemic, and it doesn’t cost any money,” Landray says. “It was completely obvious the story was going to be big, so it had better be right.”

On June 16, Landray and his co-lead, Peter Horby, held a press conference and put out a statement. Technically, that’s not the way science is supposed to work. (Nor science journalism, to be frank.) They bypassed the checks-and-balances system of getting data into shape and having it reviewed by peers before formal publication in a scientific journal. Yet four hours after that announcement, the UK’s massive National Health Service added dexamethasone to its Covid-19 treatment protocol. Landray says he felt like he had to do it. “Do I hold onto that, as our little secret, whilst patients are being treated with no evidence at all—either by not being given any drugs or all sorts of drugs? Do I hold onto this information, which by this point is pretty clear-cut, or do I inform the world?” he asks. “The answer is: You’re cursed if you do and cursed if you don’t. But by far, to me, the better option was to make the results publicly available.” 

Most researchers would be happy with changing global practice just once. But in fact, that press conference marked the second time in a month that Recovery had an influence on how hospitals treat Covid-19. In early June, the researchers announced that they were canceling the arm of the trial testing the use of the antimalaria drug hydroxychloroquine, touted by Silicon Valley disruptor-bros and the presidents of global superpowers. The Recovery trial’s data review board looked at their numbers and determined that it wasn’t worth enrolling any more subjects; the stuff just wasn’t doing any good. (Another trial, at the University of Minnesota, found no benefit in hydroxychloroquine as a preventative, either.) And although more results are inbound, the fact that Recovery packed up and moved on was a signal that hospitals should pretty much do the same. “Both of these results came out earlier than we expected,” Landray says.

The trial’s multi-armed adaptive design and its fast-twitch release of results into the world have opened up an unusual pathway of absorption into the body of accepted scientific knowledge. In fact, by most standards, the dexamethasone result hasn’t even made it all the way through science’s large intestine. The Recovery trial still hasn’t published a paper in a peer-reviewed journal, though Landray says the team has submitted one on dexamethasone and is writing one on hydroxychloroquine. Early this week the researchers published a preprint on the MedRxiv web server that went into greater detail on the groups that benefited from dexamethasone.

At this very moment, a whole world of researchers is reviewing that preprint somewhat less formally—in internal meetings (and, of course, on Twitter). At UC San Francisco’s hospital and medical school, the people who make policy and see patients debated whether they had enough information to change how they treat Covid-19. In the end, they decided, they did: The Recovery research group is respected, they published their methods and planned endpoints ahead of time, their results show a clear difference, and those results make intuitive sense.

“To me, even the press release crossed my bar of change in practice, which is a strange thing to say, because I don’t like making clinical decisions by press release,” says Bob Wachter, chair of the Department of Medicine at UC San Francisco. “But you’re talking about a drug that is quite safe when used for short periods of time, and one we have a lot of experience with. You’re talking about very impressive differences—not subtle improvement, highly statistically significant improvement. And you’re talking about it coming from a highly respected international research group who had to publish their research methods previously.”

In fact, frontline physicians were already waiting to see if steroids would make a difference in the disease. “It’s not just ‘Does it work?’ but ‘Does it have a pathophysiologic rationale? Is there a reason that it might work?’” says Wachter. And there is. Corticosteroids like dexamethasone and prednisone (“glucocorticosteroids,”

if you’re being really specific) come from people’s adrenal glands; they regulate bodily functions from metabolism to cognition—and the immune system. That’s good, because a runaway immune response is one of the ways Covid-19 turns deadly. “We know that Covid is a bipronged disease, a disease where some of the damage is being done by the virus replicating and damaging and blowing up cells … But an impressive amount of the damage comes because of your own immune system trying to kill the virus but also killing parts of you at the same time,” Wachter says.

That’s called a cytokine storm. It’s an immune response gone overboard with the hotheaded defensiveness of a person who knows they’re on the wrong side of an argument. But inhibiting that is also inhibiting the immune system, which is a tricky balance—physicians want to stop the inflammation, but not block a person’s ability to recover. The World Health Organization’s guidance for treating people with Covid-19 still recommends against the use of steroids, based on reviews of trials using the drugs against other kinds of viral pneumonia. As recently as February—which, yes, feels like 1,000 years ago—a paper in The Lancet likewise warned health care workers not to use the drugs against Covid-19, citing all kinds of bad outcomes in treating respiratory syncytial virus, influenza, and the earlier coronavirus diseases SARS and MERS.

Nobody really knows why dexamethasone seems to have such a clear benefit in Covid-19. The Recovery trial found that the patients who showed the most benefit were the ones who needed additional oxygen or were on mechanical ventilators—they were much more likely to still be alive 28 days later compared to people who were just as sick but didn’t get the drug. But it’s not completely clear from the paper how useful the drug was for people who didn’t need oxygen or ventilators; that is, for people who weren’t as ill. “There probably is enough here for most people to feel comfortable giving steroids to the sickest patients,” says William Southern, chief of hospital medicine at Montefiore Health System and Albert Einstein College of Medicine. “We don’t really yet know precisely what is the right patient population to treat with steroids. It appears the sicker someone is the more likely they are to benefit, but it’s not really clear how to characterize the population that will most likely benefit.”

In the UK study, more than 40 percent of people on ventilators who didn’t get dexamethasone were dead 28 days later. In New York at the height of the pandemic, that percentage was even higher—but Wachter says at his San Francisco hospital, it was just half that. Nobody’s really sure why. Maybe it was just that San Francisco didn’t have as many sick people and had more staff to care for each one; maybe the people in New York were sicker, or had other conditions that made them more vulnerable. But regardless, that means that under the same conditions, dexamethasone would have made more of a difference in New York than San Francisco.

Safe as dexamethasone is, the Recovery study still administered it for 10 days, longer than a typical steroid course. That might mean long-term side effects like increased susceptibility to other infections. “It will be interesting to see the long-term ramifications in terms of adverse events,” says Shitij Arora, an internal medicine physician at Montefiore who developed an early protocol for using corticosteroids on people hospitalized with Covid-19. “Not particularly lung damage as such, but some delayed infections, particularly fungal infections, which were a concern with SARS and MERS data.”

Landray agrees with the need for more monitoring of the people in the study, but he doesn’t really buy the need for finer cuts of the data. Basically, he says, you measure how much oxygen is in someone’s blood, and if their oxygen saturation is below 93 percent—if they’d need extra oxygen, or if they got worse and needed a ventilator—in his study dexamethasone cut their risk of death. “It fits with the biology. This is telling us that there comes a point in the disease where the lungs start to fail. If you reach for the oxygen cylinder, you should be reaching for the dexamethasone as well,” Landray says. “A lot of this question of, how do we work out exactly who to give it to? That’s a bigger issue if you have a treatment with horrible side effects or it costs you $10,000 a pop. Here it costs you $10 a pop, and we know the side effects for the entire course.”

Meanwhile, Landray expects still more results from Recovery. They’re going to write up the data from the canceled hydroxychloroquine arm of the trial, and still ahead are outcomes from the other drugs they’re looking at—the HIV drugs lopinavir and ritonavir, the antibiotic azithromycin, an anti-inflammatory called tocilizumab, and plasma extracted from the blood of people who’ve recovered from the disease. These kinds of trials are going on all over the world, hundreds of them, but results have been slow to arrive.

The change in the standard of care represents not just new knowledge but a reversal of previous wisdom. If the results hold, the addition of dexamethasone to the Covid-fighting medicine cabinet (and the multiprong adaptive testing model of Recovery) represents science actually getting better at fighting the disease. “Recovery is what you can do if you keep your eye on the ball, focus on the thing that matters, and build a big team motivated by getting the answer right and doing the right thing for patients, rather than be motivated by money, prestige, authorship, or anything else,” Landray says. There’s no real reason that big, fast studies like this couldn’t have spun up in the United States. But they haven’t. Recovery has identified one cheap therapeutic that saves lives, and canceled one that doesn’t … and it has still only just begun.