A large clinical trial in the U.K. did more to change how doctors treat COVID-19, in less time, than did hundreds of other studies launched in countries around the world.
Called RECOVERY and run by the University of Oxford, the trial's findings may have saved thousands, and potentially even tens of thousands of lives — a claim that can be credibly said about few other scientific studies.
RECOVERY showed dexamethasone, a cheap, widely available generic steroid, could prevent death in some of the sickest patients hospitalized with COVID-19. The result was one of the first turning points in physicians' desperate battle to treat the damaging disease.
Just as importantly, RECOVERY was able to conclusively prove the antiviral drug lopinavir/ritonavir and the highly politicized malaria pill hydroxychloroquine don't work for COVID-19 patients whose symptoms require hospital care. While negative, the data helped guide doctors away from ineffective treatment, and spurred medical investigators to devote resources to more promising interventions.
"All three of those results went against the prevailing thoughts at the time," University of Oxford professor Martin Landray, one of the lead investigators in RECOVERY, said in an interview.
RECOVERY's success is due to both its design, which aimed to deliver quick answers on whether a slate of drugs could help patients survive COVID-19, and the pandemic's scale.
Landray and his fellow researchers set out to launch a straightforward study with limited data collection requirements — important for overstretched hospitals, where nurses and doctors want to spend as little time as possible on activities that don't directly involve keeping patients alive.
Their plan grew out of the concept of "large simple trials," an approach that asks just one or two clinical questions and seeks quick results through rapid recruitment of participants and fast analysis.
More often used for highly prevalent diseases like heart disease, large simple trials haven't been tried as much in infectious disease settings. (The PALM study during the Ebola outbreak in the Democratic Republic of the Congo is one notable example.)
The COVID-19 pandemic, however, forced researchers to approach things differently. That's how Landray, whose clinical work is primarily in cardiovascular disease trials, ended up paired with infectious disease professor Peter Horby as, respectively, deputy chief and chief investigator of RECOVERY.
The study's genesis was in an email Landray sent in late February predicting reliable data would be a critical asset in the fight against the virus, particularly in the rush to try new treatments. "We need to do randomization. There's a chance that we'll just throw treatments at people that won't work," Landray recalled writing.
"One doesn't need hundreds of small trials," he said. "You need large trials that get to important answers quickly."
Landray and Horby first tried setting up the study they had in mind in Wuhan, China, where the first major COVID-19 outbreak occurred. The comparatively fast end of the epidemic there, however, meant not enough patients were recruited, while those who could've been "simply weren't" due to data collection difficulties, said Thomas Jaki, a professor at the University of Lancaster and a member of the RECOVERY team.
"You need to streamline any trial as much as you can because the demand on the frontline staff is enormous," Jaki said in an interview. "In a situation where hospitals are bursting, you don't have the luxury of those extra few minutes."
With RECOVERY, Landray, Horby and Jaki were joined by a group of clinicians, statisticians and researchers from universities across the U.K., including Richard Haynes, Edmund Juszczak, Kenneth Baillie, Lucy Chappell, Saul Faust, Katie Jeffery, Wei Shen Lim, Marion Mafham, Alan Montgomery and Kathy Rowan.
The study's main measurement is simple: whether or not a patient died in the four weeks following enrollment. Recruitment criteria, often exhaustive in clinical testing, were boiled down to a short, three-item list. And only 13 pieces of information were needed when nurses and doctors enrolled a patient into the study.
Further data could be collected thanks to the extensive record keeping of the U.K.'s National Health Service, an advantage other countries like the U.S. don't have.
The resulting enrollment is remarkable by clinical research standards. As of Dec. 8, RECOVERY had enrolled about 20,000 people, roughly 9% of the total number of COVID-19 patients who have been hospitalized in the U.K.
Mark McClellan, a former Food and Drug Administration commissioner and director of the Duke-Margolis Center for Health Policy, said RECOVERY is a model researchers in the U.S. need to consider.
"We've got a world-leading supplier of COVID patients and, at this point, it's a tiny fraction of 1% of patients that have enrolled [in trials] in this country," he said.
Landray was more critical of the U.S. efforts to date. Had hospitals in New York City, for example, begun measuring outcomes in patients taking hydroxychloroquine versus those who weren't during the first wave, "we'd have known the answer of hydroxychloroquine working or not within a few weeks," Landray said. Instead, the question of the drug's potential effect was posed again and again by scores of replicative trials.
The first drugs RECOVERY started studying were approved ones, with well-known safety profiles that helped researchers bypass more intensive safety monitoring that would typically be required for an experimental drug. But the study team has shown it can adapt, adding an antibody-based treatment from Regeneron that's still being evaluated.
Other drugs have been incorporated into RECOVERY, too, a step made possible by the study's flexible design. Along with Regeneron's drug, patients recruited to the trial could receive azithromycin, Roche's Actemra, convalescent plasma and aspirin.
McClellan said there are signs others are taking a page from RECOVERY. The University of Pittsburgh's REMAP-CAP, an adaptive trial aimed at finding better treatments for hospitalized pneumonia patients, has added COVID-19 treatment arms, as has the I-SPY trial, a multi-arm study designed to test breast cancer drugs.
The U.S. National Institutes of Health has also launched a series of adaptive studies, dubbed ACTIV, that are testing several experimental drugs as well as existing treatments.
While RECOVERY was born of the pandemic, experts see potential for this model to be used in the future, both during public health crises or even in less urgent circumstances.
"The traditional timelines of clinical trials are going to have to change," Jaki said. "It is unacceptable," he added, that a year or more can commonly pass between when a study is conceived and when the first patient is recruited.
RECOVERY, by contrast, took just nine days.
Editor's note: A reference to the study of hydrocortisone in RECOVERY was removed from this story as the population in which the drug is being tested is limited to newborn infants.