RECOVERY: The groundbreaking clinical trial that transformed COVID-19 treatment

A person in a white lab coat holds a box of dexamathasone, the drug estimated to have saved a million lives worldwide from Covid-19

On Monday 9th March, 2020, two men took a bus ride that changed the course of the COVID-19 pandemic.

Disturbed by the reports coming out of Italy about intensive care wards overflowing with desperately sick patients, Martin Landray — Professor of Medicine and Epidemiology at the University of Oxford — and Wellcome director Jeremy Farrar knew they needed to act fast.

By the time they had travelled from Marylebone station in west London to Wellcome’s headquarters in the centre of the city, a plan had come together.

New disease, no known treatments

“We were looking at a world we knew very little about,” Martin says. “We knew that this was a serious new disease that could make people really sick, we knew that there were no known treatments, and we knew that the NHS was probably going to struggle and possibly be completely overwhelmed. There were lots of ideas about treatments that might work but no definitive answers, so we urgently needed a clinical trial to figure out what to do to save lives.”

The result of this brief conversation was the Randomised Evaluation of COVID-19 Therapy, or RECOVERY for short — a groundbreaking clinical trial comparing different treatments for the most seriously ill patients in hospital. Within a matter of days, Landray and his colleague Peter Horby, Professor of Emerging Infectious Diseases and Global Health, had put together a trial protocol, applied for rapid Government funding from UKRI and NIHR, and assembled a crack team of experts to run the study.

Less than two weeks later the first patient had been recruited and within months the first results began to emerge. By June 2020, the trial definitively showed that the much-touted remedy hydroxychloroquine was ineffective, while the steroid drug dexamethasone could cut deaths by a third.

The news spread quickly around the world, changing the way that COVID patients were treated almost overnight. But there’s more to the story of RECOVERY than these big headline findings.

Getting RECOVERY up and running

While Landray and Horby have become the faces of RECOVERY, receiving knighthoods in June 2021 for their role as Chief Investigators, they would be the first to credit the army of researchers, administrators, IT staff, doctors, nurses, pharmacists and many more who have worked tirelessly behind the scenes set up and run the trial. One of them is trial coordinator Richard Haynes, Professor of Renal Medicine and Clinical Trials at the University of Oxford.

“It all kicked off at a crazy pace,” he recalls. “Martin and Peter finished the protocol over a weekend and by Thursday we had filed all the paperwork for ethics and regulatory approval. It usually takes ages to get an answer, but we had approval by the following Tuesday and recruited the first patient on Thursday. We had achieved in ten days what would normally take ten months.”

“Alongside that, we were pulling the team together, dragging people away from their other duties and bringing back others from retirement, and working closely with our three programmers to get the IT system up and running to gather and analyse all the data that would be coming out of the trial.”

“And, of course, we were doing all of this under lockdown — homeschooling our kids, worrying about elderly relatives in care homes and all the other stuff that everyone else was going through too — so it was a pretty hard time.”

Within weeks RECOVERY had opened in 100 NHS hospitals and was expanding fast. By the end of May 2020, 10,000 patients had joined the trial, and more than 45,000 patients have been recruited from nearly 180 sites across the UK to date.

“We’ve tried hard to leave no-one behind,” says Haynes. “We’ve included pregnant women and people with underlying health conditions, and children as well as adults — our youngest patient was just six days old, and our oldest has been 103!”

One question, many possible answers

As well as the logistical challenge of running the trial, the research team also had to decide which treatments to test. COVID-19 caused massive inflammation in the body, so were anti-inflammatory therapies a good idea? Or would antiviral drugs be a better approach?

While doctors around the world were using their best judgement with the treatments that were available, nobody was looking systematically at which ones were actually effective and which were ultimately a waste of time, money and lives.

Most clinical trials usually compare two treatments head to head or test a new drug against a dummy placebo, but RECOVERY put as many different treatments to the test as possible. Once an answer was reached on whether or not a particular drug worked, another would be swapped in its place.

This multi-arm approach has allowed the team to test more than fifteen treatments so far, ranging from expensive antibodies and antivirals to cheap anti-inflammatory drugs like dexamethasone and colchicine, as well as plasma donated by people who had recovered from COVID-19. Even aspirin — a drug that has been on sale for more than a century — got its turn on the trial. (Unfortunately it didn’t have an impact on survival.)

“We were very lucky that the first positive result came for dexamethasone — a drug that costs a fiver and can be used anywhere in the world,” says Haynes. “To see it becoming routinely used in the NHS within a matter of hours was incredible.”

By 23rd March 2021, the first anniversary of the UK lockdown, it was estimated that using dexamethasone had already saved a million lives worldwide. Positive results also came for the anti-inflammatory drug tocilizumab and Regeneron’s antibody combination, REGEN-COV. But as well as celebrating these successes, the negative results from the trial are just as relevant.

“By now we’ve had more negative results than positive ones, and that’s a good thing, because it helps to prevent people being being given treatments that don’t work,” explains Haynes.

“Hydroxychloroquine was being used widely in the US and elsewhere around the world, but the FDA updated their guidance very quickly when we showed it didn’t work. Peter and Martin got a lot of hate mail when we announced that result, but it’s just as important to show what doesn’t work as to prove what does.”

Going Global: Rolling out RECOVERY around the world

At the start of the pandemic, around one in four people who were admitted to hospital in the UK with COVID-19 were dying — a figure that has now halved thanks to improvements in treatment. Vaccines are also playing their part in reducing severe illness and keeping people out of ICU. However, there is also less good news as some treatments have proved to be ineffective against the recent Omicron variant. As the situation changes, RECOVERY is changing too.

“Two years ago it felt like we were a fire engine responding to an emergency,” says Haynes. “Here in the UK the house is no longer burning down — the hospitals aren’t overwhelmed and we’re not recruiting so many patients. RECOVERY now needs to become embedded in the NHS, chipping away at improving outcomes here in the UK, but also expanding to international settings where healthcare isn’t so well resourced and vaccine coverage isn’t so good.”

This international effort is being coordinated by Emmanuelle Denis, senior operations manager at the Centre for Tropical Medicine and Global Health at the University of Oxford.

“We initially started looking to expand RECOVERY internationally in the summer of 2020 when the first UK wave had died down and we weren’t able to recruit many patients here,” she says. “We began by talking to our existing collaborators in Africa and southeast Asia where we knew they already had the infrastructure and team to set up and run the trial there.”

In February 2021, RECOVERY opened in Indonesia, Nepal and Vietnam, followed by South Africa at the end of the year and Ghana due to launch soon.

“A lot of the underlying trial process is the same, but some things have been more challenging internationally,” Denis says. “Here in the UK we can connect up people’s health data through the NHS to follow them up, but that isn’t possible in countries with less advanced health information infrastructure, so we have to do more time-consuming enquiries and visits to see how people are doing.”

More broadly, RECOVERY offers a new way of doing clinical research, both here in the UK and around the world. And its high profile success has given a huge boost to public awareness of the importance of clinical trials in improving healthcare.

“I hope people see trials like RECOVERY and remember next time they’re asked to take part in a trial — it would be a great legacy to make trials a normal part of routine care that give us answers about how best to treat people, not something done by ‘guinea pigs’ in a distant building,” Hayne says.

“I’ll see twelve to fifteen people in a typical clinic and every single time there will be a point where I have to say, ‘I don’t know what’s best here.’ I would love to be able to say, ‘So let’s do a trial and find out.’”

Want to know more?

If you’re a UK taxpayer, your contributions help fund RECOVERY, via UK Research and Innovation — the UK’s largest public funder of research — and the Medical Research Council, in conjunction with NIHR. You can read more about UKRI here, and more about NIHR here.

On March 3, the RECOVERY trial team announced that a fourth drug has been found to reduce deaths in patients hospitalised with Covid-19. Baricitinib, an arthritis drug, helped reduce the risk of death in hospitalised COVID-19 patients by 13% regardless of which other coronavirus treatment they were given. Read more:

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