Covid-19: The inside story of the RECOVERY trial

Press release or peer review?

When the dexamethasone result was announced on 16 June it came unexpectedly early and not in a research paper but a media announcement. The UK government told NHS hospitals to act immediately, even though at that point the data had not yet been published in full as either a preprint or in a peer reviewed journal; it was a week later that a preprint appeared on the medRxiv preprint server.

Scientists are worried about the lack of public scrutiny of the data before major policy decisions were made, particularly given the retractions of high profile papers in journals such as the Lancet and New England Journal of Medicine just weeks earlier.2 The arm of RECOVERY evaluating hydroxychloroquine was ended earlier in June after the Medicines and Healthcare Products Agency (MHRA) asked the investigators to review the data early, prompted by the Lancet retraction. Their analysis concluded that the drug conferred no meaningful mortality benefit in the treatment of covid-19, leading to the trial’s first announcement of results, although again this was done through the media. At the time of writing the full data have still not been published.3

“I think it is irresponsible to release the results only in a press release; a press release is not evidence,” says Tobias Kurth, professor of epidemiology and public health at the Charité Berlin University of Medicine and one of The BMJ’s statistical advisers. “This habit has to stop now. Even though we are in a difficult situation and urgently need to find something that works, it is important to show all the methods and data.”

Landray’s defence is that the results were so stark that they had to be publicised, especially in the case of dexamethasone, as it was the first evidence of a treatment that reduces mortality in patients with covid-19.

What happened between the subgroups in the dexamethasone trial was very unusual, he says. “There was a very clear benefit, especially for patients on ventilators. This was a pre-specified analysis with a highly statistically significant difference between the patients depending on the level of respiratory support they were receiving at the start of the study. Importantly, we saw no benefit (and the possibility of harm) among patients not requiring any form of respiratory support.”

“If you look at Brazil, Mexico, or India, with thousands of patients dying every week, there will be many patients on ventilators who will suit [this] treatment,” Landray told The BMJ, adding that his team spent a week making sure the results were robust. They then shared their findings with “senior leaders in international healthcare,” who made it clear that the group had to take action.

“We had a choice: do we wait for full publication or make information available to the world to make their own decision? If we hadn’t released the [results], people would have said we sat on it,” he says.

Trial by design

Landray emphasises that to put the trial in context it’s important to cast our minds back to March and the sense of impending doom felt by clinicians in the UK.

“Covid-19 is a disease that affects huge numbers and where case fatality is high,” he says. “More than one in four patients in hospital die, and of those admitted to intensive care units the prospect is worse. Back in early March none of us were sure if we were going to run out of ventilators or healthcare staff. Doctors in Italy were using words such as war zone.” The priority, he says, was to find a treatment that would reduce deaths—and ideally one where doctors could access a few thousand courses rapidly.

As the pandemic broke, the World Health Organization and the European Medicines Agency emphasised the need for large randomised trials with a control group rather than many small and inconclusive studies, as had come out of previous epidemics.4

Landray and his colleagues wanted to embed research into standard clinical care and took inspiration from the large simple trials of the 1980s, in particular the International Studies of Infarct Survival (ISIS), randomised controlled trials of treatments for acute myocardial infarction. “It had to be easy for the clinician on the ground, in PPE and in a pressurised situation, and a minimal burden for the patient.,” says Landray. “Many academic and commercial trials have accumulated so much extra baggage over the years, such as long case report forms and 10 page patient consent forms.”

To Ray Sheridan, a consultant physician at the Royal Devon and Exeter NHS Foundation Trust, which recruited 49 patients to RECOVERY, it seemed as though the NHS was “turning the engines on big time.”

“You had 176 hospitals, and you could see the recruitment numbers going up astonishingly,” he says. “There was an unprecedented level of interest. I’d say 95% of patients were delighted there was a trial going on in their local hospital and felt like they were ‘doing their bit’ by being involved.”

The mammoth task of mounting a large scale trial amid the first major pandemic in 100 years was accomplished in record time. Landray and fellow chief investigator Peter Horby drafted the protocol on 10 March, and the results for the dexamethasone arm were announced just 98 days later, after more than 11 000 patients had been enrolled into the trial.

Patients enrolled in the open label RECOVERY trial are randomised to standard care or to one of six treatment arms: hydroxychloroquine (now ended), dexamethasone (also ended), lopinavir-ritonavir, azithromycin, convalescent plasma, and, in a second randomisation for patients who deteriorate, the anti-inflammatory drug tocilizumab.

For Sheridan, the trial meant that clinicians didn’t have to make snap decisions on emerging treatments. There was a lot pressure to use hydroxychloroquine and azithromycin in combination, partly because there was emerging evidence from France, he says. “But it was non-randomised, and many of those patients weren’t on oxygen, and a lot weren’t in hospital for very long.” Sheridan thought these were nothing more than pilot data, yet the study had begun to inform decision making about the pandemic.

“The RECOVERY trial stopped patients getting these treatments, and this was a relief,” says Sheridan, “Otherwise, a lot of patients would be given steroids by some consultants, hydroxychloroquine by others, and ultimately we wouldn’t be learning anything.”

But for clinical pharmacologist John Warren, formerly of the MHRA, the RECOVERY approach to drug selection was too random. He says the approach seems “like a roulette wheel—here’s an antiviral, let’s try it.”

Landray says the trial’s choice of drugs was influenced by the New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG), an expert committee of the Department of Health, and a WHO prioritisation process that took place in early 2020. The selection was ultimately governed by four principles: Is there a reason to believe the drug will work (for example, on the basis of laboratory test results or of experience from other viral infections)? Is the safety profile understood? Is the drug available in enough quantities to allow it to be tested in a trial of several thousand people? And, if the treatment is successful, can it be rapidly scaled up?

Other commentators have questioned the absence of the promising antiviral remdesivir in RECOVERY. The drug is currently being given to selected patients through the government’s Early Access to Medicines Scheme after early trial data showed that it shortened time to recovery.5The BMJ understands the lack of a remdesivir arm is because its manufacturer, Gilead, said it could offer only a limited supply of the drug and the investigators turned it down.

To this Landray would comment only that “we just couldn’t get the supply we needed.” But he added, “This is a global effort, and SOLIDARITY [a large multi-country WHO trial] is studying remdesivir in sufficient quantities. We don’t want to repeat their effort. This is not competitive, and there was a reason to say, ‘This is being done elsewhere, let’s leave them to it.’”

The trial’s legacy

For many involved in RECOVERY, the longer term issue is how the trial can reset the way clinical trials are conducted in the future. Landray says, “How can we build on the involvement of patients and clinicians and the timely access to relevant data? We now need to apply the lessons from this approach to other major health challenges such as heart disease, cancer, arthritis, and mental health.”

Ray Sheridan is keen to keep up the momentum. “We have seen things done in a really streamlined, efficient way, and people really want to hold on to that. We liked the fact that it was really pragmatic, so the moment you know a drug is not working it gets dropped and then other drugs can get added. It also shows that you can use the whole of the NHS rather than just the main academic centres.

“You have a whole lot of people in hospitals who are not usually involved in research on a day to day basis who really want to carry on.”