“Around 9 or 10 March, it become obvious that [the novel] coronavirus was going to be a major challenge worldwide. First of all, [because] there are no known treatments. Secondly, it was going to have major consequences for health, and, thirdly, this was going to have major health consequences to the healthcare system,” says University of Oxford’s Nuffield Department of Population Health professor of medicine and epidemiology Martin Landray.
This escalating pandemic situation pushed Landray and his University of Oxford colleague professor of emerging infectious diseases and global health Peter Horby to quickly to set-up a large, UK-wide, randomised study investigating a range of drugs at the same time, called the Randomised Evaluation of COVid-19 thERapY (RECOVERY) trial.
A large-scale, streamlined approach was deemed to be a particularly efficient way of providing reliable evidence about whether treatments believed to work and be safe against Covid-19 can actually live up to their potential. It builds upon lessons learnt in attempts to treat Ebola, where delays setting up clinical trials hampered efforts in treating this highly infectious viral disease.
The world’s largest Covid-19 trial
Empowered by the flexibility of the regulators, the first patient was enrolled only nine days after the pair wrote the RECOVERY trial protocol. According to Landray, it usually takes a minimum of nine months for this step to be completed.
Two months later, more than 10,000 patients are participating at almost 180 trial sites across all four countries of the UK, making it by far the largest global trial for Covid-19. Landray notes that this represents around one in seven of all Covid-19 patients in UK, emphasising that this is truly an “all-comers trial” since all patients with suspected or confirmed Covid-19, including children and neo-nates, are eligible for inclusion.
There are six drugs currently being studied in the RECOVERY trial. Although the trial’s co-chairs, Landray and Horby, do not know details about how the trial is progressing – that is the remit of the independent data monitoring committee (DMC) – interim results are expected at the end of June. If the science supports the drug, “we will tell the world, so the drugs can be used in routine care,” notes Landray.
This is precisely what happened in mid-May when interim data suggested that one of the drugs being studied, the steroid dexamethasone, reduced death from Covid-19 in one third of hospitalised patients on ventilators and one fifth of patients on oxygen.
The UK Government’s chief scientific adviser Sir Patrick Vallance noted: “This is tremendous news…showing that dexamethasone is the first drug to reduce mortality from Covid-19. It is particularly exciting as this is an inexpensive widely available medicine. This is a ground-breaking development in our fight against the disease.”
Spotlight on treatments being studied
“The choice of drugs was really determined by the prioritisation activities of the WHO [World Health Organization] and the UK Governments,” Landray notes. The criteria were “the treatment had to have some suggestion it was likely to work – whether from laboratory works or from other viral settings – we had to understand the safety issues [and] there had to be enough [supply of the] drug available to do a large trial [and for it to potentially] be scaled up as a real treatment globally.”
When the RECOVERY trial first began in mid to late March, only two drugs were included: lopinavir/ritonavir and dexamethasone.
“Lopinavir/ritonavir is a HIV treatment, [but] there’s been some suggestion it works in other respiratory viral infections,” Landray explains. “Dexamethasone is a corticosteroid, which is used widely in a number of respiratory conditions to dampen inflammation, particularly in the lungs.”
The design of the study is flexible so that other potential treatments can be included if they meet the criteria. In addition, those treatments that are shown to be ineffective can be abandoned. In late June, the RECOVERY trial chief investigators announced that lopinavir-ritonavir brought no clinical benefit to patients with Covid-19 and so closed randomisation of that arm.
The third therapy included in RECOVERY was the anti-malarial hydroxychloroquine. This drug has received an enormous amount of international attention, primarily due to US President Donald Trump championing the medicine. However, in recent weeks, a number of studies have emerged suggesting hydroxychloroquine is not as effective or safe for Covid-19 patients as initially hoped.
Although a review of data on 24 May by the DMC suggested there was: “no cogent reason to suspend recruitment for safety reasons”, following further requests from the UK’s medicines regulator, the DMC re-evaluated the results, which led the chief investigators to stop enrolling patients into this arm of the trial. Horby noted: “The RECOVERY Trial has shown that hydroxychloroquine is not an effective treatment in patients hospitalised with COVID-19. Although it is disappointing that this treatment has been shown to be ineffective, it does allow us to focus care and research on more promising drugs.”
In light of these concerns, which pushed the World Health Organization to halt its trials of the anti-malarial, the RECOVERY trial’s DMC reviewed the clinical evidence from the hydroxychloroquine arm of the trial and found “no cogent reason to suspend recruitment for safety reasons” on 24 May.
Next to enter the trial was azithromycin, which is usually as an antibiotic, but as Landray explains: “It has anti-inflammatory properties, which might be useful in the context of viral infection.”
Adding a fifth and sixth candidate
The fifth drug is tocilizumab, a drug targeted at interleukin-6, which is used to treat rheumatoid arthritis. It is believed to be effective against the cytokine storm that has been found to be deadly in Covid-19 patients. Roche manufacturers this drug under the brand name Actemra and is also studying it in a Phase III study in the US to treat the cytokine storm.
The sixth, and at the time of writing, final, therapeutic approach to be added into trial was convalescent plasma infusions from donations made by recovered Covid-19 patients.
The trial protocol explained this approach has been used to treat severe viral pneumonias and SARS-CoV infections in the 2003 SARS outbreak.
In the study, patients have been randomised to receive one of five drugs – lopinavir/ritonavir, dexamethasone, hydroxychloroquine, azithromycin and convalescent plasma – or placebo; this approach makes it easy for more treatment arms to be added. For those who have more severe disease and are particularly ill, they can be randomised into the tocilizumab arm.
Benefits of a large, streamlined trial
By studying multiple drugs in one trial, rather than studying them all separately, “there are huge operational efficiencies; you only have to get one set of approvals, we have one collection of sites, we do one set of training,” notes Landray. “There is a history in previous epidemics to do multiple trials. That is a mistake because the outcomes that matter are things like death and you need very large numbers [to measure that]. If you ask multiple questions and you’re not careful, you end up answering none of them.”
He adds: “[Another advantage is] one control group can be used for several different comparisons, so the number of patients we need is a bit smaller.”
“There are not likely to be any treatments with substantial effects, it is much more likely that each treatment has a small or modest effect,” Landray explains.
However, by studying multiple drugs in one trial, you might find more than one drug with a modest effect, and you could start to combine them, thereby reducing the death rate from Covid-19 more significantly.
Dedication of hospitals and frontline staff
In addition to the efficiencies created by having a multi-drug approach, further productivity comes from the RECOVERY trial’s particularly streamlined methods.
The researchers are collecting only data on the endpoints that really matter – survival and the need for a ventilator – and have created a consent form that is easy to use.
This reduces the burden on already ridiculously busy doctors who are carrying out the trial itself, therefore helping to facilitate cooperation even by the most overloaded hospitals, according to the trial protocol.
The scale of enrolment into the trial has been “truly unprecedented” and it is “a testament to the enthusiasm of all the clinical staff on the ground,” Landray states.
Although moving quickly has been a real challenge and required an enormous amount of work from doctors and hospitals, Landray explains: “it has been phenomenal how people from different groups have come together in the face of enormous adversity.” This trial is “an enormous credit to the UK, it shows the strength of just how set-up the UK system is for serious, large, well-conducted, randomised clinical trials.”
Bringing the price of trials down
This streamlined approach has also significantly reduced the cost of this clinical trial, compared to traditional clinical trials. “Many trials in pharma cost half a billion to a billion dollars; that’s madness. This trial cost a fraction of the price as people really focused on what matters” in terms of outcomes, Landray notes. The precise cost of this trial to date is unknown, but it is being financially supported by the UK Government through the National Institute for Health Research, as well as the Wellcome Trust, Gates Foundation and Health Data Research UK, among others.
Looking to the future, Landray concludes: “What we need to do now is make sure that we take those lessons and efforts from Covid-19 and bottle that magic for the future.”