Case study: The UK's flagship COVID-19 treatment trial - the RECOVERY trial
The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial launched in the early stages of the global coronavirus outbreak while there were no proven treatments for COVID-19. It aims to rapidly identify a range of potential therapies and assess if they can improve health outcomes for hospitalised patients.
A number of drugs have already been investigated through this flagship, NIHR-supported treatment study - which has generated practice changing evidence in record time. Many more potential treatments are currently in the process of being assessed and the RECOVERY study is continuing to recruit eligible participants across the UK.
The study is jointly funded between UK Research and Innovation (UKRI) and the NIHR - and is sponsored by University of Oxford.
RECOVERY was one of the first COVID-19 studies to be prioritised as urgent public health research by the Department of Health and Social Care. Consequently, delivery was expedited with the NIHR Clinical Research Network (CRN) playing a key role to set up the study in record time. The results speak for themselves:
- the first participant was recruited just 16 days after funding was awarded
- within the first two weeks 1,000 participants were recruited
- within three months 12,000 participants had been recruited from 176 different hospitals.
The RECOVERY trial is currently the world’s largest trial of potential COVID-19 treatments.
Chief investigator of the study, Professor Peter Horby said: “It’s the infrastructure in this country – the NHS and the National Institute of Health Research, who funded RECOVERY – that has made this possible.”
RECOVERY uses a multi-arm adaptive study design to assess new and existing/repurposed drugs as they are identified or become available.
The adaptive study design enables the researchers to evaluate multiple treatments at once against the best standard NHS care available (the control group). The data is monitored continually and drugs which are not showing promising results for COVID-19 can be dropped in favour of other drugs that may have potential benefit. This ability to be able to get an early positive, or negative, signal of efficacy has been critical during the pandemic. In addition, studies with an adaptive design are considered more efficient than studies with a fixed design. They have the potential to save both time and resources required for study set-up.
Once enrolled RECOVERY participants are randomly assigned to one of the study’s multiple treatment arms, or to the control group. All participants taking part in the study - whether in the treatment groups, or the control group - receive the best available standard care available in their institution. The study is not blinded - participants are informed which treatment they are receiving.
Participants in each of the treatment groups are assessed through a single follow-up with a researcher/clinician around 28 days after being assigned to one of the treatment groups. Information is collected on a number of patient outcomes. The primary outcome assessed is the 28 day mortality rate after randomisation. Secondary outcomes are the duration of hospitalisation, and whether or not the participants progressed to require mechanical ventilation.
The study is open to patients of all ages as much is still unknown about how and why the most severe disease seems to occur in older patients. Accordingly, the age distribution of participants randomised to the study is extremely wide, with the youngest participant so far aged under one - while the oldest patient to be recruited is 102 years old. The average age of participants in the trial is 66 years old.
You can learn more about how the NIHR supports complex and innovative trials design and delivery on our dedicated web page.
Treatment arms and results
The first drugs/therapies to be investigated through the study were:
- Lopinavir-Ritonavir (commonly used to treat HIV)
- Low-dose Dexamethasone (now only recruiting children)
- Azithromycin (a commonly used antibiotic)
- Hydroxychloroquine (an antimalarial drug)
- Tocilizumab (an anti-inflammatory treatment given by injection)
Additional treatment options were subsequently added to the study, by virtue of the adaptive design:
- REGN-COV2 - a new investigational antiviral antibody treatment and the first specifically designed COVID-19 drug to be investigated through the trial. Monoclonal antibodies are man-made proteins that act like human antibodies in the immune system. REGN-COV2 comprises two monoclonal antibodies (REGN10933 and REGN10987) and was designed specifically by scientists to block infectivity of SARS-CoV-2, the virus that causes COVID-19.
- Convalescent plasma (collected from donors who have recovered from COVID-19 and contains antibodies against the SARS-CoV-2 virus) was included, as it became more widely available as a result of patients beginning to recover from the disease.
- The anti-inflammatory drug tocilizumab was subsequently added as a second possible randomisation, which patients may receive in the event of low oxygen and inflammation being identified.
Since the study launched, an independent Data Monitoring Committee has reviewed emerging data regularly. If the evidence generated for a treatment is sufficient to affect national and global treatment of COVID-19 (i.e. better than current standard of care) results from the study are announced immediately. RECOVERY then continues and compares the remaining study treatments to the new standard of care - it adapts as the science evolves.
Three months after launch, RECOVERY has already made a huge, global impact. Specifically, the study’s evidence around dexamethasone has resulted in this cheap and widely available steroid becoming the world’s first proven drug to reduce mortality for the most seriously ill patients with the disease.
A total of 2,104 patients were randomised to the dexamethasone arm of the study, receiving the drug in low dose, once per day for up to ten days. Data was compared with a further 4,321 patients randomised to usual care alone.
Data reported in the New England Journal of Medicine shows that dexamethasone reduces the risk of dying by one-third in ventilated patients, and by one fifth in patients receiving oxygen only. Overall, dexamethasone reduced the risk of 28-day mortality by 17%. There was no benefit among those patients who did not need respiratory intervention or oxygen.
Significantly, dexamethasone is cheap, widely available internationally and is already on the World Health Organisation’s list of essential medicines - increasing the global impact of this discovery.
Prof Chris Whitty, Chief Medical Officer for England and co-leader of the NIHR said: "This is the most important trial result for COVID-19 so far. It shows significant reduction in mortality in those requiring oxygen or ventilation from a widely available, safe and well known drug. We should all be grateful to the patients who volunteered and those who made this trial possible. It will save lives around the world.”
As a direct result of the study - dexamethasone is now used across the NHS as a standard treatment for COVID-19 patients requiring ventilation or oxygen across the UK.
In addition the study has shown that other drugs previously touted as potential treatments for COVID-19 are not clinically effective. The study found no clinical benefit for hospitalised COVID-19 patients receiving the antiviral medications hydroxychloroquine or lopinavir-ritonavir.
The evidence from the RECOVERY trial has shown hydroxychloroquine, once considered a promising therapeutic candidate for COVID-19, has no clinical benefit for hospitalised patients.
Professor Peter Horby and Professor Martin Landray, chief investigators of the RECOVERY Trial, said: “There was no significant difference in the primary endpoint of 28-day mortality. There was also no evidence of beneficial effects on hospital stay duration or other outcomes. These data convincingly rule out any meaningful mortality benefit of hydroxychloroquine in patients hospitalised with COVID-19.”
Martin Landray, Professor of Medicine and Epidemiology at the Nuffield Department of Population Health, University of Oxford, and Deputy Chief Investigator, added: “There has been huge speculation and uncertainty about the role of hydroxychloroquine as a treatment for COVID-19, but an absence of reliable information from large randomised trials. The preliminary results from the RECOVERY Trial are quite clear – hydroxychloroquine does not reduce the risk of death among hospitalised patients with this new disease. This result should change medical practice worldwide and demonstrates the importance of large, randomised trials to inform decisions about both the efficacy and the safety of treatments.”
Following a review of the emerging data, the steering committee concluded that there is no beneficial effect of aniti-viral drug lopinavir-ritonavir in patients hospitalised with COVID-19 and closed randomisation to that treatment arm in June 2020.
Professor Martin Landray said: “These are clear results and once again emphasise the value of large randomised clinical trials in differentiating drugs we hope work from treatments we know do work. In many countries, current guidelines recommend lopinavir-ritonavir as a treatment for COVID-19. The results from this trial, together with those from other large randomised trials, should inform revisions to those guidelines and changes to the way individual patients are treated.”
Taking part in the RECOVERY Trial: Graeme's story
A man who beat coronavirus and was among the first participants to enrol in the RECOVERY trial has spoken of how he wanted to “step up” to help with research into treatments for the disease.
Graeme Brammall, from Cromer in Norfolk, was hospitalised for nine days at the Norfolk and Norwich University Hospital at the end of March after contracting the virus and required high dependency care. During his treatment, the 57-year-old was among the first patients to be enrolled onto the RECOVERY trial.
The father-of-six, began feeling ill at home in March. After calling 111 and a visit from a paramedic, he was taken to hospital where he learnt he had coronavirus. He was taken to the high dependency ward, to receive oxygen to help him breath, and quickly agreed to take part in RECOVERY.
He said: “At the end of the day if you can help somebody in life and help save lives, you would. How are they going to find a cure? People have to step up to the mark or we are going to be in the dark ages and not move forward.”