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RECOVERY Trial identifies another effective COVID-19 treatment

16/06/2021
This article is more than two years old.

The RECOVERY Trial, the world's largest randomised trial of potential COVID-19 treatments, has found that a monoclonal antibody combination developed by the US company Regeneron reduces deaths for hospitalised COVID-19 patients who have not mounted their own immune response.

The RECOVERY Trial, which is led from Oxford and supported by the NIHR Oxford Biomedical Research Centre (BRC), was established as a randomised clinical trial to test a range of potential treatments for patients hospitalised with COVID-19. It has now recruited more than 40,000 patients across 181 sites.

The Regeneron treatment uses a combination of two monoclonal antibodies (casirivimab and imdevimab, known as REGEN-COV in the US) that bind specifically to two different sites on the coronavirus spike protein, neutralising the ability of the virus to infect cells.

Previous studies in non-hospitalised COVID-19 patients showed that the treatment reduces viral load, shortened the time to resolution of symptoms, and significantly reduces the risk of hospitalisation or death.

In a small trial in hospitalised patients, preliminary evidence suggested a clinical benefit in patients who were seronegative, that is, they had not mounted a natural antibody response of their own when they entered the trial. RECOVERY is the first trial large enough to determine definitively whether this treatment reduces mortality in patients hospitalised with severe COVID-19.

Between 18 September 2020 and 22 May 2021, 9,785 patients hospitalised with COVID-19 were randomly allocated to receive usual care plus the antibody combination treatment by intravenous infusion, or usual care alone as part of the trial.

Of these, about one-third were seronegative, half were seropositive (they had already developed natural antibodies) and one-sixth had unknown serostatus. Among patients who received usual care alone, 28-day mortality was twice as high in those who were seronegative (30 percent) as those who were seropositive (15 percent) on entering the study.

Among patients who were seronegative at baseline, the antibody combination reduced 28-day mortality by one-fifth, compared with usual care alone (24 percent of patients in the antibody combination group died vs. 30 percent of patients in the usual care group). So, for every 100 such patients treated with the antibody combination, there would be six fewer deaths.

There was clear evidence that the effect of treatment in seronegative patients differed from that in seropositive patients. When combining the larger seropositive group (as well as those with unknown status) with the seronegative patients, there was no longer a significant effect on 28-day mortality (overall 20 percent of patients in the antibody combination group died vs. 21 percent of patients in the usual care group).

For the seronegative patients, the duration of hospital stay was four days shorter (around 13 days compared to 17 days) among those allocated to the antibody combination than the usual care group, and the proportion of patients discharged alive by day 28 was greater (64 percent vs. 58 percent).

Among the seronegative patients not on invasive mechanical ventilation at baseline, the risk of progressing to the composite endpoint of invasive mechanical ventilation or death was lower among those allocated to the antibody combination than the usual care group (30 percent vs. 37 percent). No such benefits were seen in the overall study population.

Sir Peter Horby, Professor of Emerging Infectious Diseases in the University of Oxford's Nuffield Department of Medicine, and Joint Chief Investigator for the RECOVERY trial, said: "These results are very exciting. The hope was that by giving a combination of antibodies targeting the SARS-CoV-2 virus we would be able to reduce the worst manifestations of COVID-19.

"There was, however, great uncertainty about the value of antiviral therapies in late-stage COVID-19 disease. It is wonderful to learn that even in advanced COVID-19 disease, targeting the virus can reduce mortality in patients who have failed to mount an antibody response of their own."

Joint Chief Investigator Sir Martin Landray, Professor of Medicine and Epidemiology at the University of Oxford's Nuffield Department of Population Health and the Oxford BRC's Theme Lead for Clinical Informatics and Big Data, said: "We now know that this antibody combination is not only bad for the virus but it is also good for the sickest patients who have failed to mount a natural immune response of their own. That is excellent news - it is the first time that any antiviral treatment has been shown to save lives in hospitalised COVID-19 patients. We are incredibly grateful to the many NHS staff and patients who have contributed to today's discovery."

RECOVERY participant, Kimberley Featherstone (37), was treated at Huddersfield Royal Infirmary and Calderdale Royal Hospital and randomly allocated to the monoclonal antiviral antibody combination. She said "I was certainly glad to take part in the RECOVERY Trial. I feel very lucky that the trial was up and running by the time I was taken to hospital with COVID-19, and I was able to receive this ground-breaking treatment. I'm happy that by participating, I played a part in finding out this treatment is successful."

The preliminary results of this evaluation of the monoclonal antibody combination will be available as a pre-print at medRxiv and will be submitted to a leading peer-reviewed medical journal.