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Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

RECOVERY Collaborative Group; Horby, Peter W; Mafham, Marion; Peto, Leon; Campbell, Mark; Pessoa-Amorim, Guilherme; Spata, Enti; Staplin, Natalie; Emberson, Jonathan R; Prudon, Benjamin; Hine, Paul; Brown, Thomas; Green, Christopher A; Sarkar, Rahuldeb; Desai, Purav; Yates, Bryan; Bewick, Tom; Tiberi, Simon; Felton, Tim; Baillie, J Kenneth; Buch, Maya H; Chappell, Lucy C; Day, Jeremy N; Faust, Saul N; Jaki, Thomas; Jeffery, Katie; Juszczak, Edmund; Lim, Wei Shen; Montgomery, Alan; Mumford, Andrew; Rowan, Kathryn; Thwaites, Guy; Weinreich, David M; Haynes, Richard; Landray, Martin J

Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial Thumbnail


Authors

RECOVERY Collaborative Group

Peter W Horby

Marion Mafham

Leon Peto

Mark Campbell

Guilherme Pessoa-Amorim

Enti Spata

Natalie Staplin

Jonathan R Emberson

Benjamin Prudon

Paul Hine

Thomas Brown

Christopher A Green

Rahuldeb Sarkar

Purav Desai

Bryan Yates

Tom Bewick

Simon Tiberi

Tim Felton

J Kenneth Baillie

Maya H Buch

Lucy C Chappell

Jeremy N Day

Saul N Faust

Thomas Jaki

Katie Jeffery

Wei Shen Lim

ALAN MONTGOMERY ALAN.MONTGOMERY@NOTTINGHAM.AC.UK
Director Nottingham Clinical Trials Unit

Andrew Mumford

Kathryn Rowan

Guy Thwaites

David M Weinreich

Richard Haynes

Martin J Landray



Abstract

Background: Casirivimab and imdevimab are non-competing monoclonal antibodies that bind to two different sites on the receptor binding domain of the SARS-CoV-2 spike glycoprotein, blocking viral entry into host cells. We aimed to evaluate the efficacy and safety of casirivimab and imdevimab administered in combination in patients admitted to hospital with COVID-19. Methods: RECOVERY is a randomised, controlled, open-label platform trial comparing several possible treatments with usual care in patients admitted to hospital with COVID-19. 127 UK hospitals took part in the evaluation of casirivimab and imdevimab. Eligible participants were any patients aged at least 12 years admitted to hospital with clinically suspected or laboratory-confirmed SARS-CoV-2 infection. Participants were randomly assigned (1:1) to either usual standard of care alone or usual care plus casirivimab 4 g and imdevimab 4 g administered together in a single intravenous infusion. Investigators and data assessors were masked to analyses of the outcome data during the trial. The primary outcome was 28-day all-cause mortality assessed by intention to treat, first only in patients without detectable antibodies to SARS-CoV-2 infection at randomisation (ie, those who were seronegative) and then in the overall population. Safety was assessed in all participants who received casirivimab and imdevimab. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between Sept 18, 2020, and May 22, 2021, 9785 patients enrolled in RECOVERY were eligible for casirivimab and imdevimab, of which 4839 were randomly assigned to casirivimab and imdevimab plus usual care and 4946 to usual care alone. 3153 (32%) of 9785 patients were seronegative, 5272 (54%) were seropositive, and 1360 (14%) had unknown baseline antibody status. 812 (8%) patients were known to have received at least one dose of a SARS-CoV-2 vaccine. In the primary efficacy population of seronegative patients, 396 (24%) of 1633 patients allocated to casirivimab and imdevimab versus 452 (30%) of 1520 patients allocated to usual care died within 28 days (rate ratio [RR] 0·79, 95% CI 0·69–0·91; p=0·0009). In an analysis of all randomly assigned patients (regardless of baseline antibody status), 943 (19%) of 4839 patients allocated to casirivimab and imdevimab versus 1029 (21%) of 4946 patients allocated to usual care died within 28 days (RR 0·94, 95% CI 0·86–1·02; p=0·14). The proportional effect of casirivimab and imdevimab on mortality differed significantly between seropositive and seronegative patients (p value for heterogeneity=0·002). There were no deaths attributed to the treatment, or meaningful between-group differences in the pre-specified safety outcomes of cause-specific mortality, cardiac arrhythmia, thrombosis, or major bleeding events. Serious adverse reactions reported in seven (<1%) participants were believed by the local investigator to be related to treatment with casirivimab and imdevimab. Interpretation: In patients admitted to hospital with COVID-19, the monoclonal antibody combination of casirivimab and imdevimab reduced 28-day mortality in patients who were seronegative (and therefore had not mounted their own humoral immune response) at baseline but not in those who were seropositive at baseline. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

Citation

RECOVERY Collaborative Group, Horby, P. W., Mafham, M., Peto, L., Campbell, M., Pessoa-Amorim, G., …Landray, M. J. (2022). Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet, 399(10325), 665-676. https://doi.org/10.1016/S0140-6736%2822%2900163-5

Journal Article Type Article
Acceptance Date Dec 16, 2021
Online Publication Date Feb 12, 2022
Publication Date Feb 12, 2022
Deposit Date Feb 11, 2022
Publicly Available Date Feb 11, 2022
Journal The Lancet
Print ISSN 0140-6736
Electronic ISSN 1474-547X
Peer Reviewed Peer Reviewed
Volume 399
Issue 10325
Pages 665-676
DOI https://doi.org/10.1016/S0140-6736%2822%2900163-5
Public URL https://nottingham-repository.worktribe.com/output/5693343
Publisher URL https://www.sciencedirect.com/science/article/pii/S0140673622001635

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