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

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.

Figure 1

Trial profile Casirivimab and imdevimab unavailable and casirivimab and imdevimab unsuitable groups are not mutually exclusive. *Number recruited overall during the period that adult participants could be recruited into the casirivimab and imdevimab comparison. †Includes patients allocated to tocilizumab. Until Jan 24, 2021, tocilizumab was allocated via the second randomisation to 185 (4%) of 4839 patients allocated casirivimab and imdevimab and to 271 (5%) of 4946 patients allocated to usual care.

Figure 2

Effect of allocation to casirivimab and imdevimab on 28-day mortality in (A) seronegative patients versus seropositive patients and (B) all participants overall RR=rate ratio.

Figure 3

Primary and secondary outcomes, overall and by baseline antibody status Subgroup-specific RR estimates are represented by squares (with areas of the squares proportional to the amount of statistical information) and the lines through them correspond to the 95% CIs. Open squares represent participants with unknown status, solid squares represent participants with known status. The tests for heterogeneity (ie, χ²₁) compare the log RRs in the seronegative versus seropositive subgroups (ie, excluding those with unknown antibody status). Excluded participantsare included in the overall summary diamonds. RR=risk ratio for the composite outcome of invasive mechanical ventilation or death, and rate ratio for the other outcomes.

Figure 4

Effect of allocation to casirivimab and imdevimab on 28-day mortality by baseline characteristics in seronegative patients Subgroup-specific RR estimates are represented by squares (with areas of the squares proportional to the amount of statistical information) and the lines through them correspond to the 95% CIs. The ethnicity, days since onset, and use of corticosteroids subgroups exclude patients with missing data, but these patients are included in the overall summary diamond. RR=rate ratio. χ²₁=test for heterogeneity or trend.