Casirivimab and imdevimab in patients admitted to hospital with COVID-19: RECOVERY Trial

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. RECOVERY is a randomized, controlled, open-label platform trial comparing several possible treatments with usual care in patients admitted to hospital with COVID-19. The current study is aimed to evaluate the efficacy and safety of casirivimab and imdevimab administered in combination in patients admitted to hospital with COVID-19.

Study Design:

• Eligibility criteria: Patients admitted to the hospital were eligible for the study if they had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might put the patient at significant risk.
• Total 9785 patients enrolled among which 4839 were randomly assigned to casirivimab and imdevimab plus usual care and 4946 to usual care alone.
• Primary outcome: 28-day all-cause mortality assessed by intention to treat, first only in patients without detectable antibodies to SARS-CoV-2 infection at randomization (ie, those who were seronegative) and then in the overall population.
• Secondary outcomes: Time to discharge from hospital, and, in patients not on invasive mechanical ventilation at randomisation, the composite outcome of invasive mechanical ventilation (including ECMO) or death.
• Safety was assessed in all participants who received casirivimab and imdevimab.

Results:

Baseline Characteristics:

• At randomisation, 5272 (54%) were seropositive at baseline, 3153 (32%) were seronegative, and serostatus was unknown for 1360 (14%).
• Other COVID-19 treatments was similar among patients allocated casirivimab and imdevimab and among those allocated usual care, with about 25% receiving remdesivir and about 15% receiving tocilizumab or sarilumab.

Primary Outcome:

• In the primary efficacy population of seronegative patients, 396 (24%) of 1633 patients allocated to casirivimab and imdevimab vs. 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). Significant redction by 20%
• If treated with Usual care only, seronegative patients had twice the risk of death of seropositive patients (30% vs 15% mortality)
• Casirivimab and imdevimab significantly reduced mortality in seronegative patients by 20% (absolute benefit: from 30% to 24% mortality).
• The proportional effect of casirivimab and imdevimab on mortality differed significantly between seropositive and seronegative patients (p =0·002).
• In all randomly assigned patients, there was no significant difference in the primary outcome. 943 (19%)/4839 patients of casirivimab and imdevimab vs. 1029 (21%)/4946 patients of usual care died within 28 days (RR 0·94, 95% CI 0·86–1·02; p=0·14).
• In seronegative patients, discharge alive within 28 days was more common in casirivimab and imdevimab than usual care group patients.

Secondary Outcome:

• The proportional effects of casirivimab and imdevimab on the secondary outcomes of discharge alive from hospital and invasive mechanical ventilation or death differed significantly between seropositive and seronegative patients (p <0·001).
• In seronegative patients not on invasive mechanical ventilation at baseline, casirivimab and imdevimab was associated with a lower risk of progressing to the composite secondary outcome of invasive mechanical ventilation or death.

Safety:

• In the overall study population;

    Frequency of fever (in 79 [4%] of 1792 vs 52 [3%] of 1715)

    Sudden hypotension (66 [4%] vs 39 [2%]),

• Thrombotic events (31 [2%] vs 24 [1%]) was numerically higher in the casirivimab and imdevimab group vs usual care group,
• While frequency of sudden worsening in respiratory status (369 [21%] vs 372 [22%]) and clinical haemolysis (26 [1%] vs 31 [2%]) was numerically lower casirivimab and imdevimab group vs usual care group.
• Serious adverse reactions reported in seven (<1%) participants were believed to be related to treatment with casirivimab and imdevimab.

Conclusion:

This randomised trial result support the use of combination of casirivimab and imdevimab in seronegative patients admitted to hospital with COVID-19 caused by SARS-CoV-2 variants that are sensitive to these antibodies.

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Reference: RECOVERY Collaborative Group. Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2022 Feb 12;399(10325):665-676. doi: 10.1016/S0140-6736(22)00163-5.

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