RECOVERY Trial: Efficacy and Safety of Casirivimab and Imdevimab Combination in Hospitalized COVID-19 Patients

8 Mar, 22

Introduction

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

Aim

Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial evaluated the efficacy and safety of casirivimab and imdevimab administered in combination in patients admitted to hospital with COVID-19

Patient Profile

Patients aged at least 12 years admitted to hospital with clinically suspected or laboratory-confirmed SARS-CoV-2 infection

Methods

Randomised, controlled, open-label platform trial
9785 randomly assigned between casirivimab and imdevimab, and usual care
- 4839 assigned casirivimab and imdevimab plus usual care
- 4946 assigned usual care alone

Study Treatment

Patients allocated to the antibody combination received a single dose of casirivimab 4 g and imdevimab 4 g administered together in 250 ml 0·9% saline infused intravenously over 60 min (plus or minus 15 min) as soon as possible after randomisation.

Study Endpoints

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 (i.e., those who were seronegative) and then in the overall population
Safety was assessed in all participants who received casirivimab and imdevimab

Results

5272 (54%) patients were seropositive at baseline, 3153 (32%) were seronegative, and serostatus was unknown for 1360 (14%)
In patients seronegative at baseline, casirivimab and imdevimab was associated with a significant reduction in the primary outcome of 28-day mortality compared with usual care alone

Figure 1: Primary endpoint: Mortality at 28 days

Casirivimab and imdevimab was associated with an increased rate of discharge alive from hospital within the first 28 days and a reduced rate of progression to invasive mechanical ventilation or death in seronegative patients

Table 1: Secondary Outcomes

	Casirivimab and imdevimab (n=1633)	Usual care (n=1520)	RR
Median duration of hospitalisation, days	13 (7 to >28)	17 (7 to >28)	··
Discharged from hospital within 28 days	1049 (64%)	878 (58%)	1·19
Invasive mechanical ventilation or death*	488/1599 (31%)	544/1484 (37%)	0·83
Invasive mechanical ventilation	190/1599 (12%)	202/1484 (14%)	0·87
Death	383/1599 (24%)	435/1484 (29%)	0·82
Subsidiary outcomes
Use of ventilation^†	360/1267 (28%)	373/1143 (33%)	0·87
Non-invasive ventilation	348/1267 (27%)	362/1143 (32%)	0·87
Invasive mechanical ventilation	90/1267 (7%)	120/1143 (10%)	0·68
Successful cessation of invasive mechanical ventilation^‡	10/34 (29%)	10/36 (28%)	1·19
Renal replacement therapy^§	67/1614 (4%)	65/1498 (4%)	0·96

Data are n (%), or n/N (%). RR=rate ratios for the outcomes of 28-day mortality, hospital discharge, and successful cessation of invasive mechanical ventilation, and risk ratios for other outcomes.^*Excluding patients receiving invasive mechanical ventilation at randomisation. ^†Excluding patients receiving invasive or non-invasive ventilation at randomisation. ^‡Excluding patients not receiving invasive mechanical ventilation at randomisation. ^§Excluding patients receiving renal replacement therapy at randomisation.

The proportional effect of casirivimab and imdevimab on mortality differed significantly between seropositive and seronegative patients (p value for heterogeneity=0·002)

Table 2: Primary and secondary outcomes, overall and by baseline antibody status

	Casirivimab and imdevimab	Usual care	RR
Death within 28 days (?²₁=9·8; p=0·002)
Seronegative	24%	30%	0·79
Seropositive	16%	15%	1·09
Unknown	24%	24%	0·97
All participants	19%	21%	0·94
Discharge alive from hospital (?²₁=17·2; p<0·001)
Seronegative	64%	58%	1·19
Seropositive	75%	77%	0·94
Unknown	63%	64%	0·96
All participants	70%	69%	1·02
Invasive mechanical ventilation or death (?²₁= 12·5; p<0·001)
Seronegative	31%	37%	0·83
Seropositive	19%	17%	1·10
Unknown	29%	28%	1·05
All not on invasive mechanical ventilation at randomisation	24%	25%	0·97

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

Conclusion

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
The results support the use of the monoclonal neutralising antibody 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

Reference

Lancet 2022; 399: 665–76