Association of subcutaneous or intravenous route of administration of casirivimab and imdevimab monoclonal antibodies with clinical outcomes in COVID-19

Abstract

ImportanceMonoclonal antibody (mAb) treatment decreases hospitalization and death in outpatients with mild to moderate COVID-19; however, only intravenous administration has been evaluated in randomized clinical trials of treatment. Subcutaneous administration may expand outpatient treatment capacity and qualified staff available to administer treatment, but association with patient outcomes is understudied.ObjectiveTo evaluate whether or not, i.) subcutaneous casirivimab and imdevimab treatment is associated with reduced 28-day hospitalization/death than non-treatment among mAb-eligible patients, and ii.) subcutaneous casirivimab and imdevimab treatment is clinically and statistically similar to intravenous casirivimab and imdevimab treatment.Design, Setting, and ParticipantsProspective cohort study of outpatients in a learning health system in the United States with mild to moderate COVID-19 symptoms from July 14 to October 26, 2021 who were eligible for mAb treatment under emergency use authorization. A nontreated control group of eligible patients was also selected.InterventionSubcutaneous injection or intravenous administration of the combined single dose of casirivimab 600mg and imdevimab 600mg.Main Outcomes and MeasuresThe primary outcome was the 28-day adjusted risk ratio or adjusted risk difference for hospitalization or death. Secondary outcomes included 28-day adjusted risk ratios/differences of hospitalization, death, composite endpoint of ED admission and hospitalization, and rates of adverse events.ResultsAmong 1,956 matched adults with mild to moderate COVID-19, patients who received casirivimab and imdevimab subcutaneously had a 28-day rate of hospitalization/death of 3.4% (n=652) compared to 7.8% (n=1,304) in nontreated controls [risk ratio 0.44 (95% confidence interval: 0.28 to 0.68, p < .001)]. Among 2,185 patients treated with subcutaneous (n=969) or intravenous (n=1,216) casirivimab and imdevimab, the 28-day rate of hospitalization/death was 2.8% vs. 1.7%, respectively which resulted in an adjusted risk difference of 1.5% (95% confidence interval: -0.5% to 3.5%, p=.14). The 28-day adjusted risk differences (subcutaneous – intravenous) for death, ICU admission, and mechanical ventilation were 0.3% or less, although the 95% confidence intervals were wide.Conclusions and RelevanceSubcutaneously administered casirivimab-imdevimab is associated with reduced risk-adjusted hospitalization or death amongst outpatients with mild to moderate COVID-19 compared to no treatment and indicates low adjusted risk difference compared to patients treated intravenously.Key PointsQuestionAmong outpatients with mild to moderate COVID-19, is subcutaneously administered casirivimab and imdevimab associated with improved risk-adjusted 28-day clinical outcomes compared to non-treatment with monoclonal antibodies, and clinically similar association compared to intravenously administered casirivimab and imdevimab?FindingsAmong 1,956 propensity-matched adults, outpatients who received casirivimab and imdevimab subcutaneously had a 28-day rate of hospitalization or death of 3.4% (n=652) compared to 7.8% (n=1,304) in non-treated controls [risk ratio 0.44 (95% confidence interval: 0.28 to 0.68, p < .001)]. Among 2,185 outpatients who received subcutaneous (n=969) or intravenous (n=1,216) casirivimab and imdevimab, the 28-day rate of hospitalization/death was 2.8% vs. 1.7%, respectively, which resulted in an adjusted risk difference of 1.5% (95% confidence interval: -0.5% to 3.5%, p=.14). The 28-day adjusted risk differences comparing subcutaneous to intravenous route for death, ICU admission, and mechanical ventilation were 0.3% or less, although the 95% confidence intervals were wide.MeaningSubcutaneously administered casirivimab and imdevimab is associated with reduced hospitalization or death amongst outpatients with mild to moderate COVID-19 compared to no treatment, and has a small, adjusted risk difference compared to patients treated intravenously.

Real-world Effectiveness of Casirivimab and Imdevimab in Patients With COVID-19 in the Ambulatory Setting: An Analysis of Two Large US National Claims Databases

“…Importantly, treatment with CAS+IMD appeared to have a benefit on mortality in the CDM cohort, as the 30-day estimated risk of death was much lower in the treated than untreated patients. These results further support the public health implications of this therapy, and are consistent with the real-world studies that also suggested lower mortality in patients who received mAb treatment [9,11,15,16], albeit in variants susceptible to such therapy.…”

“…Evidence from several real-world studies suggests that appropriate treatment with CAS+IMD was associated with an incidence of hospitalizations that may be 50%-90% lower than among untreated patients [4,5,8,9,16,23]. The magnitude of effects observed in the current study fell within that range and, additionally, demonstrated greater benefits among those at higher risk.…”

“…While multiple studies have reported on the real-world effectiveness of CAS+IMD [4][5][6][7][8][9][10][11][12][13][14][15][16], most only included a small number of CAS+IMD-treated patients, generally evaluating the early experience with monoclonal antibodies (mAbs), were single-center, and did not have sufficient sample size to assess effectiveness of CAS+IMD across various patient subgroups. Studies leveraging large databases with sufficient counts to assess the effectiveness of CAS+IMD in subgroups of patients at higher risk of poor outcomes are needed.…”

Real-World Effectiveness of Casirivimab and Imdevimab Among Patients Diagnosed With COVID-19 in the Ambulatory Setting: A Retrospective Cohort Study Using a Large Claims Database

“…Such activity was previously suggested by in vitro studies 5,13-16 and smaller real-world studies that reported its effectiveness for reducing all-cause hospitalization or mortality. 30,31…”

“…[10][11][12] In vitro studies suggested that CAS+IMD retains neutralization activity against most VOC including Delta but with the exception of Omicron (B.1.1.529). 5,[13][14][15][16][17] Most real-world studies assessing the effectiveness of CAS+IMD for treating COVID-19 [18][19][20][21][22][23][24][25][26][27][28][29][30] were conducted prior to Delta, and those that did overlap with the emergence of the Delta variant were single-center and of small sample size. 19,30,31 Furthermore, with the introduction of COVID-19 vaccines, an improved understanding of vulnerable groups, and the emergence of the Delta variant, it became important to evaluate the effectiveness of CAS+IMD across these patient subgroups.…”