Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection: A Randomized Clinical Trial

Abstract

Importance: Easy-to-administer anti-SARS-CoV-2 treatments may be used to prevent progression from asymptomatic infection to symptomatic disease and to reduce viral carriage.

Objective: To evaluate the effect of combination subcutaneous casirivimab and imdevimab on progression from early asymptomatic SARS-CoV-2 infection to symptomatic COVID-19.

Design, setting, and participants: Randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2-infected index case at 112 sites in the US, Romania, and Moldova enrolled July 13, 2020-January 28, 2021; follow-up ended March 11, 2021. Asymptomatic individuals (aged ≥12 years) were eligible if identified within 96 hours of index case positive test collection. Results from 314 individuals positive on SARS-CoV-2 reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) testing are reported.

Interventions: Individuals were randomized 1:1 to receive 1 dose of subcutaneous casirivimab and imdevimab, 1200 mg (600 mg of each; n = 158), or placebo (n = 156).

Main outcomes and measures: The primary end point was the proportion of seronegative participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy end points were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log10 copies/mL).

Results: Among 314 randomized participants (mean age, 41.0 years; 51.6% women), 310 (99.7%) completed the efficacy assessment period; 204 were asymptomatic and seronegative at baseline and included in the primary efficacy analysis. Subcutaneous casirivimab and imdevimab, 1200 mg, significantly prevented progression to symptomatic disease (29/100 [29.0%] vs 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% CI, 0.30-0.97]; P = .04; absolute risk difference, -13.3% [95% CI, -26.3% to -0.3%]). Casirivimab and imdevimab reduced the number of symptomatic weeks per 1000 participants (895.7 weeks vs 1637.4 weeks with placebo; P = .03), an approximately 5.6-day reduction in symptom duration per symptomatic participant. Treatment with casirivimab and imdevimab also reduced the number of high viral load weeks per 1000 participants (489.8 weeks vs 811.9 weeks with placebo; P = .001). The proportion of participants receiving casirivimab and imdevimab who had 1 or more treatment-emergent adverse event was 33.5% vs 48.1% for placebo, including events related (25.8% vs 39.7%) or not related (11.0% vs 16.0%) to COVID-19.

Conclusions and relevance: Among asymptomatic SARS-CoV-2 RT-qPCR-positive individuals living with an infected household contact, treatment with subcutaneous casirivimab and imdevimab antibody combination vs placebo significantly reduced the incidence of symptomatic COVID-19 over 28 days.

Trial registration: ClinicalTrials.gov Identifier: NCT04452318.

Conflict of interest statement

Conflict of Interest Disclosures: Drs O’Brien, Isa, Turner, Hamilton, and Herman are Regeneron employees/stockholders and have a patent pending, which has been licensed and is receiving royalties, with Regeneron. Drs Forleo-Neto, Sarkar, Hou, Chan, Musser, Davis, Ramesh, Mahmood, Kim, DiCioccio, Lipsich, Braunstein, and Weinreich and Ms Kowal are Regeneron employees/stockholders. Dr Barnabas reported receiving grants from the National Institutes of Health (NIH) and the Bill and Melinda Gates Foundation and receiving support for conference abstract and manuscript writing from Regeneron. Dr Barouch reported receiving grants from the NIH, DAPRA, MassCPR, the Bill and Melinda Gates Foundation, South Africa MRC, the Henry M. Jackson Foundation, the Musk Foundation, Janssen Pharmaceuticals, Gilead Sciences Inc, Legend, CureVac, Sanofi, Intima, Alkermes, and Zentalis; receiving personal fees from SQA, Pfizer Inc, Celsion, Laronde, Meissa, Vector Sciences, and Avidea; and authorship on current manuscripts/abstracts. Dr Cohen reported receiving study funding from the NIH, study drugs from Regeneron, manuscript writing support from Prime Global Options, and leadership roles with the HIV Prevention Trial Network, the COVID-19 Prevention Network (CoVPN), Fogarty, and McGill. Dr Hurt reported receiving grants from the National Institute of Allergy and Infectious Diseases (NIAID), support for manuscript writing from Regeneron, salary support for University of North Carolina Chapel Hill activities sponsored by Gilead Sciences, and an honorarium for developing content for a continuing education program with PRIME Education LLC. Dr Marovich reported being a federal employee who, as part of USG, through Operation Warp Speed, supported the clinical trial network involved in implementation of this effort. Dr Heirman reported being a Merck stockholder and a consultant for Regeneron. Dr Brown reported receiving study funding from the NIH and the Bill & Melinda Gates Foundation; receiving personal fees from the University of North Carolina and the Centers for Disease Control and Prevention; and serving on a data and safety monitoring board for Merck for which payment has been received for her role. Dr Hooper is a Regeneron employee/stockholder, is a former Pfizer employee and current stockholder, and has a patent pending, which has been licensed and is receiving royalties, with Regeneron. Dr Purcell is a Vir Biotechnology employee/stockholder and former Regeneron employee and current stockholder. Drs Baum, Kyratsous, Stahl, and Yancopoulos have issued patents (US patent Nos. 10 787 501, 10 954 289, and 10 975 139) and pending patents, which have been licensed and are receiving royalties, with Regeneron. No other disclosures were reported.

Figures

Figure 1.. Flow of Participants Through the Trial

aIndividuals who were randomized and were negative for SARS-CoV-2 by reverse transcriptase–quantitative polymerase chain reaction were included in Part A (n = 2621); individuals whose SARS-CoV-2 status at baseline was undetermined (ie, inconclusive or missing results) were not included in either Part A or Part B (n = 94). bOne randomized participant in the CAS/IMD group and 2 randomized participants in the placebo group were determined after randomization to have been symptomatic at baseline and were excluded from the primary analysis. This is the seronegative modified full analysis set.

Figure 2.. Prevention of Progression From Asymptomatic SARS-CoV-2 Infection to Symptomatic COVID-19 With Subcutaneous Casirivimab and Imdevimab

Analyses were conducted using the seronegative modified full analysis set. A, Cumulative incidence of time to first symptomatic infection within 14 days of a positive reverse transcriptase–quantitative polymerase chain reaction result at baseline or during the efficacy assessment period. B, Duration of symptomatic infection. The box tops and bottoms represent the interquartile range; horizontal bars within boxes, median; and diamonds, mean. Individual participant data are represented by circles.

Figure 3.. Reduction in SARS-CoV-2 Viral Load With Subcutaneous Casirivimab and Imdevimab

Analyses were conducted using the seronegative modified full analysis set. Only nonmissing available nasopharyngeal swab viral load data were used for the analysis of viral load end points. Only participants with at least 1 postbaseline viral load data point (in nasopharyngeal swab samples) were included in the analyses. A, Percentage of participants with high nasopharyngeal viral load (>4 log10 copies/mL) by duration. B, Viral load over time, and C, peak viral load postbaseline during the efficacy assessment period. The box tops and bottoms represent the interquartile range; horizontal bars within boxes, median; and diamonds, mean. Individual participant data are represented by circles.