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 | JN Learning | AMA Ed Hub [Skip to Content]
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Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 InfectionA Randomized Clinical Trial

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To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  Does treatment with a subcutaneous combination of casirivimab and imdevimab prevent progression to symptomatic COVID-19 when given to recently infected, asymptomatic individuals?

Findings  In this randomized clinical trial that included 314 SARS-CoV-2 reverse transcriptase–quantitative polymerase chain reaction–positive individuals living with an infected household contact, 29.0% of asymptomatic seronegative participants treated with subcutaneous casirivimab and imdevimab, 1200 mg (600 mg of each antibody), developed symptomatic COVID-19 over 28 days vs 42.3% of those treated with placebo. This difference was statistically significant.

Meaning  Treatment with subcutaneous casirivimab and imdevimab antibody combination compared with placebo significantly reduced the incidence of symptomatic COVID-19 among recently exposed, asymptomatic individuals.

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

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Meagan P. O’Brien, MD, Regeneron Pharmaceuticals Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591-6707 (meagan.obrien@regeneron.com).

Correction: This article was corrected for a misspelled collaborator name on May 24, 2022.

Accepted for Publication: December 24, 2021.

Published Online: January 14, 2022. doi:10.1001/jama.2021.24939

Author Contributions: Dr Barnabas had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: O’Brien, Forleo-Neto, Sarkar, Isa, Chan, Musser, Bar, Barnabas, Barouch, Cohen, Hurt, Marovich, Brown, Heirman, Davis, Turner, Ramesh, Mahmood, Hooper, Hamilton, Kim, Purcell, Baum, Kyratsous, Geba, Stahl, Lipsich, Braunstein, Herman, Yancopoulos, Weinreich.

Acquisition, analysis, or interpretation of data: O’Brien, Forleo-Neto, Sarkar, Isa, Hou, Chan, Musser, Barnabas, Barouch, Hurt, Burwen, Marovich, Davis, Turner, Ramesh, Mahmood, Hooper, Hamilton, Purcell, Kyratsous, Krainson, Perez-Perez, Mohseni, Kowal, DiCioccio, Geba, Stahl, Braunstein, Herman, Yancopoulos, Weinreich.

Drafting of the manuscript: O’Brien, Sarkar, Isa, Hou, Musser, Brown, Davis, Turner, Mahmood, Hooper, Kim, Geba, Herman, Weinreich.

Critical revision of the manuscript for important intellectual content: O’Brien, Forleo-Neto, Sarkar, Isa, Hou, Chan, Musser, Bar, Barnabas, Barouch, Cohen, Hurt, Burwen, Marovich, Brown, Heirman, Davis, Turner, Ramesh, Mahmood, Hooper, Hamilton, Purcell, Baum, Kyratsous, Krainson, Perez-Perez, Mohseni, Kowal, DiCioccio, Geba, Stahl, Lipsich, Braunstein, Herman, Yancopoulos, Weinreich.

Statistical analysis: O’Brien, Forleo-Neto, Sarkar, Hou, Chan, Musser, Marovich, Brown, Geba, Weinreich.

Obtained funding: Cohen, Lipsich.

Administrative, technical, or material support: Isa, Chan, Barouch, Hurt, Burwen, Heirman, Davis, Ramesh, Hooper, Purcell, Kowal, Stahl.

Supervision: O’Brien, Forleo-Neto, Sarkar, Isa, Musser, Bar, Barnabas, Barouch, Cohen, Hurt, Brown, Davis, Hamilton, Kyratsous, Perez-Perez, Geba, Lipsich, Braunstein, Herman, Yancopoulos, Weinreich.

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.

Funding/Support: This study was supported by Regeneron Pharmaceuticals Inc and F. Hoffmann-La Roche Ltd. This trial was conducted jointly with the NIAID, NIH. The CoVPN is supported by cooperative agreement awards from the NIAID, NIH. The work on this study was supported by awards UM1AI068619 and UM1AI148684.

Role of the Funder/Sponsor: Regeneron Pharmaceuticals Inc in collaboration with the CoVPN and the NIAID were involved in the design and conduct of the study. Regeneron and CoVPN were involved in the collection and management of data. Regeneron analyzed the data. Regeneron, the NIAID, and the CoVPN were involved in interpretation of the data; were responsible for preparation, review, and approval of the manuscript; and were involved in the decision to submit the manuscript for publication. Regeneron did not have the right to veto publication. The trial sites were funded by Regeneron or were part of the CoVPN, funded by the NIAID.

Group Information: The members of the COVID-19 Phase 3 Prevention Trial Team are listed in Supplement 3.

Disclaimer: The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank the study participants and their families; the investigational site members involved in this trial; the COVID-19 Phase 3 Prevention Trial Team; the members of the data and safety monitoring board; and Prime, Knutsford, England, for formatting and copy editing suggestions. We thank Brian Head, PhD, Caryn Trbovic, PhD, and S. Balachandra Dass, PhD, from Regeneron for assistance with development of an earlier version of the manuscript; they received compensation as employees of Regeneron.

References
1.
Buitrago-Garcia  D , Egli-Gany  D , Counotte  MJ ,  et al.  Occurrence and transmission potential of asymptomatic and presymptomatic SARS-CoV-2 infections: a living systematic review and meta-analysis.   PLoS Med. 2020;17(9):e1003346. doi:10.1371/journal.pmed.1003346PubMedGoogle ScholarCrossref
2.
Centers for Disease Control and Prevention. Clinical Questions About COVID-19: Questions and Answers. Accessed April 23, 2021. https://www.cdc.gov/coronavirus/2019-ncov/hcp/faq.html#Transmission
3.
GISAID. hCov19 Variants. Accessed July 20, 2021. https://www.gisaid.org/hcov19-variants/
4.
Higdon  MM , Wahl  B , Jones  CB ,  et al  A systematic review of COVID-19 vaccine efficacy and effectiveness against SARS-CoV-2 infection and disease.   medRxiv. Preprint posted September 25, 2021. doi:10.1101/2021.09.17.21263549Google Scholar
5.
World Health Organization. Coronavirus (COVID-19) dashboard. Accessed November 2, 2021. https://covid19.who.int/table
6.
Garcia-Beltran  WF , Lam  EC , St Denis  K ,  et al.  Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity.   Cell. 2021;184(9):2372-2383.e9. doi:10.1016/j.cell.2021.03.013PubMedGoogle ScholarCrossref
7.
Boyarsky  BJ , Werbel  WA , Avery  RK ,  et al.  Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients.   JAMA. 2021;325(21):2204-2206. doi:10.1001/jama.2021.7489PubMedGoogle ScholarCrossref
8.
Kreuzberger  N , Hirsch  C , Chai  KL ,  et al.  SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19.   Cochrane Database Syst Rev. 2021;9:CD013825. doi:10.1002/14651858.CD013825.pub2PubMedGoogle ScholarCrossref
9.
Boutron  I , Chaimani  A , Devane  D ,  et al.  Interventions for the prevention and treatment of COVID-19: a living mapping of research and living network meta-analysis.  Published online November 3, 2020.  Cochrane Database Syst Rev. doi:10.1002/14651858.CD013769Google ScholarCrossref
10.
Hansen  J , Baum  A , Pascal  KE ,  et al.  Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail.   Science. 2020;369(6506):1010-1014. doi:10.1126/science.abd0827PubMedGoogle ScholarCrossref
11.
Copin  R , Baum  A , Wloga  E ,  et al.  The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies.   Cell. 2021;184(15):3949-3961. doi:10.1016/j.cell.2021.06.002PubMedGoogle ScholarCrossref
12.
Baum  A , Fulton  BO , Wloga  E ,  et al.  Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies.   Science. 2020;369(6506):1014-1018. doi:10.1126/science.abd0831PubMedGoogle ScholarCrossref
13.
Weinreich  DM , Sivapalasingam  S , Norton  T ,  et al; Trial Investigators.  REGEN-COV antibody combination and outcomes in outpatients with Covid-19.   N Engl J Med. 2021;385(23):e81. doi:10.1056/NEJMoa2108163PubMedGoogle ScholarCrossref
14.
O’Brien  MP , Forleo-Neto  E , Musser  BJ ,  et al; Covid-19 Phase 3 Prevention Trial Team.  Subcutaneous REGEN-COV antibody combination to prevent Covid-19.   N Engl J Med. 2021;385(13):1184-1195. doi:10.1056/NEJMoa2109682PubMedGoogle ScholarCrossref
15.
US Food and Drug Administration. Fact sheet for health care providers—Emergency Use Authorization (EUA) of REGEN-COV (casirivimab and imdevimab). Revised December 2021. Accessed January 6, 2022. https://www.fda.gov/media/145611/download
16.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053Google ScholarCrossref
17.
Magesh  S , John  D , Li  WT ,  et al.  Disparities in COVID-19 outcomes by race, ethnicity, and socioeconomic status: a systematic-review and meta-analysis.   JAMA Netw Open. 2021;4(11):e2134147. doi:10.1001/jamanetworkopen.2021.34147PubMedGoogle ScholarCrossref
18.
Weinreich  DM , Sivapalasingam  S , Norton  T ,  et al; Trial Investigators.  REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19.   N Engl J Med. 2021;384(3):238-251. doi:10.1056/NEJMoa2035002PubMedGoogle ScholarCrossref
19.
Centers for Disease Control and Prevention. COVID-19: people with certain medical conditions. Accessed September 1, 2021. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html
20.
US Food and Drug Administration. Letter of authorization for emergency use of REGEN-COV (casirivimab and imdevimab). November 17, 2021. Accessed January 6, 2022. https://www.fda.gov/media/145610/download
21.
Portal-Celhay  C , Forleo-Neto  E , Eagan  W ,  et al. Dose-ranging virology study of the combination COVID-19 antibodies casirivimab and imdevimab in the outpatient setting—poster 04769. Presented at: 31st European Congress of Clinical Microbiology and Infectious Diseases [virtual meeting]; July 9-12, 2021.
22.
Baum  A , Ajithdoss  D , Copin  R ,  et al.  REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhesus macaques and hamsters.   Science. 2020;370(6520):1110-1115. doi:10.1126/science.abe2402PubMedGoogle ScholarCrossref
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