Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection
Meagan P O’brien, MD Eduardo Forleo-Neto, PhD Neena Sarkar, MD Flonza Isa, PhD; Peijie Hou, PhD Kuo-Chen Chan, PhD Bret J Musser, MD Katharine J Bar, MD Ruanne V Barnabas, MD Dan H Barouch, PhD Myron S Cohen, MD Christopher B Hurt, MD Dale R Burwen, MD, MPH Mary A Marovich, MD Elizabeth R Brown, ScD Ingeborg Heirman, PhD; John D Davis, PhD; Kenneth C Turner, PhD; Divya Divya Ramesh, PhD Adnan Mahmood, MD Andrea T Hooper, PhD Jennifer D Hamilton, PhD Yunji Kim, PharmD Lisa A Purcell, PhD Alina Baum, PhD Christos A Kyratsous, PhD; James Krainson, MD Richard Perez-Perez, DO Rizwana Mohseni, MS Bari Kowal, A Thomas Dicioccio, MD, DrPH Gregory P Geba, PhD Neil Stahl, PhD Leah Lipsich, MD Ned Braunstein, MD Gary Herman, MD George D Yancopoulos, PhD; David M Weinreich, Neal Warshoff, Liudmila Moreiras, Dario Altamirano, Dickson Ellington, Faisal Faikih, William Smith, Richard Gibson, Katie Buckner, Robert Rosen, Amy Sapp, Anita Kohli, Vicki Mcintyre, Yessica Sachdeva, Amanda Mcfarland, Dina Gibson, Kenneth Kim, Jason Ahn, Lisa Neinchel, Nayna Paryani, Amber Mottola, Eva Day, Martha Navarro, Rafaelito Victoria, Xanthe Victoria, Rene Uong, Mindy Sampson, Christopher Polk, Michael Leonard, Lewis Mccurdy, Leigh A Medaris, Zainab Shahid, Lisa Davidson, Jawad Nazir, John Lee, Amy Elliott, Swami Sathyanaryan, Mansi Oberoi, Muhammad (danial) Siddiqui, Muhammad Arsad, Kara Bruning, Sybil Hosek, Temitope Oyedele, Vanessa Sarda, Monica Mercon, Kathryn Stephenson, Boris Juelg, Chen Sabrina Tan, Rebecca Zash, Ai-Ris Collier, Jessica Ansel, Kate Jaegle, Lilia Roque-Guerrero, Ana Gomez Ramirez, Javier Capote, Gisel Paz, Michael Paasche-Orlow, Julien Dedier, Sanjay Vadgama, Ramachandra Patak, Nicolas Chronos, Cary Hefty, Judith Borger, Ifeanyi Momodu, Lindsey Carswell, Benjamin King, Ryan Starr, Scott Syndergaard, Nancy Patel, Ravikumar Patel, Ryan Sattar, Jeffrey Unger, Sheila De Jesus-Maranan, Cecilia Casaclang, Michael Seep, Celeste Brown, Joshua Whatley, Dennis Levinson, Saad Alvi, Norman James, Azazuddin Ahmed, Robinson Koilpillai, Stephanie Cassady, Jennifer Cox, Eduardo Torres, Mark J Rosenthal, Michael Winnie, Jerry Plemons, Omesh Verma, Richard Leggett, Ramon Reyes, Keith Beck, Brian Poliquin, Murtaza Mussaji, Jignesh Shah, David Sutton, Edward Pereira, Rodel Gloria, Stacey Kelly, Amy Dennis-Saltz, Mae Sheikh-Ali, Elias Saikali, James Magee, Rebecca Goldfaden, Haresh Boghara, Sunny Patel, Bari Eichelbaum, Duane Anderson, Sean Su, Alexander Akhavan, Diana Kirby, Joy Venglik, Kenneth Mayer, Taimur Khan, Marcy Gelman, Faisal A Fakih, Faisal M Fakih, Daniel Layish, Fernando Alvarado, Jose Diaz, Augusto Focil, Griselda Rosas, Stevan Correa, Michael Bogseth, Bhaktasharan Patel, Gary Tarshis, Katrina Grablin, Paul Simonelli, Stanley Martin, Alvin Sharma, Anna Chen, Pragya Dhaubhadel, Shaeesta Khan, Sreelatha Naik, Sudheer Penupolu, Thulashie Sivarajah, Tae-Sung Kwon, Lakshmi Saladi, Farbod Raiszadeh, Sharon Mannheimer, Raji Ayinla, Khaing Myint, Akari Kyaw, Donna Dowie, Robin O'reilly, Hussein Assallum, Lovelyamma Varghese, Ellen Morrison, Julie Franks, Jun Avelino Loquere, Orlando Rosario, Andrea Low, Joan Villacrucis, Alan Skolnick, Harold Minkowitz, David Leiman, Todd Price, Anatoli Krasko, Idisoro Wiener, Larry Reed, Oscar Lin, PhD; Divya Mayur Ramesh, George Alangaden, Suraj Saggar, Thomas Birch, Benjamin De La Rosa, Karyna Neyra, Erina Kunwar, Jeffrey Kingsley, April Pixler, Veronica Mcbride, Judith Aberg, Michelle Cespedes, Alexandra Abrams-Downey, Erna Kojic, Luz Lugo, Sean Liu, Nadim Salomon, David Perlman, Deena Altman, Farah Rahman, Georgina Osorio, Joseph Mathew, Sanjana Koshy, Dana Mazo, Francesca Cossarini, Sondra Middleton, Alina Jen, Erika Maria Reategui Schwarz, Miguel Trevino, Benjamin Devries, Vidya Menon, Moiz Kasubhai, Usha Venugopal, Anjana Pillai, Franscene Oulds, Matthew Hong, Wayne Harper, Lynn Eckert, Douglas Wadeson, Lisa Cohen, Joel Chua, Shyam Kottilil, Jennifer Husson, John Baddley, R Gentry Wilkerson, Shivakumar Narayanan, Uzoamaka Eke, Myint Noe, Melanie Malave Sanchez, Arthur Kim, Greg Robbins, Mark Siedner
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 Ն12 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 log 10 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.
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 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..
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