Post-acute COVID-19 outcomes including participant-reported long COVID: amubarvimab/romlusevimab versus placebo in the ACTIV-2 trial

Teresa H Evering; Carlee Moser; Nikolaus Jilg; Justin Ritz; David A Wohl; Jonathan Z Li; David Margolis; Arzhang Cyrus Javan; Joseph J Eron; Judith S Currier; Eric S Daar; Davey M Smith; Michael D Hughes; Kara W Chew; ACTIV-2/A5401 Study Team

doi:10.1016/j.eclinm.2024.102787

Post-acute COVID-19 outcomes including participant-reported long COVID: amubarvimab/romlusevimab versus placebo in the ACTIV-2 trial

EClinicalMedicine. 2024 Aug 16:75:102787. doi: 10.1016/j.eclinm.2024.102787. eCollection 2024 Sep.

Authors

Collaborators

ACTIV-2/A5401 Study Team:
Kara Chew, David Davey Smith, Eric Daar, David Wohl, Judith Currier, Joseph Eron, Arzhang Cyrus Javan, Michael Hughes, Carlee Moser, Mark Giganti, Justin Ritz, Lara Hosey, Jhoanna Roa, Nilam Patel, Kelly Colsh, Irene Rwakazina, Justine Beck, Scott Sieg, Jonathan Li, Courtney Fletcher, William Fischer, Teresa H Evering, Rachel Bender Ignacio, Sandra Cardoso, Katya Corado, Prasanna Jagannathan, Nikolaus Jilg, Alan Perelson, Sandy Pillay, Cynthia Riviere, Upinder Singh, Babafemi Taiwo, Joan Gottesman, Matthew Newell, Susan Pedersen, Joan Dragavon, Cheryl Jennings, Brian Greenfelder, William Murtaugh, Jan Kosmyna, Morgan Gapara, Akbar Shahkolahi, David Margolis, Verónica Lacal, Diego Salusso, Sebastian Nuñez, Marcelo Rodrigo Rodriguez, Luciana Laborde, Marcelo Papasidero, Luis Wehbe, Mariana Gonzalez, Felicitas Fernandez Voena, Tomas Alvarez, Amaru Lopez, Virginia Huhn, Ulises D'Andrea Nores, Pablo Dieser, Fernando Bordese, Marisa Mussi, Rodrigo de Carvalho Santana, Adriana Aparecida Tiraboschi Bárbaro, Breno Santos, Rita de Cássia Alves Lira, Andre Luiz Machado da Silva, Sandra Wagner Cardoso, Maria Pia Diniz Ribeiro, Nathália Soliva, Eduardo Vasconcellos, Jorge Eurico Ribeiro, Miriam Amaral Enéas, Jorge Pinto, Julia Fonseca de Morais Caporali, Flávia Gomes Faleiro Ferreira, Norma Erendira Rivera Martinez, Victor Casildo Bohorquez Lopez, Melchor Victor Frias, Krystle Fetalvero, Alyxzza Maranan, Jennifer Rosa, Thomas Coetzer, Maureen Mohata Sr, Umesh Lalloo, Sandy Pillay, Penelope Madlala, Larisha Pillay-Ramaya, Jaclyn Ann Bennet, Noluthando Mwelase, Nokuphiwa Mbhele, Frederick Petrick, Leonard Joubert, Rose Mbali Sr, Natasha Joseph, Mmatsie Manentsa, Eugene van der Walt, Mduduzi Sandile Lawrance Masilela, Zinhle Zwane, Tendai Chiperera, Lerato Mohapi, Suri Moonsamy, Usha Singh, Kirsten McHarry, Elizma Snyman, Pieter Lennox, James Craig Innes, Oteng Letlape, Olebogeng Jonkane, William Brumskine, Tania Adonis, Ni Ni Sein, Modulakgotla Sebe, Yacoob Vahed, Nazreen Jeewa Hussen, Ismail Mitha, Vasundhara Cheekati, Purna Cheekati, Christie Lummus, Samuel Idarraga, Andrew Kim, David N Pham, Wei-Hsin Kao, Michael M Pfeffer, Miriam Batule Dominguez, Anju Malik, Anna Bryan, Melanie Arnold, Idania Fernandez, Cinzia Karpf, Aniuska Ruiz, David Taylor, Eric Folkens, Jennifer Manne, Sigal Yawetz, Cheryl Keenan, Emeka Eziri, Carl Fichtenbaum, Jenifer Baer, Sarah Trentman, Robert Call, Leroy Vaughan, Aaron Milstone, Jamie Alex Slandzicki, Jessica Wallan, Clinton Guillory, Nancy Andrews, Leslie Hughes, Teresa H Evering, Jonathan Berardi, Celine Arar, Randall Quinn, Jorge P Amaya, Marissa Gomez-Martinez, Luis Cantu, Monica Betancourt-Garcia, Nwora Lance Okeke, Charles M Burns, Fadi Haddad, Victoria Haddad, Augusto Focil, Griselda Rosas, Susana Moyano, Yaneicy Gonzalez Rojas, Ahmad Aswad, Yevgeniy Bukhman, Manish Jain, Eugene Bukhman, Humam Farah, Rebekah McClain, Eric Daar, Sadia Shaik, Timothy Hatlen, Deepa Gotur, Joseph Surber, Jeffrey Kingsley, April Pixler, Alex Zopo, Jack Herman, Craig Herman, Ramon Leon, Boris Nikolov, Fernando Gonzalez Vergara, Ana I Gonzalez, Noemi Gonzalez, Michael Gelman, Olga Andriunas, Zarema Jagizarov, Jan Westerman, David Davis, Donna Sherer, Kelly Dooley, Becky Becker, Adaliah Wilkins, Jose Pérez, Eloy Roman, Heriberto Fernández, Bharat Mocherla, Kelly Beck, Valarie Maldonado, Jennifer Veltman, Rajesh Gandhi, Katrina Shea, Matthew Planchon, Laura Bogan Herpel, Kaushlendra K Tripathi, Donald C Day, John Pullman Sr, Erin Williams-Leber, Misty Johnson, Michelle Hecker, Ann Avery, Keila Hoover, George W Monlux, Elizabeth Juneja Jr, Arthur Wernick, Karelia Ruiz, Maureen Hernández, Yadilys Pérez, Babafemi O Taiwo, Claudia Hawkins, Baiba Berzins, Carlos Malvestutto, Heather Harber, Robyn Cicarella, Edwin DeJesus, Charlotte-Paige Rolle, Almena L Free, Sallie D Pulliam, Debra Weinstein, Rosa M Suarez, Ezequiel Socorro, Estefania Socorro, Gene Neytman, Jack Herman, Craig Herman, Raymond Easley, Mariam Aziz, Joan Swiatek, Avish Nagpal, Breanna Kompelien, Kathryn McEvoy, Susan E Hoover, Allison Lutz, Jessica Just, Manuel Hernandez, Yanly B Victoria, Gabriel Rodriguez, Upinder Singh, Prasanna Jagannathan, Divya Pathak, Joshua J Ordway, Megan Heffner, Patrick Weston, Khalilah Weston, Madhu Choudhary, Jennifer Sullivano, Olayemi Osiyemi, Myriam Izquierdo, Odelsey Torna, Brian Clemency, Renoj Varughese, Joshua Lynch, Kara Chew, Aleen Khodabakhshian, Samantha Fortier, Christopher Coyne, Alexandrea Cronin, Constance Benson, Steven Hendrickx, Rosemarie Ramirez, Anne Luetkemeyer, Suzanne Hendler, Dennis Dentoni-Lasofsky, Mobeen Rathore, Saniyyah Mahmoudi, Amna Riaz, Mario Castro, Leslie Spikes, Chase Hall, David Wohl, Jonathan Oakes, Amy James Loftis, Pablo Tebas, William Short, Michael P Dube, Saahir Khan, Luis M Mendez, Rachel Bender Ignacio, Sarah McGuffin, Chris Jonsson, Mamta K Jain, Smruthi Senthil, Kimberly Turner-Gray, Sanjay Mehta, David Davey Smith, Mary Lewinski, Masoud Azizad, Christopher Chow, Lisa Nakatani, Derrick Williamson, Hisham Atriss, Matthew Caloura, Midhun Malla, Hannah Hazard-Jenkins, Aimee Wilkin, Jamraus Fayssoux, Hannah Seagle, Rachel Presti, Alem Haile

Affiliations

¹ Weill Cornell Medicine, New York, NY, USA.
² Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³ Massachusetts General Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ University of North Carolina, Chapel Hill, NC, USA.
⁵ Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Brii Biosciences, Durham, NC, USA.
⁷ National Institutes of Health, Bethesda, MD, USA.
⁸ David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
⁹ Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁰ University of California, San Diego, CA, USA.

Abstract

Background: It is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID.

Methods: Non-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo.

Findings: Participants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53-0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID.

Interpretation: Amubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID.

Funding: National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

Keywords: COVID-19; Clinical trial; Long COVID; Monoclonal antibodies; Outpatient treatment; Post COVID conditions; Post-acute sequelae of SARS-CoV-2 infection (PASC).

Abstract

Grants and funding