Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial
Philippe Bégin, Jeannie Callum, Erin Jamula, Richard Cook, Nancy M Heddle, Alan Tinmouth, Michelle P Zeller, Guillaume Beaudoin-Bussières, Luiz Amorim, Renée Bazin, Kent Cadogan Loftsgard, Richard Carl, Michaël Chassé, Melissa M Cushing, Nick Daneman, Dana V Devine, Jeannot Dumaresq, Dean A Fergusson, Caroline Gabe, Marshall J Glesby, Na Li, Yang Liu, Allison Mcgeer, Nancy Robitaille, Bruce S Sachais, Damon C Scales, Lisa Schwartz, Nadine Shehata, Alexis F Turgeon, Heidi Wood, Ryan Zarychanski, Andrés Finzi, Danièle Marceau, Andy Huang, Holly Carr, Yulia Lin, Rosemarie Lall, Christopher Graham, Christine Arsenault, Valerie Sales, Davinder Sidhu, Makeda Semret, Caroline Hamm, Eneko Arhanchiague, Ziad Solh, Nadim Srour, Karim Soliman, Colin Yee, Vincent Laroche, Susan Nahirniak, Christina Greenaway, Menaka Pai, Andréanne Côté, Jennifer L Y Tsang, Christine Cserti-Gazdewich, Danielle Talbot, Sébastien Poulin, Rodrigo Guimaraes, Moira Rushton-Marovac, Alexandra Langlois, Shuoyan Ning, Andrew Shih, Mélissa Boileau, Harjot Singh, Donna Ledingham, Arjuna Ponnampalam, Matthew Yan, Oksana Prokopchuk-Gauk, André Poirier, Gabriel Girouard, Katerina Pavenski, Olivier Drouin, David Harris, Madeleine Durand, Emily Rimmer, Daniel Ovakim, François Ménard, Glenna Cuccarolo, Julie Carruthers, Kayla Lucier, Valérie Arsenault, Marie-Christine Auclair, Meda Avram, Michael Brassard, Sabrina Cerro, Véronica Martinez, Julie Morin, Marie Saint-Jacques, Maxime Veillette, Chantal Armali, Amie Kron, Dimpy Modi, Joanne Duncan, Pauline Justumus, Melanie St John, Geneviève St-Onge, Milena Hadzi-Tosev, Pierre-Marc Dion, Lawrence Mcgillivary, Andre Valleteau De Moulliac, Sheila A Nyman, Stephanie Perilli, Paulette Jean Van Vliet, Shannon Lane, Katerina Pavenski, Rebecca Pereira, Emily Sirotich, Julie Abelson, Saara Greene, Aditi Khandelwal, Swarni Thakar, Sarah Longo, Sai Priya Anand, Mehdi Benlarbi, Catherine Bourassa, Marianne Boutin, Jade Descôteaux-Dinelle, Gabrielle Gendron-Lepage, Guillaume Goyette, Annemarie Laumaea, Halima Medjahed, Jérémie Prévost, Jonathan Richard, Daniel Kaufmann, Elsa Brunet-Ratnasingham, Nicolas Chaumont, Michael Drebot, Alyssia Robinson, Emelissa Mendoza, Kristina Dimitrova, Kathy Manguiat, Clark Phillipson, Michael Chan, David Evans, James Lin, Lucie Boyer, Marc Cloutier, Mathieu Drouin, Éric Ducas, Nathalie Dussault, Marie-Josée Fournier, Patricia Landy, Marie-Ève Nolin, Josée Perreault, Tony Tremblay, Ishac Nazy, Feng Xie, David Liu, Michelle Wong, Gus Silverio, Kristin Walkus, Mikaela Barton, Katherine Haveman, Darlene Mueller, Ashley Scott, Matthew Moher, Gordon Wood, Tracey Roarty, Fiona Auld, Gayle Carney, Virginia Thomson, Rodrigo Onell, Keith Walley, Katie Donohoe, Crystal Brunk, Geraldine Hernandez, Tina Jacobucci, Lynda Lazosky, Puneet Mann, Geeta Raval, Ligia Araujo Zampieri, Mypinder Sekhon, Alissa Wright, Nicola James, Gaby Chang, Roy Chen, Kanwal Deol, Jorell Gantioqui, Elyse Larsen, Namita Ramdin, Margaret Roche, Kristin Rosinski, Lawrence Sham, Michelle Storms, Mark Gillrie, Etienne Mahe, Deepa Suryanarayan, Alejandra Ugarte-Torres, Traci Robinson, Mitchell Gibbs, Julia Hewsgirard, Marnie Holmes, Joanna Mccarthy, Meagan Ody, Karen Doucette, Wendy Sligl, Ashlesah Sonpar, Kimberley Robertson, Jeffrey Narayan, Leka Ravindran, Breanne Stewart, Lori Zapernick, Stephen Lee, Eric Sy, Alexander Wong, Karolina Gryzb, Sarah Craddock, Dennaye Fuchs, Danielle Myrah, Sana Sunny, Sheila Rutledge Harding, Siddarth Kogilwaimath, Nancy Hodgson, Dawn Johnson, Simona Meier, Kim Thomson, Amila Heendeniya, Brett Houston, Yoav Kenyan, Sylvain Lother, Kendiss Olafson, Barret Rush, Terry Wuerz, Dayna Solvason, Lisa Albensi, Soumya Alias, Nora Choi, Laura Curtis, Maureen Hutmacher, Hessam Kashani, Debra Lane, Nicole Marten, Tracey Pronyk-Ward, Lisa Rigaux, Rhonda Silva, Quinn Tays, Renuka Naidu, Jane Mathews, Margaret Mai, Victoria Miceli, Liz Molson, Gayathri Radhakrishnan, Linda Schaefer, Michel Haddad, Shannon Landry, Robert Chernish, Rebecca Kruisselbrink, Theresa Liu, Jayna Jeromin, Atif Siddiqui
Nature Medicine, doi:10.1038/s41591-021-01488-2
T he immune response after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in the formation of antibodies that can interfere with viral replication and infection of host cells in over 95% of patients 1 . Based on previous experience in other viral infections 2 , the use of convalescent plasma has been proposed as a therapeutic form of passive immunization for patients with acute 4 ). Early in the pandemic, several small randomized trials found no difference in clinical outcomes 5-8 . In the United States, an Extended Access Program outside of a controlled trial led to the use of convalescent plasma in over half a million patients. Data from these patients showed that the transfusion of plasma with high anti-SARS-CoV-2 antibody levels was associated with a lower risk of death in non-intubated patients compared to lower antibody levels; however, this study lacked a control group 9 . The RECOVERY trial was a large randomized trial in 11,558 hospitalized patients that found that the risk of death after the administration of high-titer plasma was not different from standard of care 10 . The Convalescent Plasma for COVID-19 Respiratory Illness (CONCOR-1) trial was a multi-center, international, open-label, randomized controlled trial designed to assess the effectiveness and safety of COVID-19 convalescent plasma in hospitalized patients. The trial used plasma collected from four blood suppliers with a range of anti-SARS-CoV-2 antibody levels. The variability in antibody titers allowed for a characterization of the effect-modifying role of functional and quantitative antibodies on the primary outcome (intubation or death at 30 d).
Results Patients. This trial was stopped at the planned interim analysis because the conditional power estimate was 1.6% (below the stopping criterion of 20%). Between 14 May 2020 and 29 January 2021, 940 patients were randomized (2:1) to convalescent plasma or standard of care in 72 hospital sites in Canada, the United States and Brazil (Fig. 1 and Supplementary Table 1 ). Two patients randomized
Online content Any methods, additional references, Nature Research reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at https://doi.org/10.1038/ s41591-021-01488-2. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Methods Trial design and oversight. CONCOR-1 was an investigator-initiated, multi-center, open-label, randomized controlled trial conducted at 72 hospital sites in Canada, the United States and Brazil 34 . Eligible patients were randomly assigned to receive either convalescent plasma or standard of care. The ). An independent data safety monitoring committee performed trial oversight and made recommendations after review of safety reports planned at every 100 patients and at the planned interim analysis based on the first 600 patients. External monitoring was performed at all sites to assess protocol adherence, reporting of adverse events and accuracy of data entry. Full details of the study design, conduct, oversight and analyses are provided in the protocol and statistical analysis plan, which are available online. Participants. Eligible participants were (1) ≥16 years of age in Canada or ≥18 years of age in the United States and Brazil; (2) admitted to the hospital ward with confirmed..
References
Abe, A simple protein-based surrogate neutralization assay for SARS-CoV-2, JCI Insight
Agarwal, Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial), Brit. Med. J
Alqahtani, Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease, Sci. Rep
Anand, High-throughput detection of antibodies targeting the SARS-CoV-2 spike in longitudinal convalescent plasma samples, Transfusion
Anand, Longitudinal analysis of humoral immunity against SARS-CoV-2 spike in convalescent individuals up to eight months post-symptom onset, Cell Rep. Med
Bajpai, efficacy of convalescent plasma therapy compared to fresh frozen plasma in severely ill COVID-19 patients: a pilot randomized controlled trial,
doi:10.1101/2020.10.25.20219337v1Bennett-Guerrero, Severe acute respiratory syndrome coronavirus 2 convalescent plasma versus standard plasma in Coronavirus Disease 2019 infected hospitalized patients in New York: a double-blind randomized trial, Crit. Care Med
Blackall, Rapid establishment of a COVID-19 convalescent plasma program in a regional health care delivery network, Transfusion
Brunet-Ratnasingham, Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality,
doi:10.1101/2021.03.18.21253907v1Budhai, How did we rapidly implement a convalescent plasma program?, Transfusion
Casadevall, Joyner, Pirofski, Neutralizing antibody LY-CoV555 for outpatient Covid-19, N. Engl. J. Med
Devasenapathy, Efficacy and safety of convalescent plasma for severe COVID-19 based on evidence in other severe respiratory viral infections: a systematic review and meta-analysis, CMAJ
Development, Team, R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing
General, None
Gharbharan, Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection, Nat. Commun
Goss, Gulick, Vaamonde, Oriela Cuevas 6 , Wanda Lafresne 6
Hamdy Salman, Ail Mohamed, Efficacy and safety of transfusing plasma from COVID-19 survivors to COVID-19 victims with severe illness. A double-blinded controlled preliminary study, Egypt. J. Anaesth
Hamilton, Lee, Arnold, Lilford, Hemming, Is convalescent plasma futile in COVID-19? A Bayesian re-analysis of the RECOVERY randomized controlled trial, Int. J. Infect. Dis
Harris, Research electronic data capture (REDCap)-a metadata-driven methodology and workflow process for providing translational research informatics support, J. Biomed. Inform
Haynes, Immune-correlates analysis of an HIV-1 vaccine efficacy trial, N. Engl. J. Med
Joyner, Convalescent plasma antibody levels and the risk of death from Covid-19, N. Engl. J. Med
Li, Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial, JAMA
Libster, Early high-titer plasma therapy to prevent severe Covid-19 in older adults, N. Engl. J. Med
Matukas, Charles, Francoeur, Lauzier, Annie La Haye 1 , Vincent Lague 1
Mendoza, Manguiat, Wood, Drebot, Two detailed plaque assay protocols for the quantification of infectious SARS-CoV-2, Curr. Protoc. Microbiol
Narick, Triulzi, Yazer, Transfusion-associated circulatory overload after plasma transfusion, Transfusion
Nature, None
O'brien, Fleming, A multiple testing procedure for clinical trials, Biometrics
O'donnell, A randomized double-blind controlled trial of convalescent plasma in adults with severe COVID-19, J. Clin. Invest
Perreault, Waning of SARS-CoV-2 RBD antibodies in longitudinal convalescent plasma samples within 4 months after symptom onset, Blood
Piechotta, Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review, Cochrane Database Syst. Rev
Ray, Clinical and immunological benefits of convalescent plasma therapy in severe COVID-19: insights from a single center open label randomised control trial,
doi:10.1101/2020.11.25.20237883v1Robinson, Liu, Wong, Sutharsan Suntharalingam 50
Schafer, Antibody potency, effector function, and combinations in protection and therapy for SARS-CoV-2 infection in vivo, J. Exp. Med
Seow, Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans, Nat. Microbiol
Simonovich, A randomized trial of convalescent plasma in Covid-19 severe pneumonia, N. Engl. J. Med
Suryadevara, Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein, Cell
Taborda, Rivera, Zaragoza, Casadevall, More is not necessarily better: prozone-like effects in passive immunization with IgG, J. Immunol
Tauzin, A single BNT162b2 mRNA dose elicits antibodies with Fc-mediated effector functions and boost pre-existing humoral and T cell responses,
doi:10.1101/2021.03.18.435972v1The, Group, Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial, Lancet
Tomaras, Vaccine-induced plasma IgA specific for the C1 region of the HIV-1 envelope blocks binding and effector function of IgG, Proc. Natl Acad. Sci
Winkler, Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions for optimal therapeutic protection, Cell
Wood, Estcourt, Mcquilten, How should we use convalescent plasma therapies for the management of COVID-19?, Blood
Wood, Fast stable restricted maximum likelihood and marginal likelihood estimation of semiparametric generalized linear models, J. R. Stat. Soc. Ser. B (Methodol.)
Wood, Generalized Additive Models: An Introduction with R, Second Edition
Zohar, Compromised humoral functional evolution tracks with SARS-CoV-2 mortality, Cell
