Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients
MD Mila B Ortigoza, PhD Hyunah Yoon, MD Keith S Goldfeld, ScD Andrea B Troxel, MD, MS Johanna P Daily, MA Yinxiang Wu, MS Yi Li, MS Danni Wu, MA Gia F Cobb, MD Gillian Baptiste, Mary O’keeffe, MD Marilou O Corpuz, MD Luis Ostrosky-Zeichner, MD Amee Amin, MD Ioannis M Zacharioudakis, MD Dushyantha T Jayaweera, MD Yanyun Wu, MD Julie V Philley, MD Megan S Devine, MD Mahalia S Desruisseaux, MD Alessandro D Santin, MD Shweta Anjan, MBBS Reeba Mathew, MD Bela Patel, MD Masayuki Nigo, MD Rabi Upadhyay, MD Tania Kupferman, MD Andrew N Dentino, MD Rahul Nanchal, MS Christian A Merlo, MD, MPH David N Hager, PhD Kartik Chandran, PhD Jonathan R Lai, PhD Johanna Rivera, PhD Chowdhury R Bikash, PhD Gorka Lasso, PhD Timothy P Hilbert, MD Monika Paroder, MD, PhD Andrea A Asencio, BA Mengling Liu, PhD; Eva Petkova, PhD; Alexander Bragat, MBA Reza Shaker, MD David D Mcpherson, MD Ralph L Sacco, MD, MS Marla J Keller, MD Corita R Grudzen, MD Judith S Hochman, MD Liise-Anne Pirofski, Fatema Z Rahman, Adeyinka O Ajayi, Sara L Rodriguez, Ana G Ledesma, Deborah Keeling, Norka Rappoport, Sam F Ebel, Jayne Kim, Michelle Chang, Kevin Chan, Payal Patel, Anne Martocci, Shivang Dave, Yousef Darwish, Monica Taveras, Victoria Shoyelu, Patrick Xin, Eduardo Iturrate, Lee C Moldolsky, Brian J Raimondo, Sarah Mendez, Patricia Hughes, Stephanie Sterling, Aaron S Lord, Shadi Yaghi, Karen Veloso, Masooma Sheikh, Erica Visconti-Ferrara, Andrew Fleming, Heekoung Youn, Baby Jane Fran, Rosario Medina, Renee Mckell, Saila Khan, Tanya Hamilton, Carlos J Sanchez, Nandini H Patel, Levi Cleare, Olivia Vergnolle, Antonio Nakouzi, Gregory Quevedo, Robert H Bortz, Ariel S Wirchnianski, Catalina Florez, Rachelle Babb, Jennifer Ayala, K Zoe Tsagaris, Andria James, Isaiah Eke, Aisha Obeidallah, Oana A Sandu, Sophie Sohval, Leana Serrano-Rahman, Joan Uehlinger, Rachel Bartash, Aya Al-Abduladheem, Inessa Gendlina, Carol Sheridan, Anna Bortnick, Jeremy Eichler, Rachel Kaufman, Sarah Yukelis, Michael Pennock, Michelle Goggin, Christine Shen, Jayabhargav Annam, Ahmed Khokhar, Daniel Barboto, Brianna J Lally, Audrey Lee, Max Lee, Xiuyi A Yang, Stephanie Allen, Avinash Malaviya, Omar Moussa, Rosa Park, Reise Sample, Andrea Bae, Galit Benoni, Lindsie L Boerger, Lisa D Baker, Martha A Luther, Lirim S Ameti, Neima Briggs, Marjorie R Golden, Michael Gormally, Gloria S Huang, Raymond M Johnson, Alyssa R Morrison, Michele Montagna-Hill, Brooke N Rivera, Grace M Cortezzo, Kay B Debski, Nicoletti, Kerry Debenedictis, Rivcah Davis, Christi Marshall, Miriam Andrea Duque Cuartas, Laura Beauchamps, Jovanna Bertran-Lopez, Jose Gonzales Zamora, Maria Delgado-Lelievre, Sheela Dominguez, Chin Chin Lee, Halina Kusack, Vela Karakeshishyan, Americo Hajaz, Dasmany Deniz, Giovanni Garcia, Katheryn Dae, Patricia Blenet, Deborah Jaffe, Lourdes Olson, Diane Sabogal, Olivia Blust, Veronica Del Prete Perez, Claudia Bornia, Vanessa Rodriguez-Perez, Vivian Calderon, Rajan Ramdev, Aaliyah Jolly, Ivonne Guzman, Richard Guerra, Sebastian Brito, Rhonda Hobbs, Rebecca Denham, John Dick, Maria D Hernandez, Laura E Nielsen, Sami M Anjum, Shelby C Mader, Taylor P Stutz, Mehriban Mammadova, Pamela Nichols, Tanya S Khan, Maha R Boktour, Brenda L Castaneda, Brenda D Benitez, Erik Hinojosa, Brenda C Guerra, Armando Ortiz, Renee S Hebbeler-Clark, Pamela J Mcshane, Rebekah Hibbard, Benji E Hawkins, Elizabeth R Dohanich, Carly Wadle, Kimberly L Greenlee, Jennifer Brooks, Christopher D Herrick, Amit Gode, Paul Bergl, Kurt Hu, Jayshil Patel, Shankar Srinivasan, Jeanette Graf, Char Klis, Kyersten Reimer, Erica Carpenter, Christine Naczek, Rae Petersen, Renee Dex, Jennifer Drossart, James Zelten, Charles Brummitt, Mengyao Liang, Lynda Yanny, Gary Dennison, Phyllis Runningen, Brian Brzezinski, Stephen Fiebig, Chris Naczek, Michelle Kasdorf, MD, MPH Lalitha Parameswaran, MD Anthony T Corcoran, MD Abhinav Rohatgi, MO Marta W Wronska, MD Xinyuan Wu, MD Ranjini Srinivasan, Fang-Ming Deng, PhD Thomas D Filardo, MD Jay Pendse, PhD Simone B Blaser, MD Olga Whyte, BSN, RN; Jacqueline M Gallagher, Ololade E Thomas, Danibel Ramos, Caroline L Sturm-Reganato, Charlotte C Fong, Ivy M Daus, Arianne Gisselle Payoen, Joseph T Chiofolo, Mark T Friedman, Ding Wen Wu, MD Jessica L Jacobson, MD Jeffrey G Schneider, MD Uzma N Sarwar, MD; Henry E Wang, MD Ryan M Huebinger, MD Goutham Dronavalli, MD Yu Bai
JAMA Internal Medicine, doi:10.1001/jamainternmed.2021.6850
and the CONTAIN COVID-19 Consortium for the CONTAIN COVID-19 Study Group IMPORTANCE There is clinical equipoise for COVID-19 convalescent plasma (CCP) use in patients hospitalized with COVID-19. OBJECTIVE To determine the safety and efficacy of CCP compared with placebo in hospitalized patients with COVID-19 receiving noninvasive supplemental oxygen. DESIGN, SETTING, AND PARTICIPANTS CONTAIN COVID-19, a randomized, double-blind, placebo-controlled trial of CCP in hospitalized adults with COVID-19, was conducted at 21 US hospitals from April 17, 2020, to March 15, 2021. The trial enrolled 941 participants who were hospitalized for 3 or less days or presented 7 or less days after symptom onset and required noninvasive oxygen supplementation. INTERVENTIONS A unit of approximately 250 mL of CCP or equivalent volume of placebo (normal saline).
MAIN OUTCOMES AND MEASURES The primary outcome was participant scores on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement on day 14 after randomization; the secondary outcome was WHO scores determined on day 28. Subgroups were analyzed with respect to age, baseline WHO score, concomitant medications, symptom duration, CCP SARS-CoV-2 titer, baseline SARS-CoV-2 serostatus, and enrollment quarter. Outcomes were analyzed using a bayesian proportional cumulative odds model. Efficacy of CCP was defined as a cumulative adjusted odds ratio (cOR) less than 1 and a clinically meaningful effect as cOR less than 0.8.
RESULTS Of 941 participants randomized (473 to placebo and 468 to CCP), 556 were men (59.1%); median age was 63 years (IQR, 52-73); 373 (39.6%) were Hispanic and 132 (14.0%) were non-Hispanic Black. The cOR for the primary outcome adjusted for site, baseline risk, WHO score, age, sex, and symptom duration was 0.94 (95% credible interval [CrI], 0.75-1.18) with posterior probability (P[cOR<1] = 72%); the cOR for the secondary adjusted outcome was 0.92 (95% CrI, 0.74-1.16; P[cOR<1] = 76%). Exploratory subgroup analyses suggested heterogeneity of treatment effect: at day 28, cORs were 0.72 (95% CrI, 0.46-1.13; P[cOR<1] = 93%) for participants enrolled in April-June 2020 and 0.65 (95% CrI, 0.41 to 1.02; P[cOR<1] = 97%) for those not receiving remdesivir and not receiving corticosteroids at randomization. Median CCP SARS-CoV-2 neutralizing titer used in April to June 2020 was 1:175 (IQR, 76-379). Any adverse events (excluding transfusion reactions) were reported for 39 (8.2%) placebo recipients and 44 (9.4%) CCP recipients (P = .57). Transfusion reactions occurred in 2 (0.4) placebo recipients and 8 (1.7) CCP recipients (P = .06).
CONCLUSIONS AND RELEVANCE In this trial, CCP did not meet the prespecified primary and secondary outcomes for CCP efficacy. However, high-titer CCP may have benefited participants early in the pandemic when remdesivir and corticosteroids were not in use.
References
Acquisition, Ortigoza, Yoon, Goldfeld, Troxel et al., Critical revision of the manuscript for important intellectual content
Agarwal, Mukherjee, Kumar, Chatterjee, Bhatnagar et al., Convalescent plasma in the management of moderate Covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial), BMJ,
doi:10.1136/bmj.m3939Avendaño-Solá, Ramos-Martínez, Muñez-Rubio, A multicenter randomized open-label clinical trial for convalescent plasma in patients hospitalized with COVID-19 pneumonia, J Clin Invest,
doi:10.1172/JCI152740Beigel, Tomashek, Dodd, ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19 -final report, N Engl J Med,
doi:10.1056/NEJMoa2007764Bortz, Iii, Florez, Laudermilch, Single-dilution COVID-19 antibody test with qualitative and quantitative readouts, mSphere,
doi:10.1128/mSphere.00224-21Bégin, Callum, Jamula, 1 Study Group. Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial, Nat Med,
doi:10.1038/s41591-021-01488-2Dieterle, Haslwanter, Bortz, Iii, A replication-competent vesicular stomatitis virus for studies of SARS-CoV-2 spike-mediated cell entry and its inhibition, Cell Host Microbe,
doi:10.1016/j.chom.2020.06.020Fibiger, Om Serumbehandling af Difteri
Focosi, Franchini, Pirofski, COVID-19 convalescent plasma and randomized clinical trials: rebuilding confidence by explaining failures and finding signals of efficacy, medRxiv,
doi:10.1101/2021.09.07.21263194Goldfeld, Wu, Tarpey, Prospective individual patient data meta-analysis: evaluating convalescent plasma for COVID-19, Stat Med,
doi:10.1002/sim.9115Hamilton, 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,
doi:10.1016/j.ijid.2021.06.034Herrera, Morano, Celikgil, Characterization of the SARS-CoV-2 S protein: biophysical, biochemical, structural, and antigenic analysis, ACS Omega,
doi:10.1021/acsomega.0c03512Horby, Lim, Emberson, None
Hróbjartsson, Gøtzsche, Gluud, The controlled clinical trial turns 100 years: Fibiger's trial of serum treatment of diphtheria, BMJ,
doi:10.1136/bmj.317.7167.1243Joyner, Carter, Senefeld, Convalescent plasma antibody levels and the risk of death from Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2031893Kraft, Hewlett, Koepsell, None
Kunze, Johnson, Van Helmond, Mortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors, Nat Commun,
doi:10.1038/s41467-021-25113-5Körper, Weiss, Zickler, Results of the CAPSID randomized trial for high-dose convalescent plasma in severe COVID-19 patients, J Clin Invest,
doi:10.1172/JCI152264Liu, Lin, Baine, Convalescent plasma treatment of severe COVID-19: a propensity Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients Original Investigation Research jamainternalmedicine.com, JAMA Internal Medicine
Maiztegui, Fernandez, De Damilano, Efficacy of immune plasma in treatment of Argentine haemorrhagic fever and association between treatment and a late neurological syndrome, Lancet,
doi:10.1016/S0140-6736(79)92335-3Mcguire, Redden, The use of convalescent human serum in influenza pneumonia-a preliminary report, Am J Public Health,
doi:10.2105/AJPH.8.10.741Plasma, Group on the Clinical Characterisation and Management of COVID-19 infection. A minimal common outcome measure set for COVID-19 clinical research, Lancet Infect Dis,
doi:10.1016/S1473-3099(20)30483-7Simonovich, Pratx, Scibona, Group. A randomized trial of convalescent plasma in Covid-19 severe pneumonia, N Engl J Med,
doi:10.1056/NEJMoa2031304Thompson, Henderson, Shah, None
Thompson, Hughes, Ngai, Rapid emergence and epidemiologic characteristics of the SARS-CoV-2 B.1.526 variant-New, MMWR Morb Mortal Wkly Rep,
doi:10.15585/mmwr.mm7019e1
