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Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized PatientsA Randomized Clinical Trial

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

Question  Does COVID-19 convalescent plasma (CCP), compared with placebo, improve the clinical status of hospitalized patients with COVID-19 requiring noninvasive supplemental oxygen?

Findings  In this randomized clinical trial including 941 patients, based on the World Health Organization 11-point Ordinal Scale for Clinical Improvement, CCP did not benefit 468 participants randomized to CCP compared with 473 randomized to placebo from April 2020 to March 2021. However, in exploratory analyses, CCP appeared to benefit those enrolled from April to June 2020, the period when most participants received high-titer CCP and were not receiving remdesivir and corticosteroids at randomization.

Meaning  In this trial, CCP did not meet prespecified outcomes for efficacy, but high-titer CCP may have benefited hospitalized patients with COVID-19 early in the pandemic when other treatments were not in use, suggesting a heterogenous treatment effect over time.

Abstract

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.

Trial Registration  ClinicalTrials.gov Identifier: NCT04364737

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Article Information

Accepted for Publication: October 1, 2021.

Published Online: December 13, 2021. doi:10.1001/jamainternmed.2021.6850

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Ortigoza MB et al. JAMA Internal Medicine.

Corresponding Author: Liise-anne Pirofski, MD, Division of Infectious Disease, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Room 610, Belfer Building, Bronx, NY 10461 (l.pirofski@einsteinmed.org).

The CONTAIN COVID-19 Consortium Authors: Lalitha Parameswaran, MD, MPH; Anthony T. Corcoran, MD; Abhinav Rohatgi, MD; Marta W. Wronska, MO; Xinyuan Wu, MD; Ranjini Srinivasan, MD; Fang-Ming Deng, MD, PhD; Thomas D. Filardo, MD; Jay Pendse, MD, PhD; Simone B. Blaser, MD; Olga Whyte, BSN, RN; Jacqueline M. Gallagher, MSN/BSN, RN; Ololade E. Thomas, MPH, BSN, RN; Danibel Ramos, BSN, RN; Caroline L. Sturm-Reganato, BA, BSN, RN; Charlotte C. Fong, BS, RN; Ivy M. Daus, BSN, RN; Arianne Gisselle Payoen, RN; Joseph T. Chiofolo, DO, MS; Mark T. Friedman, DO; Ding Wen Wu, MD, PhD; 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, MD; Carolyn Z. Grimes, DrPH; Karen W. Eldin, MD; Virginia E Umana, BS; Jessica G. Martin, MD; Timothy R. Heath, MD; Fatimah O. Bello, MD; Daru Lane Ransford, BA; Maudry Laurent-Rolle, MD, PhD, BS; Sheela V. Shenoi, MD, MPH; Oscar Bate Akide-Ndunge, PhD; Bipin Thapa, MD, MS; Jennifer L. Peterson, PhD; Kelly Knauf; Shivani U. Patel; Laura L. Cheney, MD, PhD; Christopher A. Tormey, MD; Jeanne E. Hendrickson, MD.

Affiliations of The CONTAIN COVID-19 Consortium Authors: Division of Infectious Disease, Department of Medicine, NYU Grossman School of Medicine, New York, New York (Parameswaran, Filardo); Division of Infectious Disease, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York (Sarwar, Cheney); Department of Medicine, NYU Grossman School of Medicine, New York, New York (X. Wu, Pendse, Blaser, Whyte, Gallagher, Thomas, Ramos, Sturm-Reganato, Fong, Daus, Payoen); Department of Medicine, NYU Long Island School of Medicine, Mineola, New York (Rohatgi, Wronska, Schneider); Division of Infectious Disease, Department of Internal Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston (Grimes, Umana); Department of Emergency Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston (Wang, Huebinger); Miami Clinical and Translational Science Institute, University of Miami Miller School of Medicine Miami, Florida (Ransford); Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut (Laurent-Rolle, Shenoi, Akide-Ndunge); Division of Critical Care, Department of Internal Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston (Dronavalli); Department of Internal Medicine, The University of Texas Rio Grande Valley, Edinburg (Martin, Heath, Bello); Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee (Peterson); Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland (Patel); Department of Pathology, NYU Grossman School of Medicine, New York, New York (Deng, D. W. Wu, Jacobson); Clinical and Translational Science Institute of Southern Wisconsin, Medical College of Wisconsin Milwaukee (Knauf); Department of Urology, NYU Long Island School of Medicine, Mineola, New York (Corcoran); Department of Pediatrics, NYU Grossman School of Medicine, New York, New York (Srinivasan); Department of Pathology, NYU Long Island School of Medicine, Mineola, New York (Chiofolo, Friedman); Pfizer Vaccine Clinical Research and Development, Pfizer Inc, Pearl River, New York (Sarwar); Department of Emergency Medicine, The Ohio State University, Ohio (Wang); Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston (Bai, Eldin); Department of Medicine, Medical College of Wisconsin, Milwaukee (Thapa); Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut (Tormey, Hendrickson); Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut (Hendrickson).

Author Contributions: Dr Ortigoza had full access to all data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Ortigoza and Yoon are co-first authors and contributed equally to the study.

Concept and design: Ortigoza, Yoon, Goldfeld, Troxel, Daily, Philley, Desruisseaux, Chandran, Lai, Hilbert, Paroder, Shaker, McPherson, Keller, Grudzen, Hochman, Pirofski.

Acquisition, analysis, or interpretation of data: Ortigoza, Yoon, Goldfeld, Troxel, Daily, Yinxiang Wu, Li, Danni Wu, Cobb, Baptiste, O'Keeffe, Corpuz, Ostrosky-Zeichner, Amin, Zacharioudakis, Jayaweera, Yanyun Wu, Devine, Desruisseaux, Santin, Anjan, Mathew, B. Patel, Nigo, Upadhyay, Kupferman, Dentino, Nanchal, Merlo, Hager, Chandran, Lai, Rivera, Bikash, Lasso, Paroder, Asencio, Liu, Petkova, Bragat, Sacco, Pirofski, Parameswaran, Rohatgi, Wronska, Corcoran, X. Wu, Srinivasan, Deng, Filardo, Pendse, Blaser, Whyte, Gallagher, Thomas, Ramos, Sturm-Reganato, Fong, Daus, Payoen, Chiofolo, Friedman, Jacobson, Schneider, Sarwar, Ransford, Wang, Huebinger, Dronavalli, Bai, Grimes, Eldin, Umana, Martin, Heath, Bello, Laurent-Rolle, Shenoi, Akide Ndunge, Thapa, Peterson, Knauf, S. Patel, Cheney, Tormey, Hendrickson, Ding Wen Wu.

Drafting of the manuscript: Ortigoza, Yoon, Goldfeld, Troxel, Daily, Yinxiang Wu, Li, Liu, Pirofski.

Critical revision of the manuscript for important intellectual content: Ortigoza, Yoon, Goldfeld, Troxel, Daily, Danni Wu, Cobb, Baptiste, O'Keeffe, Corpuz, Ostrosky-Zeichner, Amin, Zacharioudakis, Jayaweera., Yanyun Wu, Philley, Devine, Desruisseaux, Santin, Anjan, Mathew, B. Patel, Nigo, Upadhyay, Kupferman, Dentino, Nanchal, Merlo, Hager, Chandran, Lai, Rivera, Bikash, Lasso, Hilbert, Paroder, Asencio, Petkova, Bragat, Shaker, McPherson, Sacco, Keller, Grudzen, Hochman, Pirofski, Parameswaran, Rohatgi, Wronska, Corcoran, X. Wu, Srinivasan, Deng, Filardo, Pendse, Blaser, Whyte, Gallagher, Thomas, Ramos, Sturm-Reganato, Fong, Daus, Payoen, Chiofolo, Friedman, Jacobson, Schneider, Sarwar, Ransford, Wang, Huebinger, Dronavalli, Bai, Grimes, Eldin, Umana, Martin, Heath, Bello, Laurent-Rolle, Shenoi, Akide Ndunge, Thapa, Peterson, Knauf, S. Patel, Cheney, Tormey, Hendrickson, Ding Wen Wu. Statistical analysis: Goldfeld, Troxel, Yinxiang Wu, Li, Danni Wu, Liu, Petkova.

Obtained funding: Ortigoza, Shaker, McPherson, Sacco, Keller, Grudzen, Hochman, Pirofski.

Administrative, technical, or material support: Daily, Cobb, Baptiste, Zacharioudakis, Yanyun Wu, Philley, Desruisseaux, Santin, Anjan, Mathew, Nigo, Upadhyay, Kupferman, Merlo, Hager, Chandran, Rivera, Bikash, Hilbert, Paroder, Asencio, Bragat, Sacco, Keller, Grudzen, Hochman, Parameswaran, Corcoran, X. Wu, Srinivasan, Deng, Filardo, Blaser, Gallagher, Thomas, Ramos, Daus, Payoen, Chiofolo, Friedman, Schneider, Ransford, Wang, Huebinger, Grimes, Eldin, Umana, Martin, Bello, Laurent-Rolle, Shenoi, Akide Ndunge, Thapa, Peterson, Knauf, Cheney, Tormey, Hendrickson, Ding Wen Wu.

Supervision: Ortigoza, Yoon, Troxel, Daily, O'Keeffe, Corpuz, Ostrosky-Zeichner, Amin, Zacharioudakis, Jayaweera., Philley, Desruisseaux, Anjan, Mathew, B. Patel, Nigo, Kupferman, Nanchal, Chandran, Lai, Hilbert, Paroder, Petkova, Sacco, Keller, Grudzen, Hochman, Pirofski, Parameswaran, Schneider, Ransford, Dronavalli, Grimes, Akide Ndunge.

Conflict of Interest Disclosures: Dr Philley reported receiving personal fees from INSMED as an advisory board member, consultant, researcher, and member of the speaker’s bureau, fees from participating in trials as an investigator from Regeneron, Redhill, AN2, Electromed, and Zambon; fees from the France Foundation speaker's bureau, and fees from the RMEI educational bureau outside the submitted work. Dr Devine reported serving as an investigator for the REGENERON studies. Dr Santin reported receiving grants from Puma, Immunomedics, Gilead, and Synthon; grants and personal fees from Merck; grants from Boehringer-Ingelheim and Genentech, grants and personal fees from Tesaro; and grants and personal fees from Eisai. Dr Chandran reported receiving fees from Biovaxys Technology Corp as a science advisory board member, consulting fees from Axon Advisors Consulting, and fees from Integrum Scientific LLC as a science advisory board member outside the submitted work; in addition, Dr Lai reported receiving consultant fees from Celdara Medical and grants from the Mapp Biopharmaceutical Collaboration and Integrated BioTherapeutics Collaboration outside the submitted work; in addition, Dr Lai had a patent for SARS-CoV2 laboratory diagnostic test pending and a patent for antibodies targeting SARS-CoV2 pending. Dr Shenoi having a spouse who worked for Merck Pharmaceuticals 1997-2007 and retains company stock in his retirement account. No other disclosures were reported.

Funding/Support: CONTAIN COVID-19 was supported in part by philanthropic funds to New York University and Montefiore Medical Center/Albert Einstein College of Medicine, a grant from the G. Harold and Leila Y. Mathers Foundation (Dr Pirofski), a Damon Runyon Cancer Research Foundation Physician-Scientist award (PST-25-19 to Dr Upadhyay), and grants from the NCATS/NIH Centers for Translational Science Awards (CTSA) to New York University (UL1 TR001445), Albert Einstein College of Medicine (UL1 TR002556), Yale University (UL1 TR001863), University of Miami (UL1 TR002736), University of Texas Health Sciences Center Houston (UL1 TR003167), Johns Hopkins University (UL1 TR003098), and Medical College of Wisconsin (UL1TR001436) and by a contract (75A50120C00094) with the Biomedical Advanced Research and Development Authority (BARDA) through the Department of Health and Human Services and the Operation Warp Speed interagency program, which provided support to the New York Blood Center to provide convalescent plasma for the trial. Irma and Abram S. Croll Charitable Trust and the Michael Price Foundation provided support for antibody assays. Montefiore COVID-19 Emergency Fund provided support for clinical expenses.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The CONTAIN COVID-19 Study Group is listed in Supplement 4.

Data and Safety Monitoring Board: Chair: E. M. Antman, MD; Voting: D. Kuritzkes, MD, S. Brown, MD, MS; Eva Petkova, PhD; A. Bateman-House, PhD; and Mengling Liu, PhD; Non-voting: Ying Lu, MS; Yi Li, MS; Yingzhi Qian, MS; and Yinxiang Wu, MS.

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

Data Sharing Statement: See Supplement 5.

Additional Contributions: We thank Q2 Solutions for their contributions in performing the viral neutralization assays for this work, in particular, the efforts of Sarah Daijogo, PhD, Rohini Sandesara, PhD, and Robert Bailer, PhD (no additional compensation). We acknowledge all members of the CONTAIN Study Group for their invaluable dedication and contributions to this trial, the hospital nursing professionals and support staff, and the study participants for their courage and willingness to contribute to new scientific knowledge about convalescent plasma. In addition, we acknowledge Sarah Dunsmore, PhD (National Center for Advancing Translational Sciences), for her tireless and outstanding program management, assistance, and invaluable support of the trial. We thank Jeff LaFleur, MA, and his team at the Einstein/Montefiore Biorepository for receiving, handling, and storing plasma samples; the New York Blood Center for supplying CCP for the trial and Donna Strauss, MS, of the New York Blood Center for managing CCP distribution and shipments from the New York Blood Center to trial sites; and Mary Homer, PhD, of the Biomedical Advanced Research Development Authority for providing CCP for the trial via the New York Blood Center.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 credit toward the CME of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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