Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial

Passive Immunity Trial for Our Nation (PassITON) Investigators

doi:10.1016/j.chest.2022.06.029

Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial

Passive Immunity Trial for Our Nation (PassITON) Investigators

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

Background: Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy. Research Question: Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? Study Design and Methods: This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies (“serostatus”) at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. Results: Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58). Interpretation: Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes. Clinical Trial Registration: ClinicalTrials.gov; No.: NCT04362176; URL: www.clinicaltrials.gov

Original language	English (US)
Pages (from-to)	982-994
Number of pages	13
Journal	CHEST
Volume	162
Issue number	5
DOIs	https://doi.org/10.1016/j.chest.2022.06.029
State	Published - Nov 2022

Bibliographical note

Funding Information:
The rationale and design of this trial have been previously published 18 and are available in the protocol and statistical analysis plan included as Supplemental Data . We conducted a multicenter, blinded, placebo-controlled, randomized clinical trial to study the efficacy and safety of COVID-19 convalescent plasma as a treatment for adults hospitalized with COVID-19. Patients were enrolled at 25 US hospitals ( e-Table 1 ) between April 28, 2020, and June 1, 2021. The trial started as a single center study at Vanderbilt University Medical Center with funding from the Dolly Parton COVID-19 Research Fund and then expanded to a multicenter study in September 2020 with funding from the National Center for Advancing Translational Sciences (NCATS). A central institutional review board at Vanderbilt University Medical Center approved the study. An independent Data and Safety Monitoring Board provided trial oversight. COVID-19 convalescent plasma was used in the trial under US Food and Drug Administration Investigational New Drug number 21080. Participants or legally authorized representatives provided written informed consent prior to trial participation.

Funding Information:
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. H. C. reports grants from IDBiologics and Takeda Vaccines, grants and other from AstraZeneca , outside the submitted work; and has patents for COVID-19 human monoclonal antibodies (multiple) with licenses to AstraZeneca, IDBiologics, and Leinco and royalties paid to the US government. J. D. Casey reports grants from the National Institute of Health (NIH) outside the submitted work. J. D. Chappell reports grants from the NIH and grants from the Dolly Parton COVID-19 Research Fund during the conduct of the study. J. E. C. reports serving as a consultant for Luna Innovations, Merck , and GlaxoSmithKline , and as a member of the Scientific Advisory Board of Meissa Vaccines and being the founder of IDBiologics; the laboratory of J. E. C. received sponsored research agreements from AstraZeneca , Takeda , and IDBiologics during the conduct of the study. Vanderbilt University has applied for patents for some of the antibodies in this paper, for which J. E. C. is an inventor. W. E. A. reports grants from NCATS, during the conduct of the study, and grants from Biomedical Advanced Research and Development Authority ( BARDA) outside the submitted work. P. G. reports that he is a co-inventor with Vanderbilt University on patents for SARS-CoV-2 human monoclonal antibodies (multiple) with licenses to AstraZeneca, IDBiologics, and Leinco and the US Government has certain rights to these antibodies. M. R. D. reports grants from the NIH and the Dolly Parton COVID-19 Research Fund during the conduct of this study. A. A. G. reports grants from the NIH, Department of Defense, the Centers for Disease Control and Prevention, and AbbVie, and grants from Faron Pharmaceuticals outside the submitted work. D. J. H. reports grants and personal fees from Cytovale, personal fees from Beckman-Coulter, and grants and personal fees from Opticyte outside the submitted work. C. J. L. reports grants from the NIH, Department of Defense, and the Centers for Disease Control and Prevention outside the submitted work; research contracts from bioMérieux, AbbVie, Entegrion, and Endpoint Health outside the submitted work; stock options in Bioscape Digital outside the submitted work; and patents (not licensed) for risk stratification in sepsis and septic shock issued to Cincinnati Children’s Hospital Medical Center outside the submitted work. T. W. R. reports receiving grant funding from the NIH for conducting this study and personal fees from Cumberland Pharmaceuticals, Inc; personal fees from Sanofi, Inc; and personal fees from Cytovale, Inc outside the submitted work. W. H. S. reports receiving grant funding from the NIH for conducting this study. L. J. S. reports grants from the NIH and grants from Dolly Parton COVID-19 Research Fund during the conduct of the study. None declared (A. P. W., T. G. S., H. S., J. M., C. B. T., V. D. C., H. R. O., N. I. S., C. H.; L. C., N. J. J., S. J. J., M. J. M., E. S. H., S. R. P., M. L.-V., M. d. W., D. H., C. S. C., C. M., C. S., A. E. J., J. S. R., S. M., T. S. I., X. Q., S. J. S., A. S., R. D. F., E. J. B., R. E. S.; I. T., S. M. Y., A. J. B.-H., L. W., J. M. P., J. P. R., G. R. B.).

Funding Information:
Author contributions: W. H. S. takes responsibility for this work overall. W. H. S. and T. W. R. led execution of the clinical trial. Data analyses were conducted at Vanderbilt University Medical Center by T. G. S. and L. W. who had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Further details of author contributions are as follows: study concept and design, W. H. S. A. P. W. T. G. S. R. H. C. J. D. Chappell, J. E. C. P. G. I. T. C. J. L. J. M. P. J. M. P. J. P. R. G. R. B. and T. W. R.; acquisition of data, W. H. S. A. P. W. H. S. J. M. T. G. S. V. D. C. H. R. O. N. I. S. C. H. A. A. G. L. C. N. J. J. D. J. H. S. J. J. M. J. M. E. S. H. S. R. P. M. L.-V. W. E. A. M. d. W. D. H. C. S. C. C. M. C. S. A. E. J. J. S. R. S. M. T. S. I. X. Q. S. J. S. A. S. R. D. F. A. J. B.-H. J. D. Casey, J. M. P. J. P. R. G. R. B. and T. W. R.; laboratory analyses, R. H. C. J. D. Chappell, J. E. C. M. R. D. P. G. L. J. S. R. E. S. I. T. S. M. Y. and E. J. B.; statistical analysis, T. G. S. C. J. L. and L. W.; and drafting of the first version of the manuscript, W. H. S. All authors contributed to interpretation of data and critical revision of the manuscript for important intellectual content. Funding/support: Primary funding for this work was provided by NCATS [3UL1TR002243-04S3]. Funding for pilot work was provided by the Dolly Parton COVID-19 Research Fund. Funding for Research Electronic Data Capture, trial innovation work, and the other data tools was provided by NCATS [UL1TR002243]. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. H. C. reports grants from IDBiologics and Takeda Vaccines, grants and other from AstraZeneca, outside the submitted work; and has patents for COVID-19 human monoclonal antibodies (multiple) with licenses to AstraZeneca, IDBiologics, and Leinco and royalties paid to the US government. J. D. Casey reports grants from the National Institute of Health (NIH) outside the submitted work. J. D. Chappell reports grants from the NIH and grants from the Dolly Parton COVID-19 Research Fund during the conduct of the study. J. E. C. reports serving as a consultant for Luna Innovations, Merck, and GlaxoSmithKline, and as a member of the Scientific Advisory Board of Meissa Vaccines and being the founder of IDBiologics; the laboratory of J. E. C. received sponsored research agreements from AstraZeneca, Takeda, and IDBiologics during the conduct of the study. Vanderbilt University has applied for patents for some of the antibodies in this paper, for which J. E. C. is an inventor. W. E. A. reports grants from NCATS, during the conduct of the study, and grants from Biomedical Advanced Research and Development Authority (BARDA) outside the submitted work. P. G. reports that he is a co-inventor with Vanderbilt University on patents for SARS-CoV-2 human monoclonal antibodies (multiple) with licenses to AstraZeneca, IDBiologics, and Leinco and the US Government has certain rights to these antibodies. M. R. D. reports grants from the NIH and the Dolly Parton COVID-19 Research Fund during the conduct of this study. A. A. G. reports grants from the NIH, Department of Defense, the Centers for Disease Control and Prevention, and AbbVie, and grants from Faron Pharmaceuticals outside the submitted work. D. J. H. reports grants and personal fees from Cytovale, personal fees from Beckman-Coulter, and grants and personal fees from Opticyte outside the submitted work. C. J. L. reports grants from the NIH, Department of Defense, and the Centers for Disease Control and Prevention outside the submitted work; research contracts from bioMérieux, AbbVie, Entegrion, and Endpoint Health outside the submitted work; stock options in Bioscape Digital outside the submitted work; and patents (not licensed) for risk stratification in sepsis and septic shock issued to Cincinnati Children's Hospital Medical Center outside the submitted work. T. W. R. reports receiving grant funding from the NIH for conducting this study and personal fees from Cumberland Pharmaceuticals, Inc; personal fees from Sanofi, Inc; and personal fees from Cytovale, Inc outside the submitted work. W. H. S. reports receiving grant funding from the NIH for conducting this study. L. J. S. reports grants from the NIH and grants from Dolly Parton COVID-19 Research Fund during the conduct of the study. None declared (A. P. W. T. G. S. H. S. J. M. C. B. T. V. D. C. H. R. O. N. I. S. C. H.; L. C. N. J. J. S. J. J. M. J. M. E. S. H. S. R. P. M. L.-V. M. d. W. D. H. C. S. C. C. M. C. S. A. E. J. J. S. R. S. M. T. S. I. X. Q. S. J. S. A. S. R. D. F. E. J. B. R. E. S.; I. T. S. M. Y. A. J. B.-H. L. W. J. M. P. J. P. R. G. R. B.). Role of the sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Data-sharing statement: Data will be available approximately 90 days following publication of the primary manuscript reporting trial results. Deidentified, patient-level data with a supporting data dictionary will be available. Data from this trial are intended to be shared via the National Heart, Lung, and Blood Institute BioData Catalyst, which can be accessed at: https://biodatacatalyst.nhlbi.nih.gov/. Other contributions: The authors thank all the plasma donors who gave their time and plasma for infusion in the trial. They also thank all the patients who participated in this study. For use of the WHO anti-SARS-COV-2 antibody standard, they thank the anonymous donors of the plasma samples for their consent, which has allowed WHO International standard for anti-SARS-CoV-2 human immunoglobulin to be prepared. The authors also express our gratitude to those who have coordinated the collection of the convalescent plasma: Malcom Semple (University of Liverpool), Lance Turtle (University of Liverpool), Peter Openshaw (Imperial College London), and Kenneth Baillie (University of Edinburgh) on behalf of the ISARIC4C Investigators; and Heli Harvala Simmonds and David Roberts (National Health Service Blood and Transplant). The authors also thank National Institute for Biological Standards and Control Standards Production and Development staff for the formulation and distribution of materials. Additional information: The e-Figures, e-Sections, and e-Tables are available online under “Supplementary Data.”

Funding Information:
Funding/support: Primary funding for this work was provided by NCATS [ 3UL1TR002243-04S3 ]. Funding for pilot work was provided by the Dolly Parton COVID-19 Research Fund. Funding for Research Electronic Data Capture, trial innovation work, and the other data tools was provided by NCATS [ UL1TR002243 ].

Publisher Copyright:
© 2022 American College of Chest Physicians

Keywords

COVID-19
SARS-CoV-2
convalescent plasma
passive immunity
Humans
Adult
Treatment Outcome
Hospitalization
COVID-19/therapy
Antibodies, Viral

PubMed: MeSH publication types

Randomized Controlled Trial
Multicenter Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1016/j.chest.2022.06.029

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Cite this

@article{b0eb1403d01f42aca34c19dc64810d95,

title = "Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial",

abstract = "Background: Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy. Research Question: Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? Study Design and Methods: This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies (“serostatus”) at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. Results: Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58). Interpretation: Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes. Clinical Trial Registration: ClinicalTrials.gov; No.: NCT04362176; URL: www.clinicaltrials.gov",

keywords = "COVID-19, SARS-CoV-2, convalescent plasma, passive immunity, Humans, Adult, Treatment Outcome, Hospitalization, COVID-19/therapy, Antibodies, Viral",

author = "{Passive Immunity Trial for Our Nation (PassITON) Investigators} and Self, {Wesley H.} and Wheeler, {Allison P.} and Stewart, {Thomas G.} and Harry Schrager and Jason Mallada and Thomas, {Christopher B.} and Cataldo, {Vince D.} and O'Neal, {Hollis R.} and Shapiro, {Nathan I.} and Conor Higgins and Ginde, {Adit A.} and Lakshmi Chauhan and Johnson, {Nicholas J.} and Henning, {Daniel J.} and Jaiswal, {Stuti J.} and Mammen, {Manoj J.} and Harris, {Estelle S.} and Pannu, {Sonal R.} and Maryrose Laguio-Vila and {El Atrouni}, Wissam and {de Wit}, Marjolein and Daanish Hoda and Cohn, {Claudia S.} and Carla McWilliams and Carl Shanholtz and Jones, {Alan E.} and Raval, {Jay S.} and Simon Mucha and Ipe, {Tina S.} and Xian Qiao and Schrantz, {Stephen J.} and Aarthi Shenoy and Fremont, {Richard D.} and Brady, {Eric J.} and Carnahan, {Robert H.} and Chappell, {James D.} and Crowe, {James E.} and Denison, {Mark R.} and Pavlo Gilchuk and Stevens, {Laura J.} and Sutton, {Rachel E.} and Isaac Thomsen and Yoder, {Sandra M.} and Bistran-Hall, {Amanda J.} and Casey, {Jonathan D.} and Lindsell, {Christopher J.} and Li Wang and Pulley, {Jill M.} and Rhoads, {Jillian P.} and Bernard, {Gordon R.}",

note = "Funding Information: The rationale and design of this trial have been previously published 18 and are available in the protocol and statistical analysis plan included as Supplemental Data . We conducted a multicenter, blinded, placebo-controlled, randomized clinical trial to study the efficacy and safety of COVID-19 convalescent plasma as a treatment for adults hospitalized with COVID-19. Patients were enrolled at 25 US hospitals ( e-Table 1 ) between April 28, 2020, and June 1, 2021. The trial started as a single center study at Vanderbilt University Medical Center with funding from the Dolly Parton COVID-19 Research Fund and then expanded to a multicenter study in September 2020 with funding from the National Center for Advancing Translational Sciences (NCATS). A central institutional review board at Vanderbilt University Medical Center approved the study. An independent Data and Safety Monitoring Board provided trial oversight. COVID-19 convalescent plasma was used in the trial under US Food and Drug Administration Investigational New Drug number 21080. Participants or legally authorized representatives provided written informed consent prior to trial participation. Funding Information: Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. H. C. reports grants from IDBiologics and Takeda Vaccines, grants and other from AstraZeneca , outside the submitted work; and has patents for COVID-19 human monoclonal antibodies (multiple) with licenses to AstraZeneca, IDBiologics, and Leinco and royalties paid to the US government. J. D. Casey reports grants from the National Institute of Health (NIH) outside the submitted work. J. D. Chappell reports grants from the NIH and grants from the Dolly Parton COVID-19 Research Fund during the conduct of the study. J. E. C. reports serving as a consultant for Luna Innovations, Merck , and GlaxoSmithKline , and as a member of the Scientific Advisory Board of Meissa Vaccines and being the founder of IDBiologics; the laboratory of J. E. C. received sponsored research agreements from AstraZeneca , Takeda , and IDBiologics during the conduct of the study. Vanderbilt University has applied for patents for some of the antibodies in this paper, for which J. E. C. is an inventor. W. E. A. reports grants from NCATS, during the conduct of the study, and grants from Biomedical Advanced Research and Development Authority ( BARDA) outside the submitted work. P. G. reports that he is a co-inventor with Vanderbilt University on patents for SARS-CoV-2 human monoclonal antibodies (multiple) with licenses to AstraZeneca, IDBiologics, and Leinco and the US Government has certain rights to these antibodies. M. R. D. reports grants from the NIH and the Dolly Parton COVID-19 Research Fund during the conduct of this study. A. A. G. reports grants from the NIH, Department of Defense, the Centers for Disease Control and Prevention, and AbbVie, and grants from Faron Pharmaceuticals outside the submitted work. D. J. H. reports grants and personal fees from Cytovale, personal fees from Beckman-Coulter, and grants and personal fees from Opticyte outside the submitted work. C. J. L. reports grants from the NIH, Department of Defense, and the Centers for Disease Control and Prevention outside the submitted work; research contracts from bioM{\'e}rieux, AbbVie, Entegrion, and Endpoint Health outside the submitted work; stock options in Bioscape Digital outside the submitted work; and patents (not licensed) for risk stratification in sepsis and septic shock issued to Cincinnati Children{\textquoteright}s Hospital Medical Center outside the submitted work. T. W. R. reports receiving grant funding from the NIH for conducting this study and personal fees from Cumberland Pharmaceuticals, Inc; personal fees from Sanofi, Inc; and personal fees from Cytovale, Inc outside the submitted work. W. H. S. reports receiving grant funding from the NIH for conducting this study. L. J. S. reports grants from the NIH and grants from Dolly Parton COVID-19 Research Fund during the conduct of the study. None declared (A. P. W., T. G. S., H. S., J. M., C. B. T., V. D. C., H. R. O., N. I. S., C. H.; L. C., N. J. J., S. J. J., M. J. M., E. S. H., S. R. P., M. L.-V., M. d. W., D. H., C. S. C., C. M., C. S., A. E. J., J. S. R., S. M., T. S. I., X. Q., S. J. S., A. S., R. D. F., E. J. B., R. E. S.; I. T., S. M. Y., A. J. B.-H., L. W., J. M. P., J. P. R., G. R. B.). Funding Information: Author contributions: W. H. S. takes responsibility for this work overall. W. H. S. and T. W. R. led execution of the clinical trial. Data analyses were conducted at Vanderbilt University Medical Center by T. G. S. and L. W. who had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Further details of author contributions are as follows: study concept and design, W. H. S. A. P. W. T. G. S. R. H. C. J. D. Chappell, J. E. C. P. G. I. T. C. J. L. J. M. P. J. M. P. J. P. R. G. R. B. and T. W. R.; acquisition of data, W. H. S. A. P. W. H. S. J. M. T. G. S. V. D. C. H. R. O. N. I. S. C. H. A. A. G. L. C. N. J. J. D. J. H. S. J. J. M. J. M. E. S. H. S. R. P. M. L.-V. W. E. A. M. d. W. D. H. C. S. C. C. M. C. S. A. E. J. J. S. R. S. M. T. S. I. X. Q. S. J. S. A. S. R. D. F. A. J. B.-H. J. D. Casey, J. M. P. J. P. R. G. R. B. and T. W. R.; laboratory analyses, R. H. C. J. D. Chappell, J. E. C. M. R. D. P. G. L. J. S. R. E. S. I. T. S. M. Y. and E. J. B.; statistical analysis, T. G. S. C. J. L. and L. W.; and drafting of the first version of the manuscript, W. H. S. All authors contributed to interpretation of data and critical revision of the manuscript for important intellectual content. Funding/support: Primary funding for this work was provided by NCATS [3UL1TR002243-04S3]. Funding for pilot work was provided by the Dolly Parton COVID-19 Research Fund. Funding for Research Electronic Data Capture, trial innovation work, and the other data tools was provided by NCATS [UL1TR002243]. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. H. C. reports grants from IDBiologics and Takeda Vaccines, grants and other from AstraZeneca, outside the submitted work; and has patents for COVID-19 human monoclonal antibodies (multiple) with licenses to AstraZeneca, IDBiologics, and Leinco and royalties paid to the US government. J. D. Casey reports grants from the National Institute of Health (NIH) outside the submitted work. J. D. Chappell reports grants from the NIH and grants from the Dolly Parton COVID-19 Research Fund during the conduct of the study. J. E. C. reports serving as a consultant for Luna Innovations, Merck, and GlaxoSmithKline, and as a member of the Scientific Advisory Board of Meissa Vaccines and being the founder of IDBiologics; the laboratory of J. E. C. received sponsored research agreements from AstraZeneca, Takeda, and IDBiologics during the conduct of the study. Vanderbilt University has applied for patents for some of the antibodies in this paper, for which J. E. C. is an inventor. W. E. A. reports grants from NCATS, during the conduct of the study, and grants from Biomedical Advanced Research and Development Authority (BARDA) outside the submitted work. P. G. reports that he is a co-inventor with Vanderbilt University on patents for SARS-CoV-2 human monoclonal antibodies (multiple) with licenses to AstraZeneca, IDBiologics, and Leinco and the US Government has certain rights to these antibodies. M. R. D. reports grants from the NIH and the Dolly Parton COVID-19 Research Fund during the conduct of this study. A. A. G. reports grants from the NIH, Department of Defense, the Centers for Disease Control and Prevention, and AbbVie, and grants from Faron Pharmaceuticals outside the submitted work. D. J. H. reports grants and personal fees from Cytovale, personal fees from Beckman-Coulter, and grants and personal fees from Opticyte outside the submitted work. C. J. L. reports grants from the NIH, Department of Defense, and the Centers for Disease Control and Prevention outside the submitted work; research contracts from bioM{\'e}rieux, AbbVie, Entegrion, and Endpoint Health outside the submitted work; stock options in Bioscape Digital outside the submitted work; and patents (not licensed) for risk stratification in sepsis and septic shock issued to Cincinnati Children's Hospital Medical Center outside the submitted work. T. W. R. reports receiving grant funding from the NIH for conducting this study and personal fees from Cumberland Pharmaceuticals, Inc; personal fees from Sanofi, Inc; and personal fees from Cytovale, Inc outside the submitted work. W. H. S. reports receiving grant funding from the NIH for conducting this study. L. J. S. reports grants from the NIH and grants from Dolly Parton COVID-19 Research Fund during the conduct of the study. None declared (A. P. W. T. G. S. H. S. J. M. C. B. T. V. D. C. H. R. O. N. I. S. C. H.; L. C. N. J. J. S. J. J. M. J. M. E. S. H. S. R. P. M. L.-V. M. d. W. D. H. C. S. C. C. M. C. S. A. E. J. J. S. R. S. M. T. S. I. X. Q. S. J. S. A. S. R. D. F. E. J. B. R. E. S.; I. T. S. M. Y. A. J. B.-H. L. W. J. M. P. J. P. R. G. R. B.). Role of the sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Data-sharing statement: Data will be available approximately 90 days following publication of the primary manuscript reporting trial results. Deidentified, patient-level data with a supporting data dictionary will be available. Data from this trial are intended to be shared via the National Heart, Lung, and Blood Institute BioData Catalyst, which can be accessed at: https://biodatacatalyst.nhlbi.nih.gov/. Other contributions: The authors thank all the plasma donors who gave their time and plasma for infusion in the trial. They also thank all the patients who participated in this study. For use of the WHO anti-SARS-COV-2 antibody standard, they thank the anonymous donors of the plasma samples for their consent, which has allowed WHO International standard for anti-SARS-CoV-2 human immunoglobulin to be prepared. The authors also express our gratitude to those who have coordinated the collection of the convalescent plasma: Malcom Semple (University of Liverpool), Lance Turtle (University of Liverpool), Peter Openshaw (Imperial College London), and Kenneth Baillie (University of Edinburgh) on behalf of the ISARIC4C Investigators; and Heli Harvala Simmonds and David Roberts (National Health Service Blood and Transplant). The authors also thank National Institute for Biological Standards and Control Standards Production and Development staff for the formulation and distribution of materials. Additional information: The e-Figures, e-Sections, and e-Tables are available online under “Supplementary Data.” Funding Information: Funding/support: Primary funding for this work was provided by NCATS [ 3UL1TR002243-04S3 ]. Funding for pilot work was provided by the Dolly Parton COVID-19 Research Fund. Funding for Research Electronic Data Capture, trial innovation work, and the other data tools was provided by NCATS [ UL1TR002243 ]. Publisher Copyright: {\textcopyright} 2022 American College of Chest Physicians",

year = "2022",

month = nov,

doi = "10.1016/j.chest.2022.06.029",

language = "English (US)",

volume = "162",

pages = "982--994",

journal = "CHEST",

issn = "0012-3692",

publisher = "Elsevier Inc.",

number = "5",

}

TY - JOUR

T1 - Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19

T2 - A Blinded, Randomized, Placebo-Controlled Trial

AU - Passive Immunity Trial for Our Nation (PassITON) Investigators

AU - Self, Wesley H.

AU - Wheeler, Allison P.

AU - Stewart, Thomas G.

AU - Schrager, Harry

AU - Mallada, Jason

AU - Thomas, Christopher B.

AU - Cataldo, Vince D.

AU - O'Neal, Hollis R.

AU - Shapiro, Nathan I.

AU - Higgins, Conor

AU - Ginde, Adit A.

AU - Chauhan, Lakshmi

AU - Johnson, Nicholas J.

AU - Henning, Daniel J.

AU - Jaiswal, Stuti J.

AU - Mammen, Manoj J.

AU - Harris, Estelle S.

AU - Pannu, Sonal R.

AU - Laguio-Vila, Maryrose

AU - El Atrouni, Wissam

AU - de Wit, Marjolein

AU - Hoda, Daanish

AU - Cohn, Claudia S.

AU - McWilliams, Carla

AU - Shanholtz, Carl

AU - Jones, Alan E.

AU - Raval, Jay S.

AU - Mucha, Simon

AU - Ipe, Tina S.

AU - Qiao, Xian

AU - Schrantz, Stephen J.

AU - Shenoy, Aarthi

AU - Fremont, Richard D.

AU - Brady, Eric J.

AU - Carnahan, Robert H.

AU - Chappell, James D.

AU - Crowe, James E.

AU - Denison, Mark R.

AU - Gilchuk, Pavlo

AU - Stevens, Laura J.

AU - Sutton, Rachel E.

AU - Thomsen, Isaac

AU - Yoder, Sandra M.

AU - Bistran-Hall, Amanda J.

AU - Casey, Jonathan D.

AU - Lindsell, Christopher J.

AU - Wang, Li

AU - Pulley, Jill M.

AU - Rhoads, Jillian P.

AU - Bernard, Gordon R.

N1 - Funding Information: The rationale and design of this trial have been previously published 18 and are available in the protocol and statistical analysis plan included as Supplemental Data . We conducted a multicenter, blinded, placebo-controlled, randomized clinical trial to study the efficacy and safety of COVID-19 convalescent plasma as a treatment for adults hospitalized with COVID-19. Patients were enrolled at 25 US hospitals ( e-Table 1 ) between April 28, 2020, and June 1, 2021. The trial started as a single center study at Vanderbilt University Medical Center with funding from the Dolly Parton COVID-19 Research Fund and then expanded to a multicenter study in September 2020 with funding from the National Center for Advancing Translational Sciences (NCATS). A central institutional review board at Vanderbilt University Medical Center approved the study. An independent Data and Safety Monitoring Board provided trial oversight. COVID-19 convalescent plasma was used in the trial under US Food and Drug Administration Investigational New Drug number 21080. Participants or legally authorized representatives provided written informed consent prior to trial participation. Funding Information: Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. H. C. reports grants from IDBiologics and Takeda Vaccines, grants and other from AstraZeneca , outside the submitted work; and has patents for COVID-19 human monoclonal antibodies (multiple) with licenses to AstraZeneca, IDBiologics, and Leinco and royalties paid to the US government. J. D. Casey reports grants from the National Institute of Health (NIH) outside the submitted work. J. D. Chappell reports grants from the NIH and grants from the Dolly Parton COVID-19 Research Fund during the conduct of the study. J. E. C. reports serving as a consultant for Luna Innovations, Merck , and GlaxoSmithKline , and as a member of the Scientific Advisory Board of Meissa Vaccines and being the founder of IDBiologics; the laboratory of J. E. C. received sponsored research agreements from AstraZeneca , Takeda , and IDBiologics during the conduct of the study. Vanderbilt University has applied for patents for some of the antibodies in this paper, for which J. E. C. is an inventor. W. E. A. reports grants from NCATS, during the conduct of the study, and grants from Biomedical Advanced Research and Development Authority ( BARDA) outside the submitted work. P. G. reports that he is a co-inventor with Vanderbilt University on patents for SARS-CoV-2 human monoclonal antibodies (multiple) with licenses to AstraZeneca, IDBiologics, and Leinco and the US Government has certain rights to these antibodies. M. R. D. reports grants from the NIH and the Dolly Parton COVID-19 Research Fund during the conduct of this study. A. A. G. reports grants from the NIH, Department of Defense, the Centers for Disease Control and Prevention, and AbbVie, and grants from Faron Pharmaceuticals outside the submitted work. D. J. H. reports grants and personal fees from Cytovale, personal fees from Beckman-Coulter, and grants and personal fees from Opticyte outside the submitted work. C. J. L. reports grants from the NIH, Department of Defense, and the Centers for Disease Control and Prevention outside the submitted work; research contracts from bioMérieux, AbbVie, Entegrion, and Endpoint Health outside the submitted work; stock options in Bioscape Digital outside the submitted work; and patents (not licensed) for risk stratification in sepsis and septic shock issued to Cincinnati Children’s Hospital Medical Center outside the submitted work. T. W. R. reports receiving grant funding from the NIH for conducting this study and personal fees from Cumberland Pharmaceuticals, Inc; personal fees from Sanofi, Inc; and personal fees from Cytovale, Inc outside the submitted work. W. H. S. reports receiving grant funding from the NIH for conducting this study. L. J. S. reports grants from the NIH and grants from Dolly Parton COVID-19 Research Fund during the conduct of the study. None declared (A. P. W., T. G. S., H. S., J. M., C. B. T., V. D. C., H. R. O., N. I. S., C. H.; L. C., N. J. J., S. J. J., M. J. M., E. S. H., S. R. P., M. L.-V., M. d. W., D. H., C. S. C., C. M., C. S., A. E. J., J. S. R., S. M., T. S. I., X. Q., S. J. S., A. S., R. D. F., E. J. B., R. E. S.; I. T., S. M. Y., A. J. B.-H., L. W., J. M. P., J. P. R., G. R. B.). Funding Information: Author contributions: W. H. S. takes responsibility for this work overall. W. H. S. and T. W. R. led execution of the clinical trial. Data analyses were conducted at Vanderbilt University Medical Center by T. G. S. and L. W. who had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Further details of author contributions are as follows: study concept and design, W. H. S. A. P. W. T. G. S. R. H. C. J. D. Chappell, J. E. C. P. G. I. T. C. J. L. J. M. P. J. M. P. J. P. R. G. R. B. and T. W. R.; acquisition of data, W. H. S. A. P. W. H. S. J. M. T. G. S. V. D. C. H. R. O. N. I. S. C. H. A. A. G. L. C. N. J. J. D. J. H. S. J. J. M. J. M. E. S. H. S. R. P. M. L.-V. W. E. A. M. d. W. D. H. C. S. C. C. M. C. S. A. E. J. J. S. R. S. M. T. S. I. X. Q. S. J. S. A. S. R. D. F. A. J. B.-H. J. D. Casey, J. M. P. J. P. R. G. R. B. and T. W. R.; laboratory analyses, R. H. C. J. D. Chappell, J. E. C. M. R. D. P. G. L. J. S. R. E. S. I. T. S. M. Y. and E. J. B.; statistical analysis, T. G. S. C. J. L. and L. W.; and drafting of the first version of the manuscript, W. H. S. All authors contributed to interpretation of data and critical revision of the manuscript for important intellectual content. Funding/support: Primary funding for this work was provided by NCATS [3UL1TR002243-04S3]. Funding for pilot work was provided by the Dolly Parton COVID-19 Research Fund. Funding for Research Electronic Data Capture, trial innovation work, and the other data tools was provided by NCATS [UL1TR002243]. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. H. C. reports grants from IDBiologics and Takeda Vaccines, grants and other from AstraZeneca, outside the submitted work; and has patents for COVID-19 human monoclonal antibodies (multiple) with licenses to AstraZeneca, IDBiologics, and Leinco and royalties paid to the US government. J. D. Casey reports grants from the National Institute of Health (NIH) outside the submitted work. J. D. Chappell reports grants from the NIH and grants from the Dolly Parton COVID-19 Research Fund during the conduct of the study. J. E. C. reports serving as a consultant for Luna Innovations, Merck, and GlaxoSmithKline, and as a member of the Scientific Advisory Board of Meissa Vaccines and being the founder of IDBiologics; the laboratory of J. E. C. received sponsored research agreements from AstraZeneca, Takeda, and IDBiologics during the conduct of the study. Vanderbilt University has applied for patents for some of the antibodies in this paper, for which J. E. C. is an inventor. W. E. A. reports grants from NCATS, during the conduct of the study, and grants from Biomedical Advanced Research and Development Authority (BARDA) outside the submitted work. P. G. reports that he is a co-inventor with Vanderbilt University on patents for SARS-CoV-2 human monoclonal antibodies (multiple) with licenses to AstraZeneca, IDBiologics, and Leinco and the US Government has certain rights to these antibodies. M. R. D. reports grants from the NIH and the Dolly Parton COVID-19 Research Fund during the conduct of this study. A. A. G. reports grants from the NIH, Department of Defense, the Centers for Disease Control and Prevention, and AbbVie, and grants from Faron Pharmaceuticals outside the submitted work. D. J. H. reports grants and personal fees from Cytovale, personal fees from Beckman-Coulter, and grants and personal fees from Opticyte outside the submitted work. C. J. L. reports grants from the NIH, Department of Defense, and the Centers for Disease Control and Prevention outside the submitted work; research contracts from bioMérieux, AbbVie, Entegrion, and Endpoint Health outside the submitted work; stock options in Bioscape Digital outside the submitted work; and patents (not licensed) for risk stratification in sepsis and septic shock issued to Cincinnati Children's Hospital Medical Center outside the submitted work. T. W. R. reports receiving grant funding from the NIH for conducting this study and personal fees from Cumberland Pharmaceuticals, Inc; personal fees from Sanofi, Inc; and personal fees from Cytovale, Inc outside the submitted work. W. H. S. reports receiving grant funding from the NIH for conducting this study. L. J. S. reports grants from the NIH and grants from Dolly Parton COVID-19 Research Fund during the conduct of the study. None declared (A. P. W. T. G. S. H. S. J. M. C. B. T. V. D. C. H. R. O. N. I. S. C. H.; L. C. N. J. J. S. J. J. M. J. M. E. S. H. S. R. P. M. L.-V. M. d. W. D. H. C. S. C. C. M. C. S. A. E. J. J. S. R. S. M. T. S. I. X. Q. S. J. S. A. S. R. D. F. E. J. B. R. E. S.; I. T. S. M. Y. A. J. B.-H. L. W. J. M. P. J. P. R. G. R. B.). Role of the sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Data-sharing statement: Data will be available approximately 90 days following publication of the primary manuscript reporting trial results. Deidentified, patient-level data with a supporting data dictionary will be available. Data from this trial are intended to be shared via the National Heart, Lung, and Blood Institute BioData Catalyst, which can be accessed at: https://biodatacatalyst.nhlbi.nih.gov/. Other contributions: The authors thank all the plasma donors who gave their time and plasma for infusion in the trial. They also thank all the patients who participated in this study. For use of the WHO anti-SARS-COV-2 antibody standard, they thank the anonymous donors of the plasma samples for their consent, which has allowed WHO International standard for anti-SARS-CoV-2 human immunoglobulin to be prepared. The authors also express our gratitude to those who have coordinated the collection of the convalescent plasma: Malcom Semple (University of Liverpool), Lance Turtle (University of Liverpool), Peter Openshaw (Imperial College London), and Kenneth Baillie (University of Edinburgh) on behalf of the ISARIC4C Investigators; and Heli Harvala Simmonds and David Roberts (National Health Service Blood and Transplant). The authors also thank National Institute for Biological Standards and Control Standards Production and Development staff for the formulation and distribution of materials. Additional information: The e-Figures, e-Sections, and e-Tables are available online under “Supplementary Data.” Funding Information: Funding/support: Primary funding for this work was provided by NCATS [ 3UL1TR002243-04S3 ]. Funding for pilot work was provided by the Dolly Parton COVID-19 Research Fund. Funding for Research Electronic Data Capture, trial innovation work, and the other data tools was provided by NCATS [ UL1TR002243 ]. Publisher Copyright: © 2022 American College of Chest Physicians

PY - 2022/11

Y1 - 2022/11

N2 - Background: Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy. Research Question: Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? Study Design and Methods: This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies (“serostatus”) at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. Results: Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58). Interpretation: Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes. Clinical Trial Registration: ClinicalTrials.gov; No.: NCT04362176; URL: www.clinicaltrials.gov

AB - Background: Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy. Research Question: Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? Study Design and Methods: This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies (“serostatus”) at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. Results: Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58). Interpretation: Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes. Clinical Trial Registration: ClinicalTrials.gov; No.: NCT04362176; URL: www.clinicaltrials.gov

KW - COVID-19

KW - SARS-CoV-2

KW - convalescent plasma

KW - passive immunity

KW - Humans

KW - Adult

KW - Treatment Outcome

KW - Hospitalization

KW - COVID-19/therapy

KW - Antibodies, Viral

UR - http://www.scopus.com/inward/record.url?scp=85139060369&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85139060369&partnerID=8YFLogxK

U2 - 10.1016/j.chest.2022.06.029

DO - 10.1016/j.chest.2022.06.029

M3 - Article

C2 - 35780813

AN - SCOPUS:85139060369

SN - 0012-3692

VL - 162

SP - 982

EP - 994

JO - CHEST

JF - CHEST

IS - 5

ER -

Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial

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