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What is the pooled evidence from high-quality randomized clinical trials regarding the safety and potential benefit of convalescent plasma to treat hospitalized patients with COVID-19?
In this meta-analysis of 8 randomized clinical trials enrolling 2341 participants, individual patient data were monitored in real time and analyzed using a robust bayesian framework and advanced statistical modeling. No association of convalescent plasma with clinical outcomes was found.
These findings suggest that real-time individual patient data pooling and meta-analysis during a pandemic are feasible, offering a model for future research and providing a rich data resource.
COVID-19 convalescent plasma (CCP) is a potentially beneficial treatment for COVID-19 that requires rigorous testing.
To compile individual patient data from randomized clinical trials of CCP and to monitor the data until completion or until accumulated evidence enables reliable conclusions regarding the clinical outcomes associated with CCP.
From May to August 2020, a systematic search was performed for trials of CCP in the literature, clinical trial registry sites, and medRxiv. Domain experts at local, national, and international organizations were consulted regularly.
Eligible trials enrolled hospitalized patients with confirmed COVID-19, not receiving mechanical ventilation, and randomized them to CCP or control. The administered CCP was required to have measurable antibodies assessed locally.
Data Extraction and Synthesis
A minimal data set was submitted regularly via a secure portal, analyzed using a prespecified bayesian statistical plan, and reviewed frequently by a collective data and safety monitoring board.
Main Outcomes and Measures
Prespecified coprimary end points—the World Health Organization (WHO) 11-point ordinal scale analyzed using a proportional odds model and a binary indicator of WHO score of 7 or higher capturing the most severe outcomes including mechanical ventilation through death and analyzed using a logistic model—were assessed clinically at 14 days after randomization.
Eight international trials collectively enrolled 2369 participants (1138 randomized to control and 1231 randomized to CCP). A total of 2341 participants (median [IQR] age, 60 [50-72] years; 845 women [35.7%]) had primary outcome data as of April 2021. The median (IQR) of the ordinal WHO scale was 3 (3-6); the cumulative OR was 0.94 (95% credible interval [CrI], 0.74-1.19; posterior probability of OR <1 of 71%). A total of 352 patients (15%) had WHO score greater than or equal to 7; the OR was 0.94 (95% CrI, 0.69-1.30; posterior probability of OR <1 of 65%). Adjusted for baseline covariates, the ORs for mortality were 0.88 at day 14 (95% CrI, 0.61-1.26; posterior probability of OR <1 of 77%) and 0.85 at day 28 (95% CrI, 0.62-1.18; posterior probability of OR <1 of 84%). Heterogeneity of treatment effect sizes was observed across an array of baseline characteristics.
Conclusions and Relevance
This meta-analysis found no association of CCP with better clinical outcomes for the typical patient. These findings suggest that real-time individual patient data pooling and meta-analysis during a pandemic are feasible, offering a model for future research and providing a rich data resource.
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: December 15, 2021.
Published: January 25, 2022. doi:10.1001/jamanetworkopen.2021.47331
Correction: This article was corrected on March 4, 2022, to fix errors in Figure 3.
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Troxel AB et al. JAMA Network Open.
Corresponding Author: Andrea B. Troxel, ScD, Department of Population Health, NYU Grossman School of Medicine, 80 Madison Ave, Rm 5-55, New York, NY 10016 (email@example.com).
Author Contributions: Drs Troxel and Petkova had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Troxel, Petkova, Goldfeld, Liu, D. Wu, Duarte, Hsue, Luetkemeyer, Ortigoza, Pirofski, Rokx, Grudzen, Hochman, Antman.
Acquisition, analysis, or interpretation of data: Troxel, Petkova, Liu, Tarpey, Y. Wu, D. Wu, Agarwal, Avendaño-Solá, Bainbridge, Bar, Devos, Duarte, Gharbharan, Hsue, Kumar, Luetkemeyer, Meyfroidt, Nicola, Mukherjee, Ortigoza, Pirofski, Rijnders, Rokx, Sancho-Lopez, Shaw, Tebas, Yoon, Antman.
Drafting of the manuscript: Troxel, Petkova, Goldfeld, Liu, Tarpey, Y. Wu, Pirofski, Shaw, Antman.
Critical revision of the manuscript for important intellectual content: Troxel, Petkova, D. Wu, Agarwal, Avendaño-Solá, Bainbridge, Bar, Devos, Duarte, Gharbharan, Hsue, Kumar, Luetkemeyer, Meyfroidt, Nicola, Mukherjee, Ortigoza, Rijnders, Rokx, Sancho-Lopez, Tebas, Yoon, Grudzen, Hochman, Antman.
Statistical analysis: Troxel, Petkova, Goldfeld, Liu, Tarpey, Y. Wu, D. Wu, Shaw.
Obtained funding: Petkova, Luetkemeyer, Pirofski, Rokx, Grudzen, Hochman.
Administrative, technical, or material support: Troxel, Petkova, Agarwal, Avendaño-Solá, Bar, Gharbharan, Hochman, Antman.
Supervision: Troxel, Petkova, Liu, Agarwal, Devos, Duarte, Hsue, Nicola, Rokx, Sancho-Lopez, Antman.
Conflict of Interest Disclosures: Dr Petkova reported receiving grants from the National Institutes of Health outside the submitted work. Dr Devos reported receiving grants from Belgian Health Care Knowledge Centre during the conduct of the study. Dr Duarte reported receiving personal fees from Amgen, Astellas, Bristol Myers Squibb, Gilead Sciences, Jazz Pharmaceuticals, Kiadis Pharma, Miltenyi Biotec, Merck Sharp and Dohme, Omeros, Pfizer, Sanofi-Oncology, Sobi, and Takeda outside the submitted work. Dr Hsue reported receiving honoraria from Gilead and Merck and grants from Novartis outside the submitted work. Dr Luetkemeyer reported receiving grants from Marti and Steve Diamond Charitable Foundation (research grant support to University of California, San Francisco) during the conduct of the study. Dr Meyfroidt reported receiving grants from Belgian Health Care Knowledge Center (Dawn plasma trial funding) and grants from Research Foundation Flanders, Belgium (senior clinical investigator) outside the submitted work. Dr Nicola reported receiving grants from Fundação de Apoio à Pesquisa do Distrito Federal during the conduct of the study. Dr Pirofski reported receiving grants from Mathers Foundation during the conduct of the study. Dr Rijnders reported receiving grants from Erasmus Foundation during the conduct of the study. Dr Rokx reported receiving grants from Viiv, Gilead, and Janssen outside the submitted work. Dr Sancho-Lopez reported receiving personal fees from Bayer, Novartis, Merck, Boehringer Ingelheim, Lilly, GSK, and Incyte outside the submitted work. Dr Yoon reported receiving grants from G. Harold and Leila Y. Mathers Foundation during the conduct of the study. Dr Grudzen reported receiving grants from the National Institute on Aging, National Center for Complementary and Integrative Health, Patient-Centered Outcomes Research Institute, and Samuels Foundation outside the submitted work. Dr Hochman reported receiving grants from the National Heart, Lung, and Blood Institute during the conduct of the study. No other disclosures were reported.
Funding/Support: Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001445.
Role of the Funder/Sponsor: The funder 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.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Additional Contributions: David DeMets, PhD (University of Wisconsin, Madison), provided useful discussions, and Grace Choi, MS (University of Pennsylvania), assisted with data management and quality assurance; neither of them was compensated for their contributions. We thank the patients with COVID-19 who contributed so personally through their participation in the trials pooled here.
Additional Information: Members of the COMPILE collective Data and Safety Monitoring Board include Alison Bateman-House, PhD (NYU Grossman School of Medicine), Eric Boersma, PhD (Erasmus University Medical Center), David Glidden, PhD (University of California, San Francisco), L. Jeyaseelan, PhD (Christian Medical College), Emmanuel Lesaffre, PhD (KU Leuven), Grigorios Papageorgiou, PhD (Erasmus University Medical Center), Aitor Perez, PhD (Pivotal CR), Suman Pramanik, MD (Army Hospital Delhi), André Siqueira, MD (Instituo Nacional de Infectologica, Brasilia), John Szumowski, MD (University of California, San Francisco), Séverine Vermeire, MD (KU Leuven), and John Younger, MD (University City Science Center).
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