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[Preprint]. 2021 Dec 21:2021.12.10.21267485.

doi: 10.1101/2021.12.10.21267485.

Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma

David J Sullivan¹, Kelly A Gebo¹, Shmuel Shoham¹, Evan M Bloch¹, Bryan Lau¹, Aarthi G Shenoy¹, Giselle S Mosnaim¹, Thomas J Gniadek¹, Yuriko Fukuta¹, Bela Patel¹, Sonya L Heath¹, Adam C Levine¹, Barry R Meisenberg¹, Emily S Spivak¹, Shweta Anjan¹, Moises A Huaman¹, Janis E Blair¹, Judith S Currier¹, James H Paxton¹, Jonathan M Gerber¹, Joann R Petrini¹, Patrick B Broderick¹, William Rausch¹, Marie Elena Cordisco¹, Jean Hammel¹, Benjamin Greenblatt¹, Valerie C Cluzet¹, Daniel Cruser¹, Kevin Oei¹, Matthew Abinante¹, Laura L Hammitt¹, Catherine G Sutcliffe¹, Donald N Forthal¹, Martin S Zand¹, Edward R Cachay¹, Jay S Raval¹, Seble G Kassaye¹, E Colin Foster¹, Michael Roth¹, Christi E Marshall¹, Anusha Yarava¹, Karen Lane¹, Nichol A McBee¹, Amy L Gawad¹, Nicky Karlen¹, Atika Singh¹, Daniel E Ford¹, Douglas A Jabs¹, Lawrence J Appel¹, David M Shade¹, Stephan Ehrhardt¹, Sheriza N Baksh¹, Oliver Laeyendecker¹, Andrew Pekosz¹, Sabra L Klein¹, Arturo Casadevall¹, Aaron A R Tobian¹, Daniel F Hanley¹

Affiliations

Affiliation

¹ Department of Medicine, Division of Infectious Diseases (S.S., K.G.) Department of Pathology (E.B., C.M. A.T.), Department of Neurology, Brain Injury Outcomes Division (A.Y., K.L., N. M., A.G., N.K. D.H.), Department of Ophthalmology (DJ), Welch Center (L.A.), Institute for Clinical and Translational Research (D.F.), Johns Hopkins University School of Medicine; the Departments of Molecular Microbiology and Immunology (A.C., D.S., S.K., A.P.), International Health (L.H., C.S.), and Epidemiology (B.L., D.S., S.E.) Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH (O.L.); Department of Medicine, Division of Hematology and Oncology, Medstar Washington Hospital Center, Washington, DC (A.S.); Division of Allergy and Immunology, Department of Medicine (G.M.), Department of Pathology (T.G.), Northshore University Health System, Evanston, IL; Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX (Y.F.); Department of Medicine, Divisions of Pulmonary and Critical Care Medicine, University of Texas Health Science Center, Houston, TX (B.P.); Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL (S.H.); Department of Emergency Medicine, Rhode Island Hospital/Brown University, Providence, RI (A.L.); Luminis Health, Annapolis, MD (B. M.); Department of Medicine, Division of Infectious Diseases, University of Utah, Salt Lake City, UT (E.S); Department of Medicine, Division of Infectious Diseases, University of Miami, Miller School of Medicine, Miami, FL (S.A.); Department of Medicine, Division of Infectious Diseases University of Cincinnati, Cincinnati, OH (M.H.); Department of Medicine, Division of Infectious Diseases, Mayo Clinic Hospital, Phoenix, AZ (J.B.); Department of Medicine, Division of Infectious Diseases, University of California, Los Angeles, Los Angeles, CA (J.C.); Department of Emergency Medicine, Wayne State University, Detroit, MI (J.P.); Department of Medicine, Division of Hematology and Oncology, University of Massachusetts, Worchester, MA (J.G.); Nuvance Health, Danbury, CT (J.P., W.R., M.E.C); Nuvance Health Danbury Hospital, Danbury, CT (P.B.); Nuvance Health Norwalk Hospital, Norwalk, CT (J.H., B.G.); Nuvance Health Vassar Brothers Medical Center, Poughkeepsie, NY (V.C., D.C.); Ascada Research, Fullerton, CA (K.O, M.A.); Department of Medicine, Division of Infectious Diseases, University of California, Irvine, Irvine, CA (D.F.); Department of Medicine, University of Rochester, Rochester, NY (M.Z.); Department of Medicine, Division of Infectious Diseases, University of California, San Diego, San Diego, CA (E.C.); Department of Pathology, University of New Mexico, Albuquerque, NM (J.R.); Department of Medicine, Division of Infectious Diseases, Medstar Georgetown University Hospital, Washington, D.C. (S.K.), The Bliss Group, New York City, NY, (M.R.) The Next Practice, Austin, TX (C.F.).

PMID: 34981068
PMCID: PMC8722611
DOI: 10.1101/2021.12.10.21267485

Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma

David J Sullivan et al. medRxiv. 2021.

[Preprint]. 2021 Dec 21:2021.12.10.21267485.

doi: 10.1101/2021.12.10.21267485.

Authors

Affiliation

¹ Department of Medicine, Division of Infectious Diseases (S.S., K.G.) Department of Pathology (E.B., C.M. A.T.), Department of Neurology, Brain Injury Outcomes Division (A.Y., K.L., N. M., A.G., N.K. D.H.), Department of Ophthalmology (DJ), Welch Center (L.A.), Institute for Clinical and Translational Research (D.F.), Johns Hopkins University School of Medicine; the Departments of Molecular Microbiology and Immunology (A.C., D.S., S.K., A.P.), International Health (L.H., C.S.), and Epidemiology (B.L., D.S., S.E.) Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH (O.L.); Department of Medicine, Division of Hematology and Oncology, Medstar Washington Hospital Center, Washington, DC (A.S.); Division of Allergy and Immunology, Department of Medicine (G.M.), Department of Pathology (T.G.), Northshore University Health System, Evanston, IL; Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX (Y.F.); Department of Medicine, Divisions of Pulmonary and Critical Care Medicine, University of Texas Health Science Center, Houston, TX (B.P.); Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL (S.H.); Department of Emergency Medicine, Rhode Island Hospital/Brown University, Providence, RI (A.L.); Luminis Health, Annapolis, MD (B. M.); Department of Medicine, Division of Infectious Diseases, University of Utah, Salt Lake City, UT (E.S); Department of Medicine, Division of Infectious Diseases, University of Miami, Miller School of Medicine, Miami, FL (S.A.); Department of Medicine, Division of Infectious Diseases University of Cincinnati, Cincinnati, OH (M.H.); Department of Medicine, Division of Infectious Diseases, Mayo Clinic Hospital, Phoenix, AZ (J.B.); Department of Medicine, Division of Infectious Diseases, University of California, Los Angeles, Los Angeles, CA (J.C.); Department of Emergency Medicine, Wayne State University, Detroit, MI (J.P.); Department of Medicine, Division of Hematology and Oncology, University of Massachusetts, Worchester, MA (J.G.); Nuvance Health, Danbury, CT (J.P., W.R., M.E.C); Nuvance Health Danbury Hospital, Danbury, CT (P.B.); Nuvance Health Norwalk Hospital, Norwalk, CT (J.H., B.G.); Nuvance Health Vassar Brothers Medical Center, Poughkeepsie, NY (V.C., D.C.); Ascada Research, Fullerton, CA (K.O, M.A.); Department of Medicine, Division of Infectious Diseases, University of California, Irvine, Irvine, CA (D.F.); Department of Medicine, University of Rochester, Rochester, NY (M.Z.); Department of Medicine, Division of Infectious Diseases, University of California, San Diego, San Diego, CA (E.C.); Department of Pathology, University of New Mexico, Albuquerque, NM (J.R.); Department of Medicine, Division of Infectious Diseases, Medstar Georgetown University Hospital, Washington, D.C. (S.K.), The Bliss Group, New York City, NY, (M.R.) The Next Practice, Austin, TX (C.F.).

PMID: 34981068
PMCID: PMC8722611
DOI: 10.1101/2021.12.10.21267485

Abstract

Background: The efficacy of polyclonal high titer convalescent plasma to prevent serious complications of COVID-19 in outpatients with recent onset of illness is uncertain.

Methods: This multicenter, double-blind randomized controlled trial compared the efficacy and safety of SARS-CoV-2 high titer convalescent plasma to placebo control plasma in symptomatic adults ≥18 years positive for SARS-CoV-2 regardless of risk factors for disease progression or vaccine status. Participants with symptom onset within 8 days were enrolled, then transfused within the subsequent day. The measured primary outcome was COVID-19-related hospitalization within 28 days of plasma transfusion. The enrollment period was June 3, 2020 to October 1, 2021.

Results: A total of 1225 participants were randomized and 1181 transfused. In the pre-specified modified intention-to-treat analysis that excluded those not transfused, the primary endpoint occurred in 37 of 589 (6.3%) who received placebo control plasma and in 17 of 592 (2.9%) participants who received convalescent plasma (relative risk, 0.46; one-sided 95% upper bound confidence interval 0.733; P=0.004) corresponding to a 54% risk reduction. Examination with a model adjusting for covariates related to the outcome did not change the conclusions.

Conclusion: Early administration of high titer SARS-CoV-2 convalescent plasma reduced outpatient hospitalizations by more than 50%. High titer convalescent plasma is an effective early outpatient COVID-19 treatment with the advantages of low cost, wide availability, and rapid resilience to variant emergence from viral genetic drift in the face of a changing pandemic.

Trial registration: ClinicalTrials.gov number, NCT04373460.

Keywords: COVID-19; COVID-19 convalescent plasma; SARS-CoV-2; blood transfusion; therapy.

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Figures

**Figure 1.. Enrollment, Randomization and Treatment Populations**
Potential participants who a diagnostic test positive for SARS-CoV-2 and < 8 days of COVID-19 were assessed both for eligibility by study personnel and by investigators to confirm that they were safe for outpatient management. Participants may have had >1 reason for exclusion from the trial. The intention-to-treat population included all randomized participants and the modified-ITT excluded randomized participants who did not receive assigned trial product.

**Figure 2.. Probability of hospitalization**
a). Cumulative incidence of COVID-19 related hospitalization, unadjusted with confidence interval presented along with TMLE model estimates; b). adjusted estimated difference in the expected time to hospitalization (> 0: increased expected days to hospitalization for CCP); c). adjusted estimate of the risk difference between treatment arms (<0: lower risk of hospitalization for CCP). 95% CI=One-sided 95% confidence interval.

See this image and copyright information in PMC

Comment in

Experience with COVID-19 convalescent plasma provides vital guidance to future pandemics.
Hartmann J, Bloch EM, Burnouf T. Hartmann J, et al. Transfusion. 2022 Mar;62(3):681-684. doi: 10.1111/trf.16810. Epub 2022 Jan 30. Transfusion. 2022. PMID: 35098540 No abstract available.

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This is a preprint.

Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma

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Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma

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