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Seventy\u2010five participants were randomized from November 2020 to June 2021 in a double\u2010blind, multi\u2010site, placebo\u2010controlled, randomized trial (VA CURES\u20101) evaluating the impact of CCP vs. saline in Veterans hospitalized with COVID\u201019 with hypoxemia. The composite primary outcome was acute hypoxemic respiratory failure or all\u2010cause death by Day 29. We analyzed clinical outcomes, nasal viral RNA, plasma cytokines and viral evolution over time. Among 40 participants receiving saline and 35 receiving CCP with high neutralizing titers (median 1:1420), the percent reaching the primary outcome was similar (10%), as were time to clinical recovery and to nasal viral clearance. By whole genome sequencing, viral molecular complexity evolved pre\u2010 to posttreatment more frequently in recipients of saline vs. CCP (4 of 7 (57.1%) vs. 1 of 4 (25%), respectively), based on numbers of mixed allele positions. Numbers of amino acid\u2010changing, non\u2010synonymous mutations in the spike protein were greater in saline vs. CCP recipients. Both outcomes suggested purifying selection (reduced overall viral infection complexity) following CCP. In conclusion, convalescent plasma showed no significant clinical impact but may influence SARS\u2010CoV\u20102 complexity.<\/jats:p><jats:p><jats:bold>Trial Registration:<\/jats:bold> <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/ClinicalTrials.gov\">ClinicalTrials.gov<\/jats:ext-link> Identifier: NCT04539275<\/jats:p>","DOI":"10.1002\/jmv.70349","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T04:19:35Z","timestamp":1747887575000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of High\u2010Titer Convalescent Plasma on Clinical and Virologic Outcomes Among Veterans Hospitalized With SARS\u2010CoV\u20102 Infection: VA CoronavirUs Research and Efficacy Studies\u20101 (VA CURES\u20101)"],"prefix":"10.1002","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2702-5729","authenticated-orcid":false,"given":"Edward N.","family":"Janoff","sequence":"first","affiliation":[{"name":"Rocky Mountain Regional VA Medical Center Aurora Colorado USA"},{"name":"University of Colorado Denver School of Medicine Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei\u2010Chiung","family":"Shih","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs Cooperative Studies Program Coordinating Center Palo Alto California USA"},{"name":"Stanford University School of Medicine Stanford California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Curtis","family":"Donskey","sequence":"additional","affiliation":[{"name":"Case Western Reserve University School of Medicine Cleveland Ohio USA"},{"name":"Louis Stokes Cleveland VA Medical Center Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilana","family":"Belitskaya\u2010Levy","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs Cooperative Studies Program Coordinating Center Palo Alto California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norbert","family":"Brau","sequence":"additional","affiliation":[{"name":"James J. 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