Abstract: The Journal of Clinical Investigation   CLINICAL MEDICINE A randomized controlled study of convalescent plasma for individuals hospitalized with COVID-19 pneumonia Katharine J. Bar,1 Pamela A. Shaw,1,2 Grace H. Choi,1 Nicole Aqui,1 Andrew Fesnak,1 Jasper B. Yang,1,2 Haideliza Soto-Calderon,1 Lizette Grajales,1 Julie Starr,1 Michelle Andronov,1 Miranda Mastellone,1 Chigozie Amonu,1 Geoff Feret,1 Maureen DeMarshall,1 Marie Buchanan,1 Maria Caturla,1 James Gordon,1 Alan Wanicur,1 M. Alexandra Monroy,1 Felicity Mampe,1 Emily Lindemuth,1 Sigrid Gouma,1 Anne M. Mullin,1 Holly Barilla,1 Anastasiya Pronina,1 Leah Irwin,1 Raeann Thomas,1 Risa A. Eichinger,1 Faye Demuth,1 Eline T. Luning Prak,1 Jose L. Pascual,1 William R. Short,1 Michal A. Elovitz,1 Jillian Baron,1 Nuala J. Meyer,1 Kathleen O. Degnan,1 Ian Frank,1 Scott E. Hensley,1 Donald L. Siegel,1 and Pablo Tebas1 Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 2Kaiser Permanente Washington Health Research Group, Seattle, Washington, USA. 1 BACKGROUND. Antibody-based strategies for COVID-19 have shown promise in prevention and treatment of early disease. COVID-19 convalescent plasma (CCP) has been widely used but results from randomized trials supporting its benefit in hospitalized patients with pneumonia are limited. Here, we assess the efficacy of CCP in severely ill, hospitalized adults with COVID-19 pneumonia. METHODS. We performed a randomized control trial (PennCCP2), with 80 adults hospitalized with COVID-19 pneumonia, comparing up to 2 units of locally sourced CCP plus standard care versus standard care alone. The primary efficacy endpoint was comparison of a clinical severity score. Key secondary outcomes include 14- and 28-day mortality, 14- and 28-day maximum 8-point WHO ordinal score (WHO8) score, duration of supplemental oxygenation or mechanical ventilation, respiratory SARS-CoV-2 RNA, and anti–SARS-CoV-2 antibodies. RESULTS. Eighty hospitalized adults with confirmed COVID-19 pneumonia were enrolled at median day 6 of symptoms and day 1 of hospitalization; 60% were anti–SARS-CoV-2 antibody seronegative. Participants had a median of 3 comorbidities, including risk factors for severe COVID-19 and immunosuppression. CCP treatment was safe and conferred significant benefit by clinical severity score (median [MED] and interquartile range [IQR] 10 [5.5–30] vs. 7 [2.75–12.25], P = 0.037) and 28-day mortality (n = 10, 26% vs. n = 2, 5%; P = 0.013). All other prespecified outcome measures showed weak evidence toward benefit of CCP. CONCLUSION. Two units of locally sourced CCP administered early in hospitalization to majority seronegative participants conferred a significant benefit in clinical severity score and 28-day mortality. Results suggest CCP may benefit select populations, especially those with comorbidities who are treated early. TRIAL REGISTRATION. ClinicalTrials.gov NCT04397757. FUNDING. University of Pennsylvania.