COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials

Background Monoclonal antibody and antiviral treatments for COVID-19 disease remain largely unavailable worldwide, and existing monoclonal antibodies may be less active against circulating omicron variants. Although treatment with COVID-19 convalescent plasma (CCP) is promising, randomized clinical trials (RCTs) among outpatients have shown mixed results. Methods We conducted an individual participant data meta-analysis from all outpatient CCP RCTs to assess the overall risk reduction for all-cause hospitalizations by day 28 in all participants who had transfusion initiated. Relevant trials were identified by searching MEDLINE, Embase, MedRxiv, WHO, Cochrane Library, and Web of Science from January 2020 to September 2022. Results Five included studies from four countries enrolled and transfused 2,620 adult patients. Comorbidities were present in 1,795 (69%). The anti-Spike or virus neutralizing antibody titer range across all trials was broad. 160 (12.2%) of 1315 control patients were hospitalized, versus 111 (8.5%) of 1305 CCP-treated patients, yielding a 3.7% (95%CI: 1.3%-6.0%; p=.001) ARR and 30.1% RRR for all-cause hospitalization. The effect size was greatest in those with both early transfusion and high titer with a 7.6% ARR (95%CI: 4.0%-11.1%; p=.0001) accompanied by at 51.4% RRR. No significant reduction in hospitalization was seen with treatment > 5 days after symptom onset or in those receiving CCP with antibody titers below the median titer. Conclusions Among outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization. CCP may be most effective when given within 5 days of symptom onset and when antibody titer is higher. Key Points While the outpatient COVID-19 randomized controlled trial meta-analysis indicated heterogeneity in participant risk factors and convalescent plasma, the combined CCP efficacy for reducing hospitalization was significant, improving with transfusion within 5 days of symptom onset and high antibody neutralization levels. ### Competing Interest Statement RL report receiving fees for serving as investigators from Pfizer; FP reports receiving fees for serving as a principal investigator from Pfizer, DJS reports AliquantumRx Founder and Board member with stock options (macrolide for malaria), Hemex Health malaria diagnostics consulting and royalties for malaria diagnostic test control standards to Alere- all outside of submitted work. BR reports advisory board membership for Roche and Astra-Zeneca on a COVID-19 therapy and membership of DSMB of a COVID-19 treatment study by Exevir. ### Funding Statement This work was supported principally by the U.S. Department of Defense s (DOD) Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND), in collaboration with the Defense Health Agency (DHA) (contract number: W911QY2090012), with additional support from Bloomberg Philanthropies, State of Maryland, the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID)3R01AI152078-01S1, NIH National Center for Advancing Translational Sciences (NCATS) U24TR001609, Division of Intramural Research NIAID NIH, Mental Wellness Foundation, Moriah Fund, Octapharma, HealthNetwork Foundation and the Shear Family Foundation. CoV-Early was supported by a research grant from ZonMw, the Netherlands (10430062010001). Sanquin Blood Supply provided convalescent plasma free of charge for study sites in the Netherlands. CONV-ERT was sponsored by the Fight AIDS and Infectious Diseases Foundation (Badalona, Spain) with funding from the pharmaceutical company, Grifols Worldwide Operations (Dublin, Ireland), and the Crowdfunding campaign, YoMeCorono. The study received support from the Hospital Universitari Germans Trias i Pujol, and Banc de Sang i Teixits de Catalunya. CCP-Argentina was supported by the Bill and Melinda Gates Foundation and by the Fundacion INFANT Pandemic Fund, which received contributions from Laboratorio Roemmers, Bodega Vistalba, Swiss Medical Group, Laboratorios Bago, Laboratorio Raffo, Laboratorios Monserrat y Eclair, Tuteur Sacifia, TASA Logistica, Fundacion Inversiones y Representaciones, Puerto Asis Investments, and Fundacion Hematologica Sarmiento and individual contributions from Alec Oxenford, Carlos Kulish and family, Renato Montefiore and family, Irene Gorodisch, Alejandro Gorodisch, the Braun family, Agustin Otero-Monsegur, and Luis R. Otero. C3PO was supported by awards (1OT2HL156812-01, U24NS100659, and U24NS100655) from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health and by a contract (75A50120C00094) with the Biomedical Advanced Research and Development Authority (BARDA) through the Department of Health and Human Services and the Operation Warp Speed interagency program. Support included funding and material support in the form of plasma and testing supplies. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This is an individual patient meta-analysis of 5 outpatient trials each of which obtained ethical approval by review boards listed as follows: IRB of Johns Hopkins University gave ethical approval of the CSSC study. The CONV-ERT study protocol was approved by the Ethics Committee at Hospital Germans Trias i Pujol. The medical ethical review board of the Erasmus 108 MC gave approval for the conduction of the COV-Early study. Advarra gave approval for the C3PO study. In Argentina the trial was approved by the individual IRB at participating centers and by the state of Buenos Aires I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data is available from individual authors upon request.