High-titre methylene blue-treated convalescent plasma as an early treatment for outpatients with COVID-19: a randomised, placebo-controlled trial

Fight AIDS and Infectious Diseases Foundation, Badalona, Spain; Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain. Electronic address: aalemany@flsida.org. ISGlobal, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain. Fight AIDS and Infectious Diseases Foundation, Badalona, Spain; Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain; Hospital Universitari Parc Taulí, I3PT, Sabadell, Spain. Emergency Department, Bellvitge University Hospital, Hospitalet de Llobregat, Spain. Fight AIDS and Infectious Diseases Foundation, Badalona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain. Unitat de Suport a la Recerca de la Catalunya Central, Fundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina, Sant Fruitós de Bages, Spain; Health Promotion in Rural Areas Research Group, Gerència Territorial de la Catalunya Central, Institut Català de la Salut, Sant Fruitós de Bages, Spain; Universitat de Vic-Universitat Central de Catalunya, Vic, Spain. Unitat de Suport a la Recerca de la Catalunya Central, Fundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina, Sant Fruitós de Bages, Spain. Salut Catalunya Central, Hospital de Berga, Berga, Spain. Fight AIDS and Infectious Diseases Foundation, Badalona, Spain; Clinical Research Support Unit, HUB-IDIBELL, Bellvitge University Hospital and Bellvitge Biomedical Research Institute, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain; Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain. Fight AIDS and Infectious Diseases Foundation, Badalona, Spain. Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. Emergency Department, Bellvitge University Hospital, Hospitalet de Llobregat, Spain; Clinical Research Support Unit, HUB-IDIBELL, Bellvitge University Hospital and Bellvitge Biomedical Research Institute, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain. Blood Bank Department, Banc de Sang i Teixits, Barcelona, Spain. Fight AIDS and Infectious Diseases Foundation, Badalona, Spain; Blood Bank Department, Banc de Sang i Teixits, Barcelona, Spain. Fight AIDS and Infectious Diseases Foundation, Badalona, Spain; Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain. Bioclever, Barcelona, Spain. Gerència Territorial Metropolitana Nord, Institut Català de la Salut, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain; Gerència Territorial Metropolitana Nord, Institut Català de la Salut, Barcelona, Spain. Gerència Territorial de la Catalunya Central, Institut Català de la Salut, Barcelona, Spain. Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain. IrsiCaixa AIDS Research Institute, Germans Trias i Pujol Research Institute, Can Ruti Campus, Badalona, Spain. Universitat de Vic-Universitat Central de Catalunya, Vic, Spain; IrsiCaixa AIDS Research Institute, Germans Trias i Pujol Research Institute, Can Ruti Campus, Badalona, Spain. Microbiology Department, Clinical Laboratory Metropolitana Nord, Badalona, Barcelona, Spain. Hospital for Tropical Diseases, London, UK; Clinical Research Department, London School of Hygiene and Tropical Medicine, London, UK. ISGlobal, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain; Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública, Madrid, Spain; ICREA, Pg Lluís Companys 23, Barcelona, Spain; Pediatrics Department, Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues, Barcelona, Spain; Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique. Management Department, Clinical Laboratory Metropolitana Nord, Badalona, Barcelona, Spain. Fight AIDS and Infectious Diseases Foundation, Badalona, Spain; Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain; Universitat de Vic-Universitat Central de Catalunya, Vic, Spain; IrsiCaixa AIDS Research Institute, Germans Trias i Pujol Research Institute, Can Ruti Campus, Badalona, Spain. Fight AIDS and Infectious Diseases Foundation, Badalona, Spain; Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Universitat de Vic-Universitat Central de Catalunya, Vic, Spain; Lihir Medical Centre, International SOS, Lihir Island, Papua New Guinea.

The Lancet. Respiratory medicine. 2022
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Abstract
BACKGROUND Convalescent plasma has been proposed as an early treatment to interrupt the progression of early COVID-19 to severe disease, but there is little definitive evidence. We aimed to assess whether early treatment with convalescent plasma reduces the risk of hospitalisation and reduces SARS-CoV-2 viral load among outpatients with COVID-19. METHODS We did a multicentre, double-blind, randomised, placebo-controlled trial in four health-care centres in Catalonia, Spain. Adult outpatients aged 50 years or older with the onset of mild COVID-19 symptoms 7 days or less before randomisation were eligible for enrolment. Participants were randomly assigned (1:1) to receive one intravenous infusion of either 250-300 mL of ABO-compatible high anti-SARS-CoV-2 IgG titres (EUROIMMUN ratio ≥6) methylene blue-treated convalescent plasma (experimental group) or 250 mL of sterile 0·9% saline solution (control). Randomisation was done with the use of a central web-based system with concealment of the trial group assignment and no stratification. To preserve masking, we used opaque tubular bags that covered the investigational product and the infusion catheter. The coprimary endpoints were the incidence of hospitalisation within 28 days from baseline and the mean change in viral load (in log(10) copies per mL) in nasopharyngeal swabs from baseline to day 7. The trial was stopped early following a data safety monitoring board recommendation because more than 85% of the target population had received a COVID-19 vaccine. Primary efficacy analyses were done in the intention-to-treat population, safety was assessed in all patients who received the investigational product. This study is registered with ClinicalTrials.gov, NCT04621123. FINDINGS Between Nov 10, 2020, and July 28, 2021, we assessed 909 patients with confirmed COVID-19 for inclusion in the trial, 376 of whom were eligible and were randomly assigned to treatment (convalescent plasma n=188 [serum antibody-negative n=160]; placebo n=188 [serum antibody-negative n=166]). Median age was 56 years (IQR 52-62) and the mean symptom duration was 4·4 days (SD 1·4) before random assignment. In the intention-to-treat population, hospitalisation within 28 days from baseline occurred in 22 (12%) participants who received convalescent plasma versus 21 (11%) who received placebo (relative risk 1·05 [95% CI 0·78 to 1·41]). The mean change in viral load from baseline to day 7 was -2·41 log(10) copies per mL (SD 1·32) with convalescent plasma and -2·32 log(10) copies per mL (1·43) with placebo (crude difference -0·10 log(10) copies per mL [95% CI -0·35 to 0·15]). One participant with mild COVID-19 developed a thromboembolic event 7 days after convalescent plasma infusion, which was reported as a serious adverse event possibly related to COVID-19 or to the experimental intervention. INTERPRETATION Methylene blue-treated convalescent plasma did not prevent progression from mild to severe illness and did not reduce viral load in outpatients with COVID-19. Therefore, formal recommendations to support the use of convalescent plasma in outpatients with COVID-19 cannot be concluded. FUNDING Grifols, Crowdfunding campaign YoMeCorono.
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Language : eng
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