High-titre methylene blue-treated convalescent plasma as an early treatment for outpatients with COVID-19: a randomised, placebo-controlled trial
MD Andrea Alemany, MD Pere Millat-Martinez, Hospital Clinic ( Marc Corbacho-Monné, Pierre Malchair, Dan Ouchi, Anna Ruiz-Comellas, Anna Ramírez-Morros, Joana Rodríguez Codina, Rosa Amado Simon, Sebastian Videla, Gèlia Costes, Mar Capdevila-Jáuregui, Pamela Torrano-Soler, Alba San José, Glòria Bonet Papell, Jordi Puig, Aurema Otero, Jose Carlos Ruibal Suarez, Alvaro Zarauza Pellejero, Ferran Llopis Roca, Orlando Rodriguez Cortez, Vanesa Garcia Garcia, Josep Vidal-Alaball, Anna Millan, Enric Contreras, Joan-Ramon Grifols, Àgueda Ancochea, Ivan Galvan-Femenia, Francini Piccolo Ferreira, Mireia Bonet, Jordi Cantoni, Núria Prat, Jordi Ara, Anna Forcada Arcarons, Magí Farré, Edwards Pradenas, Julià Blanco, Miquel Àngel Rodriguez-Arias, Gema Fernández Rivas, Michael Marks, Quique Bassat, Ignacio Blanco, Bàrbara Baro, Bonaventura Clotet, Oriol Mitjà, Susana Ferrer, Mireia Gallardo, Maria Ubals, Camila González-Beiras, Martí Vall-Mayans, Clara Suñer, Clàudia Laporte-Villar, Aroa Nieto, Xavier Comas-Leon, Zahida Jiménez, Ferran Ramírez-Viaplana, Maria Delgado-Capel, Beatriz Díez Sánchez, Maria Pons Barber, Cristian Gonzalez Ruiz, Laura Navarrete Gonzalez, David González García, Ainhoa Vivero Larraza, Victor Carceles Peiró, Clàudia Roquer López, Neus Robert, Carles Palet, Carlota Gudiol, Pablo Casares Gonzalez, Gemma Arcos Vila, Begoña Flores Aguilera, Graciela Rodríguez-Sevilla, Macarena Dastis Arias, Judit Roca Font, Katherine M Carrasco Matos, Glòria Saüch Valmaña, Carla Vidal Obradors, Silvia Tarres García, Margarida Curriu Sabatès, Raquel Nieto Rodríguez, Rosa Línio, Míriam Fornos, Natàlia Casamitjana, Eva Alonso, Núria Martínez, Laura Analía Maglio, Laura Comellas Fernandez, Nadia Garcia, Luis Hernández, Maria Isabel González, Anna Bravo, Yolanda García, Silvia Sauleda Oliveras, Tatiana Vertiz, Sergio Benavent, Andrea Sofia Bianco, Joaquim Verdaguer, Ney Nicanor Briones Zambrano, Maria Viozquez Meya, Águeda Hernández, Cristina Casaña Lopez, Antoni E Bordoy, Victoria González Soler, Montserrat Giménez, Alexa París, Silvia Marfil, Benjamin Trinité, Eulàlia Grau
The Lancet Respiratory Medicine, doi:10.1016/s2213-2600(21)00545-2
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 intentionto-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..
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. We thank Gerard Carot-Sans for providing medical writing support with manuscript preparation and Roser Escrig for her support in the study design and medical writing assistance with the study documentation. We also thank Laia Bertran, Mireia Clua, Jordi Mitjà, Claudia Laporte, Sergi Gavilan, Joan Mercado, and Enric Nieto for the operational and financial management of the project. We thank the personnel from the Fight Aids and Infectious Diseases Foundation for their support in administration, human resources, and supply chain management. We thank the independent data safety monitoring board for their time and dedication: Cinta Hierro (Catalan Institute of Oncology, Badalona, Spain), Natalia Tovar (Hospital Clinic, Barcelona, Spain), Binh Ngo (University of Southern California, Los Angeles, CA, USA), David Boulware (University of Minnesota, Minneapolis, MN, USA), and Robin Mogg (Bill and Melinda Gates Research Institute, Seattle, WA, USA). We thank the reviewers for substantial comments that helped improve and clarify the strengths and drawbacks of the experimental intervention and study methodology.
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