Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients

Pere Millat-Martinez, Arvind Gharbharan, Andrea Alemany, Casper Rokx, Corine Geurtsvankessel, Grigorios Papageourgiou, Nan van Geloven, Carlijn Jordans, Geert Groeneveld, Francis Swaneveld, Ellen van der Schoot, Marc Corbacho-Monné, Dan Ouchi, Francini Piccolo Ferreira, Pierre Malchair, Sebastian Videla, Vanesa García García, Anna Ruiz-Comellas, Anna Ramírez-Morros, Joana Rodriguez Codina, Rosa Amado Simon, Joan-Ramon Grifols, Julian Blanco, Ignacio Blanco, Jordi Ara, Quique Bassat, Bonaventura Clotet, Bàrbara Baro, Andrea Troxel, Jaap Jan Zwaginga, Oriol Mitjà, Bart J A Rijnders, CoV-Early study group, COnV-ert study group, Arvind Gharbharan, Casper Rokx, Carlijn Jordans, Corine Geurtsvankessel, Grigorios Papageourgiou, Bart Rijnders, Peter Katsikis, Yvonne Müller, Marion Koopmans, Susanne Bogers, Jelle Miedema, Henk Russcher, Cees Scherpenisse, Rene van Engen, Ayten Karisli, Hannelore Götz, Jelle Struik, Lotte Rokx-Niemantsverdriet, Nan van Geloven, Geert Groeneveld, Jaap Jan Zwaginga, Lisa Zwaginga, Josine Oud, Romy Meier, Erik van Zwet, Simon Mooijaart, Arjan Albersen, Francis Swaneveld, Ellen van der Schoot, Hans Vrielink, Leo van de Watering, Boris Hogema, Peter van Wijngaarden, Ronald van Etten, Adriaan van Gammeren, Nanda Maas, Betty van Ginneken, Jan den Hollander, Jose Verstijnen, Juliette van den Berg-Rahman, Faiz Karim, Siepke Hiddema, Kim van Elst, Elena van Leeuwen-Segarceanu, Annette Reitsma, Karin Molenkamp, Robert Soetekouw, Caterina Band, José de Droog, Jolanda Lammers, Lonneke Buitenhuis, Douwe Postma, David Koster, Michaèl Lukens, Thea Scholtens, Maartje van den Boomgaard, Machiel Vonk, Linda Kampschreur, Marit van Vonderen, Loes Vrolijk, Chantal Reusken, Johan Reimerink, Heli Harvala, Andrea Alemany, Marc Corbacho-Monné, Dan Ouchi, Bonaventura Clotet, Oriol Mitjà, Gèlia Costes, Mar Capdevila-Jáuregui, Pamela Torrano-Soler, Alba San José, Zahida Jiménez, Ferran Ramírez-Viaplana, Susana Ferrer, Mireia Gallardo, Maria Ubals, Camila González-Beiras, Martí Vall-Mayans, Miquel Angel Rodriguez-Arias, Clara Suñer, Jordi Puig, Aroa Nieto, Ivan Galvan-Femenia, Xavier Comas-Leon, Pere Millat-Martínez, Quique Bassat, Bàrbara Baro, Ignacio Blanco, Jordi Ara, Glòria Bonet Papell, 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, Magí Ferrer, Pierre Malchair, Sebastian Videla, Vanesa García García, Carlota Gudiol, Aurema Otero, Jose Carlos Ruibal Suarez, Alvaro Zarauza Pellejero, Ferran Llopis Roca, Orlando Rodriguez Cortez, Pablo Casares Gonzalez, Gemma Arcos Vila, Begoña Flores Aguilera, Graciela Rodríguez-Sevilla, Macarena Dastis Arias, Anna Ruiz-Comellas, Anna Ramírez-Morros, Judit Roca Font, Katherine M Carrasco Matos, Glòria Saüch Valmaña, Carla Vidal Obradors, Joana Rodríguez Codina, Rosa Amado Simon, Silvia Tarres García, Margarida Curriu Sabatès, Raquel Nieto Rodríguez, Joan-Ramon Grífols, Anna Millan, Enric Contreras, Àgueda Ancochea, Rosa Línio, Miriam Fornos, Natàlia Casamitjana, Eva Alonso, Núria Martinez, Laura Analía Maglio, Laura Comellas Fernandez, Nadia Garcia, Luis Hernández, María Isabel González, Anna Bravo, Yolanda García, Núria Prat, Joaquim Verdaguer, Thatiana Vértiz Guidotti, Sergio Benavent, Andrea Sofia Bianco, Ney Nicanor Briones Zambrano, Maria Viozquez Meya, Anna Forcada, Josep Vidal-Alaball, Montserrat Giménez, Alexa París, Gema Fernández Rivas, Cristina Casañ Lopez, Águeda Hernández, Antoni E Bordoy, Victoria González Soler, Julian Blanco, Edwars Pradenas, Silvia Marfil, Benjamin Trinité, Francini Piccolo Ferreira, Mireia Bonet, Jordi Cantoni, Michael Marks, Pere Millat-Martinez, Arvind Gharbharan, Andrea Alemany, Casper Rokx, Corine Geurtsvankessel, Grigorios Papageourgiou, Nan van Geloven, Carlijn Jordans, Geert Groeneveld, Francis Swaneveld, Ellen van der Schoot, Marc Corbacho-Monné, Dan Ouchi, Francini Piccolo Ferreira, Pierre Malchair, Sebastian Videla, Vanesa García García, Anna Ruiz-Comellas, Anna Ramírez-Morros, Joana Rodriguez Codina, Rosa Amado Simon, Joan-Ramon Grifols, Julian Blanco, Ignacio Blanco, Jordi Ara, Quique Bassat, Bonaventura Clotet, Bàrbara Baro, Andrea Troxel, Jaap Jan Zwaginga, Oriol Mitjà, Bart J A Rijnders, CoV-Early study group, COnV-ert study group, Arvind Gharbharan, Casper Rokx, Carlijn Jordans, Corine Geurtsvankessel, Grigorios Papageourgiou, Bart Rijnders, Peter Katsikis, Yvonne Müller, Marion Koopmans, Susanne Bogers, Jelle Miedema, Henk Russcher, Cees Scherpenisse, Rene van Engen, Ayten Karisli, Hannelore Götz, Jelle Struik, Lotte Rokx-Niemantsverdriet, Nan van Geloven, Geert Groeneveld, Jaap Jan Zwaginga, Lisa Zwaginga, Josine Oud, Romy Meier, Erik van Zwet, Simon Mooijaart, Arjan Albersen, Francis Swaneveld, Ellen van der Schoot, Hans Vrielink, Leo van de Watering, Boris Hogema, Peter van Wijngaarden, Ronald van Etten, Adriaan van Gammeren, Nanda Maas, Betty van Ginneken, Jan den Hollander, Jose Verstijnen, Juliette van den Berg-Rahman, Faiz Karim, Siepke Hiddema, Kim van Elst, Elena van Leeuwen-Segarceanu, Annette Reitsma, Karin Molenkamp, Robert Soetekouw, Caterina Band, José de Droog, Jolanda Lammers, Lonneke Buitenhuis, Douwe Postma, David Koster, Michaèl Lukens, Thea Scholtens, Maartje van den Boomgaard, Machiel Vonk, Linda Kampschreur, Marit van Vonderen, Loes Vrolijk, Chantal Reusken, Johan Reimerink, Heli Harvala, Andrea Alemany, Marc Corbacho-Monné, Dan Ouchi, Bonaventura Clotet, Oriol Mitjà, Gèlia Costes, Mar Capdevila-Jáuregui, Pamela Torrano-Soler, Alba San José, Zahida Jiménez, Ferran Ramírez-Viaplana, Susana Ferrer, Mireia Gallardo, Maria Ubals, Camila González-Beiras, Martí Vall-Mayans, Miquel Angel Rodriguez-Arias, Clara Suñer, Jordi Puig, Aroa Nieto, Ivan Galvan-Femenia, Xavier Comas-Leon, Pere Millat-Martínez, Quique Bassat, Bàrbara Baro, Ignacio Blanco, Jordi Ara, Glòria Bonet Papell, 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, Magí Ferrer, Pierre Malchair, Sebastian Videla, Vanesa García García, Carlota Gudiol, Aurema Otero, Jose Carlos Ruibal Suarez, Alvaro Zarauza Pellejero, Ferran Llopis Roca, Orlando Rodriguez Cortez, Pablo Casares Gonzalez, Gemma Arcos Vila, Begoña Flores Aguilera, Graciela Rodríguez-Sevilla, Macarena Dastis Arias, Anna Ruiz-Comellas, Anna Ramírez-Morros, Judit Roca Font, Katherine M Carrasco Matos, Glòria Saüch Valmaña, Carla Vidal Obradors, Joana Rodríguez Codina, Rosa Amado Simon, Silvia Tarres García, Margarida Curriu Sabatès, Raquel Nieto Rodríguez, Joan-Ramon Grífols, Anna Millan, Enric Contreras, Àgueda Ancochea, Rosa Línio, Miriam Fornos, Natàlia Casamitjana, Eva Alonso, Núria Martinez, Laura Analía Maglio, Laura Comellas Fernandez, Nadia Garcia, Luis Hernández, María Isabel González, Anna Bravo, Yolanda García, Núria Prat, Joaquim Verdaguer, Thatiana Vértiz Guidotti, Sergio Benavent, Andrea Sofia Bianco, Ney Nicanor Briones Zambrano, Maria Viozquez Meya, Anna Forcada, Josep Vidal-Alaball, Montserrat Giménez, Alexa París, Gema Fernández Rivas, Cristina Casañ Lopez, Águeda Hernández, Antoni E Bordoy, Victoria González Soler, Julian Blanco, Edwars Pradenas, Silvia Marfil, Benjamin Trinité, Francini Piccolo Ferreira, Mireia Bonet, Jordi Cantoni, Michael Marks

Abstract

Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when <20% of recruitment target was achieved. A Bayesian-adaptive individual patient data meta-analysis was implemented. Outpatients aged ≥50 years and symptomatic for ≤7days were included. The intervention consisted of 200-300mL of CP with a predefined minimum level of antibodies. Primary endpoints were a 5-point disease severity scale and a composite of hospitalization or death by 28 days. Amongst the 797 patients included, 390 received CP and 392 placebo; they had a median age of 58 years, 1 comorbidity, 5 days symptoms and 93% had negative IgG antibody-test. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of CP for improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311); OR for hospitalization or death was 0.919 (CI 0.592-1.416). CP effect on hospital admission or death was largest in patients with ≤5 days of symptoms (OR 0.658, 95%CI 0.394-1.085). CP did not decrease the time to full symptom resolution.

Trial registration: Clinicaltrials.gov NCT04621123 and NCT04589949.

Registration: NCT04621123 and NCT04589949 on https://www.

Clinicaltrials: gov.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1. CONSORT flow diagram.
Fig. 1. CONSORT flow diagram.
Figure shows the CONSORT flow diagram of the COMPILEhome patients. 833 patients were screened at a study site and 782 were included for analysis.
Fig. 2. Distribution for COVID-19 severity at…
Fig. 2. Distribution for COVID-19 severity at 28 days.
CP Convalescent plasma. Figure shows the distribution of the outcome of the patients in the 28 days after inclusion across the 5-point disease severity scale: 1 = recovered before day 8 after transfusion, 2 = continued symptoms after day 7, 3 = hospital admission, 4 = invasive ventilation, 5 = death. Moving from lighter to darker shading represents increasing scores on the severity scale. The darker shade includes point 4 and 5 of the scale (invasive ventilation or death).
Fig. 3. Time to full symptom resolution…
Fig. 3. Time to full symptom resolution up to day 28 (end of follow-up).
CP Convalescent plasma. Log-rank test p = 0.66. The dotted error bars represent the 95% CI.

References

    1. Horby P, et al. Dexamethasone in hospitalized patients with Covid-19. N. Engl. J. Med. 2021;384:693–704. doi: 10.1056/NEJMoa2021436.
    1. Brown MJ, Alazawi W, Kanoni S. Interleukin-6 receptor antagonists in critically Ill patients with Covid-19. N. Engl. J. Med. 2021;385:1147. doi: 10.1056/NEJMc2108482.
    1. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet397 1637–1645 (2021).
    1. Dougan M, et al. Bamlanivimab plus etesevimab in mild or moderate Covid-19. N. Engl. J. Med. 2021;385(Oct):1382–1392. doi: 10.1056/NEJMoa2102685.
    1. Gottlieb RL, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. Jama. 2021;325:632–644. doi: 10.1001/jama.2021.0202.
    1. Weinreich DM, et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N. Engl. J. Med. 2020;384:238–251. doi: 10.1056/NEJMoa2035002.
    1. Weinreich D. M. et al. REGEN-COV antibody cocktail clinical outcomes study in Covid-19 outpatients. medRxiv10.1101/2021.05.19.21257469 (2021).
    1. Garraud O, et al. Plasma therapy against infectious pathogens, as of yesterday, today and tomorrow. Transfus. Clin. Biol. 2016;23:39–44. doi: 10.1016/j.tracli.2015.12.003.
    1. Mair-Jenkins J, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J. Infect. Dis. 2015;211:80–90. doi: 10.1093/infdis/jiu396.
    1. Estcourt LJ, et al. Effect of convalescent plasma on organ support-free days in critically ill patients with COVID-19: a randomized clinical trial. Jama. 2021;326:1690–1702. doi: 10.1001/jama.2021.18178.
    1. Simonovich VA, et al. A randomized trial of convalescent plasma in Covid-19 severe pneumonia. N. Engl. J. Med. 2021;384:619–629. doi: 10.1056/NEJMoa2031304.
    1. Agarwal A, et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial) Bmj. 2020;371:m3939. doi: 10.1136/bmj.m3939.
    1. Li L, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. Jama. 2020;324:460–470. doi: 10.1001/jama.2020.10044.
    1. O’Donnell M. R. et al. A randomized double-blind controlled trial of convalescent plasma in adults with severe COVID-19. J. Clin. Investig. 131 (2021).
    1. Avendaño-Solà C. et al. Convalescent plasma for COVID-19: a multicenter, randomized clinical trial: medRxiv10.1101/2020.08.26.20182444 (2020).
    1. Janiaud P, et al. Association of convalescent plasma treatment with clinical outcomes in patients with COVID-19: a systematic review and meta-analysis. Jama. 2021;325:1185–1195. doi: 10.1001/jama.2021.2747.
    1. RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial. Lancet397, 2049–2059(2021).
    1. Bégin P, et al. Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial. Nat. Med. 2021;27(Nov):2012–2024. doi: 10.1038/s41591-021-01488-2.
    1. Gharbharan A, et al. Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection. Nat. Commun. 2021;12:3189. doi: 10.1038/s41467-021-23469-2.
    1. Libster R, et al. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N. Engl. J. Med. 2021;384:610–618. doi: 10.1056/NEJMoa2033700.
    1. Korley FK, et al. Early convalescent plasma for high-risk outpatients with Covid-19. N. Engl. J. Med. 2021;385(Nov):1951–1960. doi: 10.1056/NEJMoa2103784.
    1. Petkova E, Antman EM, Troxel AB. Pooling data from individual clinical trials in the COVID-19 era. Jama. 2020;324:543–545. doi: 10.1001/jama.2020.13042.
    1. Nguyen D. et al. SARS-CoV-2 neutralising antibody testing in Europe: towards harmonisation of neutralising antibody titres for better use of convalescent plasma and comparability of trial data. Euro Surveill. 26 (2021).
    1. Arnold Egloff S. A. et al. Convalescent plasma associates with reduced mortality and improved clinical trajectory in patients hospitalized with COVID-19. J. .Clin. Investig. 131 (2021).
    1. Joyner MJ, et al. Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients. Mayo Clin. Proc. 2020;95:1888–1897. doi: 10.1016/j.mayocp.2020.06.028.
    1. Gharbharan A, et al. Effects of treatment of COVID-19 with convalescent plasma in 25 B-cell depleted patients. Clin. Infect. Dis. 2022;74:1271–1274. doi: 10.1093/cid/ciab647.
    1. Haagmans BL, et al. SARS-CoV-2 neutralizing human antibodies protect against lower respiratory tract disease in a Hamster Model. J. Infect. Dis. 2021;223:2020–2028. doi: 10.1093/infdis/jiab289.
    1. Sullivan D. J. et al. Randomized controlled trial of early outpatient COVID-19 treatment with high-titer convalescent plasma. medRxiv10.1101/2021.12.10.21267485 (2021).

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren