Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial
Prof François-Xavier Lescure, Hitoshi Honda, Robert A Fowler, MD Jennifer Sloane Lazar, PhD, P Wung MD, O Hagino MD Genming Shi, Peter Wung, Naimish Patel, Owen Hagino, Ignacio J Bazzalo, Marcelo M Casas, Sebastián A Nuñez, Yael Pere, Carlos M Ibarrola, Marco A Solis Aramayo, Maria C Cuesta, Andrea E Duarte, Pablo M Gutierrez Fernandez, Maria A Iannantuono, Erica A Miyazaki, Javier P Silvio, Dario G Scublinsky, Alessandra Bales, Daniela Catarino, Elie Fiss, Sara Mohrbacher, Victor Sato, Antonio Baylao, Adilson Cavalcante, Francini Correa, Celso A De Andrade, Juvencio Furtado, Nelson Ribeiro Filho, Valéria Telles, Leopoldo T Trevelin, Ricardo Vipich, Rodrigo Boldo, Paula Borges, Suzana Lobo, Graziela Luckemeyer, Luana Machado, Maysa B Alves, Ana C Iglessias, Marianna M Lago, Daniel W Santos, Hugo Chapdelaine, Emilia L Falcone, Rahima Jamal, Me-Linh Luong, Madeleine Durand, Stephane Doucet, François-Martin Carrier, Bryan A Coburn, Lorenzo Del Sorbo, Sharon L Walmsley, Sara Belga, Luke Y Chen, Allison D Mah, Theodore Steiner, Alissa J Wright, J Hajek, Neill Adhikari, Robert A Fowler, Nick Daneman, Kosar A Khwaja, Jason Shahin, Carolina Gonzalez, Rafael Silva, Marcelo Lindh, Gabriel Maluenda, Patricia Fernandez, Maite Oyonarte, Martin Lasso, Alexandre Boyer, Didier Bronnimann, Hoang-Nam Bui, Charles Cazanave, Helene Chaussade, Arnaud Desclaux, Mailys Ducours, Alexandre Duvignaud, Denis Malvy, Lisa Martin, Didier Neau, Duc Nguyen, Thierry Pistone, Gaetane Soubrane-Wirth, Julie Leitao, Clotilde Allavena, Charlotte Biron, Sabelline Bouchez, Benjamin Gaborit, Antoine Gregoire, Paul Le Turnier, Anne-Sophie Lecompte, Raphael Lecomte, Maeva Lefebvre, Francois Raffi, David Boutoille, Pascale H Morineau, Romain Guéry, Emmanuel Chatelus, Nathalie Dumoussaud, Renaud Felten, Florina Luca, Bernard Goichot, Francis Schneider, Marie-Caroline Taquet, Matthieu Groh, Mathilde Roumier, Mathilde Neuville, Antoine Bachelard, Valentina Isernia, Prof François-Xavier Lescure, Bao-Chau Phung, Anne Rachline, Aurelie Sautereau, Dorothee Vallois, Yves Bleher, Delphine Boucher, Clémentine Coudon, Jean Esnault, Thomas Guimard, Sophie Leautez-Nainville, Dominique Merrien, Marine Morrier, Pauline Motte-Vincent, Romain Gabeff, Hélène Leclerc, Céline Cozic, Romain Decours, Ronan Février, Gwenhael Colin, Sophie Abgrall, Dorothee Vignes, Raluca Sterpu, Mira Kuellmar, Melanie Meersch-Dini, Raphael Weiss, Alexander Zarbock, Christiane Antony, Marc Berger, Thorsten Brenner, Christian Taube, Frank Herbstreit, Sebastian Dolff, Margarethe Konik, Karsten Schmidt, Markus Zettler, Oliver Witzke, Boris Boell, Jorge Garcia Borrega, Philipp Koehler, Thomas Zander, Fabian Dusse, Othman Al-Sawaf, Philipp Köhler, Dennis Eichenauer, Matthias Kochanek, Alexander Shimabukuro-Vornhagen, Sibylle Mellinghoff, Annika Claßen, Jan-Michel Heger, Charlotte Meyer-Schwickerath, Paul Liedgens, Katrin Heindel, Ana Belkin, Asaf Biber, Mayan Gilboa, Itzchak Levy, Vladislav Litachevsky, Galia Rahav, Anat Finesod Wiedner, Tal Zilberman-Daniels, Yonatan Oster, Jacob Strahilevitz, Sigal Sviri, Elena M Baldissera, Corrado Campochiaro, Giulio Cavalli, Lorenzo Dagna, Giacomo De Luca, Emanuel Della Torre, Alessandro Tomelleri, Davide Bernasconi De Luca, Amedeo F Capetti, Massimo Coen, Maria V Cossu, Massimo Galli, Andrea Giacomelli, Guido A Gubertini, Stefano Rusconi, Giulia J Burastero, Margherita Digaetano, Giovanni Guaraldi, Marianna Meschiari, Cristina Mussini, Cinzia Puzzolante, Sara Volpi, Marina Aiello, Alarico Ariani, Alfredo A Chetta, Annalisa Frizzelli, Andrea Ticinesi, Domenico Tuttolomondo, Stefano Aliberti, Francesco B Blasi, Marta F Di Pasquale, Sofia Misuraca, Tommaso Pilocane, Edoardo Simonetta, Alessio M Aghelmo, Claudio Angelini, Enrico Brunetta, Giorgio W Canonica, Michele Ciccarelli, Sara Dal Farra, Maria De Santis, Sebastian Ferri, Marco Folci, Giacomo M Guidelli, Enrico M Heffler, Ferdinando Loiacono, Giacomo Malipiero, Giovanni Paoletti, Rosa Pedale, Francesca A Puggioni, Francesca Racca, Aurora Zumbo, Morihiko Satou, Hitoshi Honda, Tatyana Lisun, Denis Protsenko, Nikolay Rubtsov, Irina Beloglazova, Daria Fomina, Mariana Lysenko, Sofia Serdotetskova, Vitali Firstov, Ivan Gordeev, Ilia Kokorin, Ksenia Komissarova, Nina Lapochkina, Elena Luchinkina, Valentin Malimon, Sevinch Mamedguseyinova, Ksenia Polubatonova, Natalia Suvorova, Jose Arribas, Alberto M Borobia Perez, Fernando De La Calle Prieto
The Lancet Respiratory Medicine, doi:10.1016/s2213-2600(21)00099-0
Background Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19.
Methods We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12•0 days [95% CI 9•0 to 15•0]) and sarilumab 200 mg (10•0 days [9•0 to 12•0]; hazard ratio [HR] 1•03 [95% CI 0•75 to 1•40]; logrank p=0•96) or sarilumab 400 mg (10•0 days [9•0 to 13•0]; HR 1•14 [95% CI 0•84 to 1•54]; log-rank p=0•34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference -1•7 [-9•3 to 5•8]; p=0•63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0•2 [-6•9 to 7•4]; p=0•85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8•9% [95% CI -7•7 to 25•5]; p=0•25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group...
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{'given': 'Dorothee', 'family': 'Vignes', 'sequence': 'additional', 'affiliation': []},
{'given': 'Raluca', 'family': 'Sterpu', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mira', 'family': 'Kuellmar', 'sequence': 'additional', 'affiliation': []},
{'given': 'Melanie', 'family': 'Meersch-Dini', 'sequence': 'additional', 'affiliation': []},
{'given': 'Raphael', 'family': 'Weiss', 'sequence': 'additional', 'affiliation': []},
{'given': 'Alexander', 'family': 'Zarbock', 'sequence': 'additional', 'affiliation': []},
{'given': 'Christiane', 'family': 'Antony', 'sequence': 'additional', 'affiliation': []},
{'given': 'Marc', 'family': 'Berger', 'sequence': 'additional', 'affiliation': []},
{'given': 'Thorsten', 'family': 'Brenner', 'sequence': 'additional', 'affiliation': []},
{'given': 'Christian', 'family': 'Taube', 'sequence': 'additional', 'affiliation': []},
{'given': 'Frank', 'family': 'Herbstreit', 'sequence': 'additional', 'affiliation': []},
{'given': 'Sebastian', 'family': 'Dolff', 'sequence': 'additional', 'affiliation': []},
{'given': 'Margarethe', 'family': 'Konik', 'sequence': 'additional', 'affiliation': []},
{'given': 'Karsten', 'family': 'Schmidt', 'sequence': 'additional', 'affiliation': []},
{'given': 'Markus', 'family': 'Zettler', 'sequence': 'additional', 'affiliation': []},
{'given': 'Oliver', 'family': 'Witzke', 'sequence': 'additional', 'affiliation': []},
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{'given': 'Jorge', 'family': 'Garcia Borrega', 'sequence': 'additional', 'affiliation': []},
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{'given': 'Katrin', 'family': 'Heindel', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ana', 'family': 'Belkin', 'sequence': 'additional', 'affiliation': []},
{'given': 'Asaf', 'family': 'Biber', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mayan', 'family': 'Gilboa', 'sequence': 'additional', 'affiliation': []},
{'given': 'Itzchak', 'family': 'Levy', 'sequence': 'additional', 'affiliation': []},
{'given': 'Vladislav', 'family': 'Litachevsky', 'sequence': 'additional', 'affiliation': []},
{'given': 'Galia', 'family': 'Rahav', 'sequence': 'additional', 'affiliation': []},
{'given': 'Anat', 'family': 'Finesod Wiedner', 'sequence': 'additional', 'affiliation': []},
{'given': 'Tal', 'family': 'Zilberman-Daniels', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yonatan', 'family': 'Oster', 'sequence': 'additional', 'affiliation': []},
{'given': 'Jacob', 'family': 'Strahilevitz', 'sequence': 'additional', 'affiliation': []},
{'given': 'Sigal', 'family': 'Sviri', 'sequence': 'additional', 'affiliation': []},
{'given': 'Elena M.', 'family': 'Baldissera', 'sequence': 'additional', 'affiliation': []},
{'given': 'Corrado', 'family': 'Campochiaro', 'sequence': 'additional', 'affiliation': []},
{'given': 'Giulio', 'family': 'Cavalli', 'sequence': 'additional', 'affiliation': []},
{'given': 'Lorenzo', 'family': 'Dagna', 'sequence': 'additional', 'affiliation': []},
{'given': 'Giacomo', 'family': 'De Luca', 'sequence': 'additional', 'affiliation': []},
{'given': 'Emanuel', 'family': 'Della Torre', 'sequence': 'additional', 'affiliation': []},
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{'given': 'Amedeo F.', 'family': 'Capetti', 'sequence': 'additional', 'affiliation': []},
{'given': 'Massimo', 'family': 'Coen', 'sequence': 'additional', 'affiliation': []},
{'given': 'Maria V.', 'family': 'Cossu', 'sequence': 'additional', 'affiliation': []},
{'given': 'Massimo', 'family': 'Galli', 'sequence': 'additional', 'affiliation': []},
{'given': 'Andrea', 'family': 'Giacomelli', 'sequence': 'additional', 'affiliation': []},
{'given': 'Guido A.', 'family': 'Gubertini', 'sequence': 'additional', 'affiliation': []},
{'given': 'Stefano', 'family': 'Rusconi', 'sequence': 'additional', 'affiliation': []},
{'given': 'Giulia J.', 'family': 'Burastero', 'sequence': 'additional', 'affiliation': []},
{'given': 'Margherita', 'family': 'Digaetano', 'sequence': 'additional', 'affiliation': []},
{'given': 'Giovanni', 'family': 'Guaraldi', 'sequence': 'additional', 'affiliation': []},
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{'given': 'Cristina', 'family': 'Mussini', 'sequence': 'additional', 'affiliation': []},
{'given': 'Cinzia', 'family': 'Puzzolante', 'sequence': 'additional', 'affiliation': []},
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{'given': 'Alarico', 'family': 'Ariani', 'sequence': 'additional', 'affiliation': []},
{'given': 'Alfredo A.', 'family': 'Chetta', 'sequence': 'additional', 'affiliation': []},
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{'given': 'Francesco B.', 'family': 'Blasi', 'sequence': 'additional', 'affiliation': []},
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{'given': 'Edoardo', 'family': 'Simonetta', 'sequence': 'additional', 'affiliation': []},
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{'given': 'Enrico', 'family': 'Brunetta', 'sequence': 'additional', 'affiliation': []},
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