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Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia
Authors :
Hermine, Olivier Mariette, Xavier Tharaux, Pierre-Louis Resche-Rigon, Matthieu Porcher, Raphaël Ravaud, Philippe Bureau, Serge Dougados, Maxime Tibi, Annick Azoulay, Elie Cadranel, Jacques Emmerich, Joseph Fartoukh, Muriel Guidet, Bertrand Humbert, Marc Lacombe, Karine Mahevas, Matthieu Pene, Frédéric Pourchet-Martinez, Valérie Schlemmer, Frédéric Yazdanpanah, Yazdan Baron, Gabriel Perrodeau, Elodie Vanhoye, Damien Kedzia, Cécile Demerville, Lauren Gysembergh-Houal, Anne Bourgoin, Alexandre Dalibey, Sarah Raked, Nabil Mameri, Lakhdar Alary, Stéphanie Hamiria, Samir Bariz, Thinhinane Semri, Hala Hai, Dhiaa Meriem Benafla, Moustafa Belloul, Mohamed Vauboin, Pernelle Flamand, Saskia Pacheco, Claire Walter-Petrich, Anouk Stan, Emilia Benarab, Souad Nyanou, Corine Montlahuc, Claire Biard, Lucie Charreteur, Robin Dupré, Celine Cardet, Kévin Lehmann, Blandine Baghli, Kamyl Madeleine, Claire DOrtenzio, Eric Puéchal, Oriane Semaille, Caroline Savale, Laurent Harrois, Anatole Figueiredo, Samy Duranteau, Jacques Anguel, Nadia Monnet, Xavier Richard, Christian Teboul, Jean-Louis Durand, Philippe Tissieres, Pierre Jevnikar, Mitja Montani, David Pavy, Stéphan Noel, Nicolas Lambotte, Olivier Escaut, Lelia Jauréguiberry, Stéphane Baudry, Elodie Verny, Christiane Lefèvre, Edouard Zaidan, Mohamad Le Tiec, Clotilde Le Tiec Verstuyft, Céline Verstuyft Roques, Anne-Marie Grimaldi, Lamiae Molinari, Domitille Leprun, Gaël Fourreau, Alain Cylly, Laurent Virlouvet, Myriam Meftali, Ramdane Fabre, Solène Licois, Marion Mamoune, Asmaa Boudali, Yacine Georgin-Lavialle, Sophie Senet, Patricia Soria, Angèle Parrot, Antoine François, Hélène Rozensztajn, Nathalie Blin, Emmanuelle Choinier, Pascaline Camuset, Juliette Rech, Jean-Simon Canellas, Antony Rolland-Debord, Camille Lemarié, Nadège Belaube, Nicolas Nadal, Marine Siguier, Martin Petit-Hoang, Camille Chas, Julie Drouet, Elodie Lemoine, Matthieu Phibel, Audrey Aunay, Lucie Bertrand, Eliane Ravato, Sylviane Vayssettes, Marie Adda, Anne Wilpotte, Celine Thibaut, Pélagie Fillon, Julie Debrix, Isabelle Fellahi, Soraya Bastard, Jean-Philippe Lefèvre, Guillaume Fallet, Vincent Gottenberg, Jacques-Eric Hansmann, Yves Andres, Emmanuel Bayer, Sophie Becker, Guillaume Blanc, Frédéric Brin, Stéphane Castelain, Vincent Chatelus, Emmanuel Chatron, Eva Collange, Olivier Danion, François De Blay, Frédéric Demonsant, Eric Diemunsch, Pierre Diemunsch, Sophie Felten, Renaud Goichot, Bernard Greigert, Valentin Guffroy, Aurélien Heger, Bob Hutt, Anne Kaeuffer, Charlotte Kassegne, Loic Korganow, Anne Sophie Le Borgne, Pierrick Lefebvre, Nicolas Martin, Tristan Mertes, Paul Michel Metzger, Catherine Meyer, Nicolas Nisand, Gabriel Noll, Eric Oberlin, Mathieu Ohlmann-Caillard, Sophie Poindron, Vincent Pottecher, Julien Ruch, Yvon Sublon, Cédric Tayebi, Hakim Weill, François Mekinian, Arsène Chopin, Dorothée Fain, Olivier Garnier, Marc Krause Le Garrec, Jessica Morgand, Marjolaine Pacanowski, Jerome Urbina, Tomas Mcavoy, Chloe Pereira, Maria Aratus, Gladys Berard, Laurence Simon, Tabassome Daguenel Nguyen, Anne Antignac, Marie Leplay, Céline Arlet, Jean-Benoit Diehl, Jean-Luc Bellenfant, Florence Blanchard, Anne Buffet, Alexandre Cholley, Bernard Fayol, Antoine Flamarion, Edouard Godier, Anne Gorget, Thomas Hamada, Sophie-Rym Hauw-Berlemont, Caroline Hulot, Jean- Se´bastien Lebeaux, David Livrozet, Marine Michon, Adrien Neuschwander, Arthur Penet, Marie-Aude Planquette, Benjamin Ranque, Brigitte Sanchez, Olivier Volle, Geoffroy Briois, Sandrine Cornic, Mathias Elisee, Virginie Jesuthasan, Denis Djadi-Prat, Juliette Jouany, Pauline Junquera, Ramon Henriques, Mickael Kebir, Amina Lehir, Isabelle Meunier, Jeanne Patin, Florence Paquet, Vale´rie Tre´Han, Anne Vigna, Ve´ronique Sabatier, Brigitte Bergerot, Damien Jouve, Charle`ne Knosp, Camille Lenoir, Olivia Mahtal, Nassim Resmini, Léa Lescure, Xavier Ghosn, Jade Bachelard, Antoine Bironne, Timothee Borie, Raphael Bounhiol, Agathe Boussard, Catherine Chauffier, Jeanne Chalal, Solaya Chalal, Lynda Chansombat, Malikhone Crespin, Paul Crestani, Bruno Daconceicao, Olivia Deconinck, Laurene Dieude, hilippe Dossier, Antoine Dubert, Marie Ducrocq, Greggory Fuentes, Axelle Gervais, Anne Gilbert, Marie Isernia, Valentina Ismael, Sophie Joly, Veronique Julia, Zelie Lariven, Sylvie Le Gac, Sylvie Le Pluart, Diane Louni, Francoise Ndiaye, Awa Papo, Thomas Parisey, Marion Phung, Bao Pourbaix, Annabelle Rachline, Anne Rioux, Christophe Sautereau, Aurelie Steg, Gabriel Tharini, Hassan Valayer, Simon Vallois, Dorothee Vermes, Paul Volpe, Thomas Nguyen, Yann Honsel, Vasco Weiss, Emmanuel Codorniu, Anaïs Zarrouk, Virginie De Lastours, Victoire Uzzan, Matthieu Gamany, Naura Rahli, Roza Louis, Zeina Boutboul, David Galicier, Lionel Amara, Yaël Archer, Gabrielle Benattia, Amira Bergeron, Anne Bondeelle, Louise De Castro, Nathalie Clément, Melissa Darmont, Michaël Denis, Blandine Dupin, Clairelyne Feredj, Elsa Feyeux, Delphine Joseph, Adrien Lengliné, Etienne Le Guen, Pierre Liégeon, Geoffroy Lorillon, Gwenaël Mabrouki, Asmaa Mariotte, Eric Martin De Frémont, Grégoire Mirouse, Adrien Molina, Jean-Michel Peffault De Latour, Régis Oksenhendler, Eric Saussereau, Julien Tazi, Abdellatif Tudesq, Jean-Jacques Zafrani, Lara Brindele, Isabelle Bugnet, Emmanuelle Celli Lebras, Karine Chabert, Julien Djaghout, Lalia Fauvaux, Catherine Jegu, Anne Lise Kozaliewicz, Ewa Meunier, Martine Tremorin, Marie-Thérèse Davoine, Claire Madeleine, Isabelle Caillat-Zucman, Sophie Delaugerre, Constance Morin, Florence Sene, Damien Burlacu, Ruxandra Chousterman, Benjamin Megarbane, Bruno Richette, Pascal Riveline, Jean-Pierre Frazier, Aline Vicaut, Eric Berton, Laure Hadjam, Tassadit Vasquez-Ibarra, Miguel Alejandro Jourdaine, Clément Jacob, Aude Smati, Julie Renaud, Stéphane Manivet, Philippe Pernin, Claire Suarez, Lydia Semerano, Luca Abad, Sebastien Benainous, Ruben Bloch Queyrat, Coralie Bonnet, Nicolas Brahmi, Sabrina Cailhol, johann Cohen, Yves Comparon, Celine Cordel, Hugues Dhote, Robin Dournon, Nathalie Duchemann, Boris Ebstein, Nathan Giroux-Leprieur, Benedicte Goupil De Bouille, Jeanne Jacolot, Anne Nunes, Hilario Oziel, Johanna Rathouin, Vanessa Rigal, Marthe Roulot, Dominique Tantet, Claire Uzunhan, Yurdagul Costedoat-Chalumeau, Nathalie Ait Hamou, Zakaria Benghanem, Sarah Blanche, Philippe Canoui, Etienne Carlier, Nicolas Chaigne, Benjamin Contejean, Adrien Dunogue, Bertrand Dupland, Pierre Durel - Maurisse, Aurélie Gauzit, Remy Jaubert, Paul Joumaa, Hassan Jozwiak, Mathieu Kerneis, Solen Lachatre, Marie Lafoeste, Hélène Legendre, Paul Luong Nguyen, Liem Binh Marey, Jonathan Morbieu, Caroline Mouthon, Luc Nguyen, Lee Palmieri, Lola-Jade Regent, Alexis Szwebel, Tali-Anne Terrier, Benjamin Guerin, Corinne Zerbit, Jérémie Cheref, Kahina Chitour, Kamil Cisse, Mamadou Salif Clarke, Ada Clavere, Gaelle Dusanter, Isabelle Gaudefroy, Caroline Jallouli, Moez Kolta, Sami Le Bourlout, Catherine Marin, Nathalie Menage, Nathalie Moores, Alexandre Peigney, Isabelle Pierron, Cédric Saleh-Mghir, Samira Vallet, Mathilde Michel, Marc Melica, Giovanna Lelievre, Jean-Daniel Fois, Elena Lim, Pascal Matignon, Marie Guillaud, Constance Thiemele, Alaki Schmitz, David Bouhris, Marion Belazouz, Syllia Languille, Laetitia Mekontso-Dessaps, Armand Sadaoui, Thiziri Mayaux, Julien Cacoub, Patrice Corvol, Jean-Christophe Louapre, Céline Sambin, Sara Mariani, Louise-Laure Karachi, Carine Tubach, Florence Estellat, Candice Gimeno, Linda Martin, Karine Bah, Aïcha Keo, Vixra Ouamri, Sabrine Messaoudi, Yasmine Yelles, Nessima Faye, Pierre Cavelot, Sébastien Larcheveque, Cecile Annonay, Laurence Benhida, Jaouad Zahrate-Ghoul, Aida Hammal, Soumeya Belilita, Ridha Lecronier, Marie Beurton, Alexandra Haudebourg, Luc Deleris, Robin Le Marec, Julien Virolle, Sara Nemlaghi, Safaa Bureau, Côme Mora, Pierre De Sarcus, Martin Clovet, Olivier Duceau, Baptiste Grisot, Paul Henri Pari, Marie hélène Arzoine, Jérémy Clarac, Ulrich Faure, Morgane Delemazure, Julie Decavele, Maxence Morawiec, Elise Demoule, Alexandre Dres, Martin Vautier, Mathieu Allenbach, Yves Benveniste, Olivier Leroux, Gaelle Rigolet, Aude Guillaume-Jugnot, Perrine Domont, Fanny Desbois, Anne Claire Comarmond, Cloé Champtiaux, Nicolas Toquet, Segolene Ghembaza, Amine Vieira, Matheus Maalouf, Georgina Boleto, Gonçalo Ferfar, Yasmina Charbonnier, Fanny Aguilar, Claire Alby-Laurent, Fanny Alyanakian, Marie-Alexandra Bakouboula, Prissile Broissand, Christine Burger, Carole Campos-Vega, Clara Chavarot, Nathalie Choupeaux, Laure Elie, Caroline Fournier, Benjamin Granville, Sophie Issorat, Elodie Rouzaud, Claire Vimpere, Damien Geri, Guillaume Derridj, Nawal Sguiouar, Naima Meddah, Hakim Djadel, Mourad Chambrin-Lauvray, Helene Duclos-Vallée, Jean-Charles Saliba, Faouzi Sacleux, Sophie-Caroline Koumis, Ilias Michot, Jean-Marie Stoclin, Annabelle Colomba, Emeline Pommeret, Fanny Willekens, Chistophe Da Silva, Rosa Dejean, Valérie Mekid, Yasmina Ben-Mabrouk, Ines Pradon, Caroline Drouard, 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Julien Nizard, Mandy Denies, Fanette Gros, Hélène Mourad, Jean-Jacques Sacco, Emmanuelle Renet, Sophie CHU Necker - Enfants Malades [AP-HP] Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163) Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité) Service de Rhumatologie [CHU Bicêtre] Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184) Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM) Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)) Hôpital Européen Georges Pompidou [APHP] (HEGP) Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité) Equipe 2 : ECSTRA - Epidémiologie Clinique, STatistique, pour la Recherche en Santé (CRESS - U1153) Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)) Conservatoire National des Arts et Métiers [CNAM] (CNAM) HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM) HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) Hopital Saint-Louis [AP-HP] (AP-HP) Centre d'épidémiologie Clinique [Hôtel-Dieu] Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Hôtel Dieu CHU Tenon [AP-HP] Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU) CHU Saint-Antoine [AP-HP] Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP) Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU) CHU Pitié-Salpêtrière [AP-HP] Centre de recherche en Myologie – U974 SU-INSERM Service de Département de médecine interne et immunologie clinique [CHU Pitié-Salpêtrière] (DMIIC) Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU) CORIMUNO-19 Collaborative Group Porcher, Raphaël Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158) ANR-21-COVR-0024,ACT-LONG-COVID,Caractérisation clinique et biologique du syndrome d'activation mastocytaire dans le COVID long et prédisposition génétique(2021)
Source :
JAMA Internal Medicine, JAMA Internal Medicine, 2021, 181 (1), pp.32-40. ⟨10.1001/jamainternmed.2020.6820⟩
Publication Year :
2021
Publisher :
American Medical Association (AMA), 2021.
Abstract
International audience; Importance Severe pneumonia with hyperinflammation and elevated interleukin-6 is a common presentation of coronavirus disease 2019 (COVID-19).Objective To determine whether tocilizumab (TCZ) improves outcomes of patients hospitalized with moderate-to-severe COVID-19 pneumonia.Design, Setting, and Particpants This cohort-embedded, investigator-initiated, multicenter, open-label, bayesian randomized clinical trial investigating patients with COVID-19 and moderate or severe pneumonia requiring at least 3 L/min of oxygen but without ventilation or admission to the intensive care unit was conducted between March 31, 2020, to April 18, 2020, with follow-up through 28 days. Patients were recruited from 9 university hospitals in France. Analyses were performed on an intention-to-treat basis with no correction for multiplicity for secondary outcomes.Interventions Patients were randomly assigned to receive TCZ, 8 mg/kg, intravenously plus usual care on day 1 and on day 3 if clinically indicated (TCZ group) or to receive usual care alone (UC group). Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants.Main Outcomes and Measures Primary outcomes were scores higher than 5 on the World Health Organization 10-point Clinical Progression Scale (WHO-CPS) on day 4 and survival without need of ventilation (including noninvasive ventilation) at day 14. Secondary outcomes were clinical status assessed with the WHO-CPS scores at day 7 and day 14, overall survival, time to discharge, time to oxygen supply independency, biological factors such as C-reactive protein level, and adverse events.Results Of 131 patients, 64 patients were randomly assigned to the TCZ group and 67 to UC group; 1 patient in the TCZ group withdrew consent and was not included in the analysis. Of the 130 patients, 42 were women (32%), and median (interquartile range) age was 64 (57.1-74.3) years. In the TCZ group, 12 patients had a WHO-CPS score greater than 5 at day 4 vs 19 in the UC group (median posterior absolute risk difference [ARD] −9.0%; 90% credible interval [CrI], −21.0 to 3.1), with a posterior probability of negative ARD of 89.0% not achieving the 95% predefined efficacy threshold. At day 14, 12% (95% CI −28% to 4%) fewer patients needed noninvasive ventilation (NIV) or mechanical ventilation (MV) or died in the TCZ group than in the UC group (24% vs 36%, median posterior hazard ratio [HR] 0.58; 90% CrI, 0.33-1.00), with a posterior probability of HR less than 1 of 95.0%, achieving the predefined efficacy threshold. The HR for MV or death was 0.58 (90% CrI, 0.30 to 1.09). At day 28, 7 patients had died in the TCZ group and 8 in the UC group (adjusted HR, 0.92; 95% CI 0.33-2.53). Serious adverse events occurred in 20 (32%) patients in the TCZ group and 29 (43%) in the UC group (P = .21).Conclusions and Relevance In this randomized clinical trial of patients with COVID-19 and pneumonia requiring oxygen support but not admitted to the intensive care unit, TCZ did not reduce WHO-CPS scores lower than 5 at day 4 but might have reduced the risk of NIV, MV, or death by day 14. No difference on day 28 mortality was found. Further studies are necessary for confirming these preliminary results.Trial Registration ClinicalTrials.gov Identifier: NCT04331808
Details
Language :
English
ISSN :
21686106 and 21686114
Database :
OpenAIRE
Journal :
JAMA Internal Medicine
Accession number :
edsair.dedup.wf.001..8601985efea846285e8bf2b7e7415da5
Full Text :
https://doi.org/10.1001/jamainternmed.2020.6820