Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia
Authors: Olivier Hermine, Xavier Mariette, Pierre-Louis Tharaux, Matthieu Resche-Rigon, Raphaël Porcher, Philippe Ravaud, Serge Bureau, Maxime Dougados, Annick Tibi, Elie Azoulay, Jacques Cadranel, Joseph Emmerich, Muriel Fartoukh, Bertrand Guidet, Marc Humbert, Karine Lacombe, Matthieu Mahevas, Frédéric Pene, Valérie Pourchet-Martinez, Frédéric Schlemmer, Yazdan Yazdanpanah, Gabriel Baron, Elodie Perrodeau, Damien Vanhoye, Cécile Kedzia, Lauren Demerville, Anne Gysembergh-Houal, Alexandre Bourgoin, Sarah Dalibey, Matthieu Resche-Rigon, Nabil Raked, Lakhdar Mameri, Stéphanie Alary, Samir Hamiria, Thinhinane Bariz, Hala Semri, Dhiaa Meriem Hai, Moustafa Benafla, Mohamed Belloul, Pernelle Vauboin, Saskia Flamand, Claire Pacheco, Anouk Walter-Petrich, Emilia Stan, Souad Benarab, Corine Nyanou, Claire Montlahuc, Lucie Biard, Robin Charreteur, Celine Dupré, Kévin Cardet, Blandine Lehmann, Kamyl Baghli, Claire Madeleine, Eric D'Ortenzio, Oriane Puéchal, Caroline Semaille, Laurent Savale, Anatole Harrois, Samy Figueiredo, Jacques Duranteau, Nadia Anguel, Xavier Monnet, Christian Richard, Jean-Louis Teboul, Philippe Durand, Pierre Tissieres, Mitja Jevnikar, David Montani, Stéphan Pavy, Nicolas Noel, Olivier Lambotte, Lelia Escaut, Stéphane Jauréguiberry, Elodie Baudry, Christiane Verny, Edouard Lefèvre, Mohamad Zaidan, Clotilde Le Tiec Le Tiec, Céline Verstuyft Verstuyft, Anne-Marie Roques, Lamiae Grimaldi, Domitille Molinari, Gaël Leprun, Alain Fourreau, Laurent Cylly, Myriam Virlouvet, Ramdane Meftali, Solène Fabre, Marion Licois, Asmaa Mamoune, Yacine Boudali, Sophie Georgin-Lavialle, Patricia Senet, Angèle Soria, Antoine Parrot, Hélène François, Nathalie Rozensztajn, Emmanuelle Blin, Pascaline Choinier, Juliette Camuset, Jean-Simon Rech, Antony Canellas, Camille Rolland-Debord, Nadège Lemarié, Nicolas Belaube, Marine Nadal, Martin Siguier, Camille Petit-Hoang, Julie Chas, Elodie Drouet, Matthieu Lemoine, Audrey Phibel, Lucie Aunay, Eliane Bertrand, Sylviane Ravato, Marie Vayssettes, Anne Adda, Celine Wilpotte, Pélagie Thibaut, Julie Fillon, Isabelle Debrix, Soraya Fellahi, Jean-Philippe Bastard, Guillaume Lefèvre, Vincent Fallet, Jacques-Eric Gottenberg, Yves Hansmann, Emmanuel Andres, Sophie Bayer, Guillaume Becker, Frédéric Blanc, Stéphane Brin, Vincent Castelain, Emmanuel Chatelus, Eva Chatron, Olivier Collange, François Danion, Frédéric De Blay, Eric Demonsant, Pierre Diemunsch, Sophie Diemunsch, Renaud Felten, Bernard Goichot, Valentin Greigert, Aurélien Guffroy, Bob Heger, Anne Hutt, Charlotte Kaeuffer, Loic Kassegne, Anne Sophie Korganow, Pierrick Le Borgne, Nicolas Lefebvre, Tristan Martin, Paul Michel Mertes, Catherine Metzger, Nicolas Meyer, Gabriel Nisand, Eric Noll, Mathieu Oberlin, Sophie Ohlmann-Caillard, Vincent Poindron, Julien Pottecher, Yvon Ruch, Cédric Sublon, Hakim Tayebi, François Weill, Arsène Mekinian, Dorothée Chopin, Olivier Fain, Marc Garnier, Jessica Krause Le Garrec, Marjolaine Morgand, Jerome Pacanowski, Tomas Urbina, Chloe Mcavoy, Maria Pereira, Gladys Aratus, Laurence Berard, Tabassome Simon, Anne Daguenel Nguyen, Marie Antignac, Céline Leplay, Jean-Benoit Arlet, Jean-Luc Diehl, Florence Bellenfant, Anne Blanchard, Alexandre Buffet, Bernard Cholley, Antoine Fayol, Edouard Flamarion, Anne Godier, Thomas Gorget, Sophie-Rym Hamada, Caroline Hauw-Berlemont, Jean- Sébastien Hulot, David Lebeaux, Marine Livrozet, Adrien Michon, Arthur Neuschwander, Marie-Aude Penet, Benjamin Planquette, Brigitte Ranque, Olivier Sanchez, Geoffroy Volle, Sandrine Briois, Mathias Cornic, Virginie Elisee, Denis, Jesuthasan, Juliette Djadi-Prat, Pauline Jouany, Ramon Junquera, Mickael Henriques, Amina Kebir, Isabelle Lehir, Jeanne Meunier, Florence Patin, Valérie Paquet, Anne TréHan, Véronique Vigna, Brigitte Sabatier, Damien Bergerot, Charlène Jouve, Camille Knosp, Olivia Lenoir, Nassim Mahtal, Léa Resmini, Xavier Lescure, Jade Ghosn, Antoine Bachelard, Timothee Bironne, Raphael Borie, Agathe Bounhiol, Catherine Boussard, Jeanne Chauffier, Solaya Chalal, Lynda Chalal, Malikhone Chansombat, Paul Crespin, Bruno Crestani, Olivia Daconceicao, Laurene Deconinck, hilippe Dieude, Antoine Dossier, Marie Dubert, Greggory Ducrocq, Axelle Fuentes, Anne Gervais, Marie Gilbert, Valentina Isernia, Sophie Ismael, Veronique Joly, Zelie Julia, Sylvie Lariven, Sylvie Le Gac, Diane Le Pluart, Francoise Louni, Awa Ndiaye, Thomas Papo, Marion Parisey, Bao Phung, Annabelle Pourbaix, Anne Rachline, Christophe Rioux, Aurelie Sautereau, Gabriel Steg, Hassan Tharini, Simon Valayer, Dorothee Vallois, Paul Vermes, Thomas Volpe, Yann Nguyen, Vasco Honsel, Emmanuel Weiss, Anaïs Codorniu, Virginie Zarrouk, Victoire De Lastours, Matthieu Uzzan, Naura Gamany, Roza Rahli, Zeina Louis, David Boutboul, Lionel Galicier, Yaël Amara, Gabrielle Archer, Amira Benattia, Anne Bergeron, Louise Bondeelle, Nathalie De Castro, Melissa Clément, Michaël Darmont, Blandine Denis, Clairelyne Dupin, Elsa Feredj, Delphine Feyeux, Adrien Joseph, Etienne Lengliné, Pierre Le Guen, Geoffroy Liégeon, Gwenaël Lorillon, Asmaa Mabrouki, Eric Mariotte, Grégoire Martin De Frémont, Adrien Mirouse, Jean-Michel Molina, Régis Peffault De Latour, Eric Oksenhendler, Julien Saussereau, Abdellatif Tazi, Jean-Jacques Tudesq, Lara Zafrani, Isabelle Brindele, Emmanuelle Bugnet, Karine Celli Lebras, Julien Chabert, Lalia Djaghout, Catherine Fauvaux, Anne Lise Jegu, Ewa Kozaliewicz, Martine Meunier, Marie-Thérèse Tremorin, Claire Davoine, Isabelle Madeleine, Sophie Caillat-Zucman, Constance Delaugerre, Florence Morin, Damien Sene, Ruxandra Burlacu, Benjamin Chousterman, Bruno Megarbane, Pascal Richette, Jean-Pierre Riveline, Aline Frazier, Eric Vicaut, Laure Berton, Tassadit Hadjam, Miguel Alejandro Vasquez-Ibarra, Clément Jourdaine, Aude Jacob, Julie Smati, Stéphane Renaud, Philippe Manivet, Claire Pernin, Lydia Suarez, Luca Semerano, Sebastien Abad, Ruben Benainous, Coralie Bloch Queyrat, Nicolas Bonnet, Sabrina Brahmi, johann Cailhol, Yves Cohen, Celine Comparon, Hugues Cordel, Robin Dhote, Nathalie Dournon, Boris Duchemann, Nathan Ebstein, Benedicte Giroux-Leprieur, Jeanne Goupil De Bouille, Anne Jacolot, Hilario Nunes, Johanna Oziel, Vanessa Rathouin, Marthe Rigal, Dominique Roulot, Claire Tantet, Yurdagul Uzunhan, Nathalie Costedoat-Chalumeau, Zakaria Ait Hamou, Sarah Benghanem, Philippe Blanche, Etienne Canoui, Nicolas Carlier, Benjamin Chaigne, Adrien Contejean, Bertrand Dunogue, Pierre Dupland, Aurélie Durel - Maurisse, Remy Gauzit, Paul Jaubert, Hassan Joumaa, Mathieu Jozwiak, Solen Kerneis, Marie Lachatre, Hélène Lafoeste, Paul Legendre, Liem Binh Luong Nguyen, Jonathan Marey, Caroline Morbieu, Luc Mouthon, Lee Nguyen, Lola-Jade Palmieri, Alexis Regent, Tali-Anne Szwebel, Benjamin Terrier, Corinne Guerin, Jérémie Zerbit, Kahina Cheref, Kamil Chitour, Mamadou Salif Cisse, Ada Clarke, Gaelle Clavere, Isabelle Dusanter, Caroline Gaudefroy, Moez Jallouli, Sami Kolta, Catherine Le Bourlout, Nathalie Marin, Nathalie Menage, Alexandre Moores, Isabelle Peigney, Cédric Pierron, Samira Saleh-Mghir, Mathilde Vallet, Marc Michel, Giovanna Melica, Jean-Daniel Lelievre, Elena Fois, Pascal Lim, Marie Matignon, Constance Guillaud, Alaki Thiemele, David Schmitz, Marion Bouhris, Syllia Belazouz, Laetitia Languille, Armand Mekontso-Dessaps, Thiziri Sadaoui, Julien Mayaux, Patrice Cacoub, Jean-Christophe Corvol, Céline Louapre, Sara Sambin, Louise-Laure Mariani, Carine Karachi, Florence Tubach, Candice Estellat, Linda Gimeno, Karine Martin, Aïcha Bah, Vixra Keo, Sabrine Ouamri, Yasmine Messaoudi, Nessima Yelles, Pierre Faye, Sébastien Cavelot, Cecile Larcheveque, Laurence Annonay, Jaouad Benhida, Aida Zahrate-Ghoul, Soumeya Hammal, Ridha Belilita, Marie Lecronier, Alexandra Beurton, Luc Haudebourg, Robin Deleris, Julien Le Marec, Sara Virolle, Safaa Nemlaghi, Côme Bureau, Pierre Mora, Martin De Sarcus, Olivier Clovet, Baptiste Duceau, Paul Henri Grisot, Marie hélène Pari, Jérémy Arzoine, Ulrich Clarac, Morgane Faure, Julie Delemazure, Maxence Decavele, Elise Morawiec, Alexandre Demoule, Martin Dres, Mathieu Vautier, Yves Allenbach, Olivier Benveniste, Gaelle Leroux, Aude Rigolet, Perrine Guillaume-Jugnot, Fanny Domont, Anne Claire Desbois, Cloé Comarmond, Nicolas Champtiaux, Segolene Toquet, Amine Ghembaza, Matheus Vieira, Georgina Maalouf, Gonçalo Boleto, Yasmina Ferfar, Fanny Charbonnier, Claire Aguilar, Fanny Alby-Laurent, Marie-Alexandra Alyanakian, Prissile Bakouboula, Christine Broissand, Carole Burger, Clara Campos-Vega, Nathalie Chavarot, Laure Choupeaux, Caroline Elie, Benjamin Fournier, Sophie Granville, Elodie Issorat, Claire Rouzaud, Damien Vimpere, Guillaume Geri, Nawal Derridj, Naima Sguiouar, Hakim Meddah, Mourad Djadel, Helene Chambrin-Lauvray, Jean-Charles Duclos-Vallée, Faouzi Saliba, Sophie-Caroline Sacleux, Ilias Koumis, Jean-Marie Michot, Annabelle Stoclin, Emeline Colomba, Fanny Pommeret, Chistophe Willekens, Rosa Da Silva, Valérie Dejean, Yasmina Mekid, Ines Ben-Mabrouk, Caroline Pradon, Laurence Drouard, Valérie Camara-Clayette, Alexandre Morel, Gilles Garcia, Abolfazl Mohebbi, Férial Berbour, Mélanie Dehais, Anne-Lise Pouliquen, Alison Klasen, Loren Soyez-Herkert, Jonathan London, Younes Keroumi, Emmanuelle Guillot, Guillaume Grailles, Younes El Amine, Fanny Defrancq, Hanane Fodil, Chaouki Bouras, Dominique Dautel, Nicolas Gambier, Thierno Dieye, Boris Bienvenu, Victor Lancon, Laurence Lecomte, Kristina Beziriganyan, Belkacem Asselate, Laure Allanic, Elena Kiouris, Marie-Hélène Legros, Christine Lemagner, Pascal Martel, Vincent Provitolo, Félix Ackermann, Mathilde Le Marchand, Aurélie Clan Hew Wai, Dimitri Fremont, Elisabeth Coupez, Mireille Adda, Frédéric Duée, Lise Bernard, Antoine Gros, Estelle Henry, Claire Courtin, Anne Pattyn, Pierre-Grégoire Guinot, Marc Bardou, Agnes Maurer, Julie Jambon, Amélie Cransac, Corinne Pernot, Bruno Mourvillier, Amélie Servettaz, Gaetan Deslée, Alain Wynckel, Philippe Benoit, Eric Marquis, Damien Roux, Coralie Gernez, Cécile Yelnik, Julien Poissy, Mandy Nizard, Fanette Denies, Hélène Gros, Jean-Jacques Mourad, Emmanuelle Sacco, Sophie Renet
Journal: JAMA Internal Medicine (2020)

<h3>Importance</h3> Severe pneumonia with hyperinflammation and elevated interleukin-6 is a common presentation of coronavirus disease 2019 (COVID-19). <h3>Objective</h3> To determine whether tocilizumab (TCZ) improves outcomes of patients hospitalized with moderate-to-severe COVID-19 pneumonia. <h3>Design, Setting, and Particpants</h3> 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. <h3>Interventions</h3> 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. <h3>Main Outcomes and Measures</h3> 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. <h3>Results</h3> 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 (<i>P</i> = .21). <h3>Conclusions and Relevance</h3> 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. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT04331808