학술논문
Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial
Document Type
Report
Author
Traseid, Marius; Arribas, José R.; Assoumou, Lambert; Holten, Aleksander Rygh; Poissy, Julien; TerziÄ, Vida; Mazzaferri, Fulvia; Baéo, Jesús Rodríguez; Eustace, Joe; Hites, Maya; Joannidis, Michael; Paiva, José-Artur; Reuter, Jean; Püntmann, Isabel; Patrick-Brown, Thale D. J. H.; Westerheim, Elin; Nezvalova-Henriksen, Katerina; Beniguel, Lydie; Dahl, Tuva Barresdatter; Bouscambert, Maude; Halanova, Monika; Péterfi, Zoltán; Tsiodras, Sotirios; Rezek, Michael; Briel, Matthias; Ãnal, Serhat; Schlegel, Martin; Ader, Florence; Lacombe, Karine; Amdal, Cecilie Delphin; Rodrigues, Serge; Tonby, Kristian; Gaudet, Alexandre; Heggelund, Lars; Mootien, Joy; Johannessen, Asgeir; Maller, Jannicke Horjen; Pollan, Beatriz Diaz; Tveita, Anders Aune; Kildal, Anders Benjamin; Richard, Jean-Christophe; Dalgard, Olav; Simensen, Victoria Charlotte; Baldé, Aliou; de Gastines, Lucie; del Ãlamo, Marta; Aydin, Burç; Lund-Johansen, Fridtjof; Trabaud, Mary-Anne; Diallo, Alpha; Halvorsen, Bente; Rattingen, John-Arne; Tacconelli, Evelina; Yazdanpanah, Yazdan; Olsen, Inge C.; Costagliola, Dominique; Dyrhol-Riise, Anne Ma; Stiksrud, Birgitte; Jenum, Synne; MacPherson, Magnhild Eide; Aarskog, Nikolai Ravn; Rastad, Kjerstin; Skeie, Linda Gail; Dahl, Ãsne; Steen, Jeanette Konstance; Nur, Sarah; Segers, Filip; Korsan, Katrine Andersen; Sethupathy, Ashwini; Sandstå, Ann Jorunn; Paulsen, Gunn-Janne; Ueland, Thor; Michelsen, Annika; Aukrust, Pål; Berdal, Jan Erik; Melkeraaen, Ingunn; Tollefsen, Merete Moen; Andreassen, Jessica; Dokken, Jannicke; Müller, Karl Erik; Woll, Bjarn Martin; Opsand, Hanne; Bogen, Mette; Rad, Linn-Therese; Steinsvik, Trude; Ãsheim-Hansen, Bjarn; Bjerkreim, Randi Haukaas; Berg, Ãse; Moen, Solfrid; Kvalheim, Stina; Strand, Kristian; Gravrok, Berit; Skogen, Vegard; Lorentzen, Elias Myrvoll; Schive, Simen Walberg; Rossvoll, Lasse; Hoel, Hedda; Engebråten, Simon; Martinsson, Mia Schie; Thallinger, Monica; Ãdnanes, Elise; Hannula, Raisa; Bremnes, Nina; Liyanarachi, Kristin; Ehrnström, Birgitta; Kvalshaug, Martin; Berge, Kari; Bygdås, Marte; Gustafsson, Linda; AballiB, Saad; Strand, Marianne; Andersen, Britt; Barratt-Due, Andreas; Henriksen, Katerina Nezvalova; Kåsine, Trine; Favory, Raphaël; Nseir, Saad; Preau, Sebastien; Jourdain, Mercé; Ledoux, Geoffrey; Durand, Arthur; Houard, Marion; Moreau, Anne-Sophie; Rouzé, Anahita; Tortuyaux, Romain; Degouy, Guillaume; Levy, Clémentin; Liu, Vincent; Dognon, Nicolas; Mariller, Laure; Delcourte, Claire; Reguig, Zineb; Cerf, Amélie; Cuvelliez, Marie; Kipnis, Eric; Boyer-Beysserre, Marielle; Bignon, Anne; Parmentier, Laurie; Meddour, Damia; Frade, Sarah; Timsit, Jean-François; Peiffer-Smadja, Nathan; Wicky, Paul-Henri; De Montmollin, Etienne; Bouadma, Lila; Dessajan, Julien; Sonneville, Romain; Patrier, Juliette; Presente, Simona; Sylia, Zmihi; Rioux, Christophe; Thy, Michaël; Collias, Lio; Bouaraba, Yasmine; Dobremel, Nikita; Dureau, Anne-Florence; Oudeville, Pierre; Pointurier, Valentin; Rabouel, Yannick; Stiel, Laure; Alzina, Camille; Ramstein, Camille; Ait-Oufella, Hafid; Hamoudi, Fatima; Urbina, Thomas; Zerbib, Yoann; Maizel, Julien; Wilpotte, Celine; Piroth, Lionel; Blot, Mathieu; Sixt, Thibault; Moretto, Florian; Charles, Carole; Gohier, Sandrine; Roux, Damien; Le Breton, Camille; Gernez, Coralie; Thiry, Ingrid; Baboi, Loredana; Malvy, Denis; Boyer, Alexandre; Perreau, Pauline; Armellini, Maddalena; De Luca, Giulia; Di Pietro, Ospedale S. M. Massimo; Romanin, Benedetta; Brogi, Michela; Castelli, Francesco; Amadasi, Silvia; Barchiesi, Francesco; Canovari, Benedetta; Coppola, Nicola; Pisaturo, Mariantonietta; Russo, Antonio; Occhiello, Laura; Cataldo, Francesco; Rillo, Marta Mora; Queiruga, Javier; Seco, Enrique; Stewart, Stefan; Borobia, Alberto M.; Moraga, Paloma; Prieto, Rocío; García, Irene; Rivera, Carlota; Narro, José Luis; Chacón, Natalia; de la Rosa, Sandra; Macías, María; Barrera, Lydia; Serna, Almudena; Palomo, Virginia; Sánchez, Maria Isabel García; Gutiérrez, David; Campos, Ana Silva; Garfia, Miguel Ãngel Gómez; Toyos, Elvira Bonilla; Cabrera, Judith Sanabria; Lucena, María Isabel; Lapique, Eva Larranaga; Englert, Pierre; Khalil, Zineb; Jacobs, Frédérique; Malaise, Justine; Mukangenzi, Odette; Smissaert, Cinderella; Hildebrand, Marc; Martiny, Delphine; Vervacke, Audrey; Scarnière, Axelle; Yin, Nicolas; Michel, Charlotte; Seyler, Lucie; Allard, Sabine; Van Laethem, Johan; Verschelden, Gil; Meeuwissen, Annelies; De Waele, Alex; Van Buggenhout, Virgini; Monteyne, Dora; Noppe, Nils; Belkhir, Leila; Yombi, Jean Cyr; De Greef, Julien; Mesland, Jean Baptiste; De Ghellinck, Léopold; Kin, Valérie; D'Aoust, Céline; Bouvier, Anne; Dekeister, Anne- Charlotte; Hawia, Estelle; Gaillet, Adeline; Deshorme, Hélène; Halleux, Severine; Galand, Vanessa; Roncon-Albuquerque, Roberto; Santos, Luís Linhares; Vieira, César Burgi; Magalhaes, Rosana; Ferreira, Sónia; Bernardo, Mariana; Jackson, Arthur; Sadlier, Corinna; O'Connell, Sarah; Blair, Matthew; Manning, Edmund; Cusack, Fiona; Kelly, Niamh; Stephenson, Hannah; Keane, Ruben; Murphy, Aisling; Cunnane, Michele; Keane, Fionnuala; O'Regan, Mary-Claire; de Barra, Eoghan; Bellone, Aimee McGreal; O'Regan, Siobhan; Carey, Patrick; Harte, Jeffrey; Coakley, Peter; Heeney, Aoife; Ryan, Dorothy; Curley, Gerard; McConkey, Samuel; Sulaiman, Imran; Costello, Richard; McNally, Cora; Foley, Claire; Trainor, Sophie; Jacob, Benson; Vengathodi, Suchitra; Kent, Brian; Bergin, Colm; Townsend, Liam; Kerr, Colm; Panti, Nalini; Sanz, Alberto Garcia; Benny, Binny; Dea, Edel O.; Galvin, Niamh; Burke, Claire; Galvin, Aisling; Aisiyabi, Sara; Lobo, Deepanjali; Laffey, John; McNicolas, Bairbre; Cosgrave, David; Sheehan, J. R.; Nita, Ciprian; Hanley, Ciara; Kelly, Claire; Kernan, Maeve; Murray, Jonathan; Staub, Thérèse; Henin, Thomas; Damilot, Gaelle; Bintener, Tania; Colling, Joelle; Ferretti, Christian; Werer, Christophe; Stammet, Pascal; Braquet, Pierre; Arendt, Vic; Calvo, Esther; Michaux, Christian; Mediouni, Chouaib; Znati, Ali; Montanes, Gloria; Garcia, Laetitia; Thomé, Claudius; Breitkopf, Robert; Peer, Andreas; Lehner, Georg; Bellman, Romuald; Ditlbacher, Adelheid; Finkenstedt, Armin; Zotter, Klemens; Hernandez, Christian Preuss; Rajsic, Sasa; Lanthaler, Barbara; Greil, Richard; Tamás, Kiss; Kovácsné-Levang, Szilvia; Sipos, David; Kappéter, Agnes; Halda-Kiss, Bernadett; Madarassi-Papp, Edit; Hajdu, Edit; Bende, Balázs; Konstantinos, Thomas; Moschopoulos, Charalambos; Labrou, Eleni; Tsakona, Maria; Grigoropoulos, Ioannis; Kotanidou, Anastasia; Fragkou, Paraskevi; Theodorakopoulou, Maria; Pantazi, Eugenia; Jahai, Edison; Moukouli, Maria; Siafakas, Dimitrios; Mühlbauer, Bernd; Dembinski, Rolf; Stich, Kathrin; Schneider, Gerhard; Nagy, Andrej; Grodová, Karolína; Kubelová, Michaela; Soucková, Lenka; Svábová, Helena Kartáková; Demlová, Regina; Sonderlichová, Simona; Unal, Serhat; Inkaya, A. C.; de Bono, Stephanie; Kartman, Cynthia E.; Adams, David H.; Crowe, Brenda; Yazdanapanah, Yazdan; Ødegård, Tone; Bakkehai, Gine; Autran, Brigitte; Bjarås, Magnar; Lambellerie, Xavier de-; Mezzarri, Fulvia; Guedj, Jeremie; Esperou, Helene; Lumbroso, Julia; Welte, Tobias; Calmy, Alexandra; Pischke, Saren; Treweek, Shaun; Goetghebeur, Els; Doussau, Adelaide; Weiss, Laurence; Hulstaert, Frank; Botgros, Radu; del Alamo, Marta; Chung, Florence; Zeitlinger, Markus; Escalera, Begonya N.; Csajka, Chantal; Williams, Clare; Amstutz, Alain; Rüegg, Corina Silvia; Burdet, Charles; Massonnaud, Clement; Belhadi, Drifa; Mentré, France; Aroun, Massinissa; Ehrmann, Stephan; Espoerou, Helene; Falk, Ragnhild Sarum; Bjordal, Kristin; Bakkehai, Gina
Source
Critical Care. January 10, 2023, Vol. 27 Issue 1
Subject
Language
English
ISSN
1364-8535
Abstract
Author(s): Marius Traseid[sup.1,2] , José R. Arribas[sup.3,4] , Lambert Assoumou[sup.5] , Aleksander Rygh Holten[sup.2,6] , Julien Poissy[sup.7,8] , Vida TerziÄ[sup.9,10] , Fulvia Mazzaferri[sup.11] , Jesús Rodríguez Baéo[sup.12,13,14] , Joe Eustace[sup.15] [...]
Background Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49-69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI - 0.1% [- 8*3 to 8*0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (- 3.2% [- 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu (2022-500385-99-00). Keywords: COVID-19, Vaccination, Safety, Baricitinib
Background Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49-69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI - 0.1% [- 8*3 to 8*0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (- 3.2% [- 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu (2022-500385-99-00). Keywords: COVID-19, Vaccination, Safety, Baricitinib