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
Authors: Trøseid Marius , Arribas José R. , Assoumou Lambert , Holten Aleksander Rygh , Poissy Julien , Terzić Vida , Mazzaferri Fulvia , Baño 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 Børresdatter , Bouscambert Maude , Halanova Monika , Péterfi Zoltán , Tsiodras Sotirios , Rezek Michael , Briel Matthias , Ünal Serhat , Schlegel Martin , Ader Florence , Lacombe Karine , Amdal Cecilie Delphin , Rodrigues Serge , Tonby Kristian , Gaudet Alexandre , Heggelund Lars , Mootien Joy , Johannessen Asgeir , Møller 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 Álamo Marta , Aydin Burç , Lund-Johansen Fridtjof , Trabaud Mary-Anne , Diallo Alpha , Halvorsen Bente , Røttingen John-Arne , Tacconelli Evelina , Yazdanpanah Yazdan , Olsen Inge C. , Costagliola Dominique ,   EU SolidAct study group, Dyrhol-Riise Anne Ma , Stiksrud Birgitte , Jenum Synne , MacPherson Magnhild Eide , Aarskog Nikolai Ravn , Røstad Kjerstin , Skeie Linda Gail , Dahl Åsne , 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 Bjørn Martin , Opsand Hanne , Bogen Mette , Rød Linn-Therese , Steinsvik Trude , Åsheim-Hansen Bjørn , Bjerkreim Randi Haukaas , Berg Åse , 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 , Ådnanes Elise , Hannula Raisa , Bremnes Nina , Liyanarachi Kristin , Ehrnström Birgitta , Kvalshaug Martin , Berge Kari , Bygdås Marte , Gustafsson Linda , AballiB Saad , Strand Marianne , Andersen Britt , Aukrust Pål , Barratt-Due Andreas , Henriksen Katerina Nezvalova , Kåsine Trine , Dyrhol-Riise Anne Ma , Berdal Jan Erik , 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 Ángel 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 , Součková Lenka , Švábová Helena Kartáková , Demlová Regina , Sonderlichová Simona , Unal Serhat , Inkaya A. C. , de Bono Stephanie , Kartman Cynthia E. , Adams David H. , Crowe Brenda , Yazdanapanah Yazdan , Unal Serhat , Schneider Gerhard , Mühlbauer Bernd , Ødegård Tone , Bakkehøi Gine , Autran Brigitte , Bjørås Magnar , Lambellerie Xavier de- , Mezzarri Fulvia , Guedj Jeremie , Esperou Helene , Lumbroso Julia , Welte Tobias , Calmy Alexandra , Pischke Søren , Treweek Shaun , Goetghebeur Els , Doussau Adelaide , Weiss Laurence , Hulstaert Frank , Botgros Radu , del Alamo Marta , Chung Florence , Lumbroso Julia , Zeitlinger Markus , Escalera Begonya N. , Csajka Chantal , Williams Clare , Amstutz Alain , Rüegg Corina Silvia , Burdet Charles , Massonnaud Clement , Belhadi Drifa , Mentré France , Aroun Massinissa , Mentré France , Ehrmann Stephan , Espoerou Helene , Burdet Charles , Falk Ragnhild Sørum , Bjordal Kristin , Bakkehøi Gina , Ødegård Tone , Barratt-Due Andreas 
Published: January 2023

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).