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

Critical Care

Research

Zoltán Péterfi¹  Olav Dalgard²  Maya Hites³  Jean Reuter⁴  Alexandre Gaudet⁵  Martin Schlegel⁶  Anders Benjamin Kildal⁷  Monika Halanova⁸  Katerina Nezvalova-Henriksen⁹  Burç Aydin^1,10  Fridtjof Lund-Johansen^1,10  Jannicke Horjen Møller^1,11  Anders Aune Tveita^1,12  Jesús Rodríguez Baño^1,13  Inge C. Olsen^1,14  Kristian Tonby^1,15  Victoria Charlotte Simensen^1,16  Fulvia Mazzaferri^1,17  Thale D. J. H. Patrick-Brown^1,18  Marta del Álamo^1,19  Serhat Ünal^2,20  Florence Ader^2,21  José R. Arribas^2,22  Beatriz Diaz Pollan^2,23  Aleksander Rygh Holten^2,24  Asgeir Johannessen^2,25  Isabel Püntmann^2,26  José-Artur Paiva^2,27  Maude Bouscambert^2,28  Mary-Anne Trabaud^2,29  Julien Poissy^3,30  Alpha Diallo^3,31  Vida Terzić^3,31  Lucie de Gastines^3,31  Lars Heggelund^3,32  Michael Joannidis^3,33  Sotirios Tsiodras^3,34  John-Arne Røttingen^3,35  Tuva Børresdatter Dahl^3,36  Bente Halvorsen^3,37  Cecilie Delphin Amdal^3,38  Marius Trøseid^3,39  Elin Westerheim^4,40  Jean-Christophe Richard^4,41  Joy Mootien^4,42  Serge Rodrigues^4,43  Lydie Beniguel^4,43  Dominique Costagliola^4,43  Aliou Baldé^4,43  Lambert Assoumou^4,43  Karine Lacombe^4,44  Michael Rezek^4,45  Matthias Briel^4,46  Joe Eustace^4,47  Yazdan Yazdanpanah^4,48  Evelina Tacconelli^4,49 

[1] 1St Department of Internal Medicine, Division of Infectology, University of Pécs, Pécs, Hungary;Akershus University Hospital, Lørenskog, Norway;Institute of Clinical Medicine, University of Oslo, Oslo, Norway;Brussels University Hospital-Erasme, Brussels, Belgium;Université Libre de Bruxelles, Brussels, Belgium;Centre Hospitalier de Luxembourg, Service de Réanimation-Soins Intensifs, 1210, Luxembourg, Luxembourg;Critical Care Center, Department of Intensive Care Medicine, CHU Lille, 59000, Lille, France;Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR9017-CIIL-Centre d’Infection Et d’Immunité de Lille, 59000, Lille, France;Department of Anesthesiology and Intensive Care Medicine, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany;Department of Anesthesiology and Intensive Care, University Hospital of North Norway, Tromsø, Norway;Department of Epidemiology, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Košice, Slovakia;Department of Haematology, Oslo University Hospital and Oslo Hospital Pharmacy, Oslo, Norway;Department of Immunology, Oslo University Hospital, Oslo, Norway;Department of Intensive Care Medicine, Stavanger University Hospital, Stavanger, Norway;Department of Medicine, Bærum Hospital, Vestre Viken, Bærum, Norway;Department of Medicine, Virgen Macarena University Hospital, Seville, Spain;University of Sevilla and Biomedicines Institute of Seville (IBiS)/CSIC, Seville, Spain;CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain;Department of Research Support for Clinical Trials, Oslo University Hospital, Oslo, Norway;Deptartment of Infectious Diseases, Oslo University Hospital, Oslo, Norway;Institute of Clinical Medicine, University of Oslo, Oslo, Norway;Division of Health Services, Department of Global Health, Norwegian Institute of Public Health, Oslo, Norway;Division of Infectious Diseases, Department of Diagnostics and Public Health, University of Verona, Verona, Italy;Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway;Institute of Clinical Medicine, University of Oslo, Oslo, Norway;ECRIN, Paris, France;Hacettepe University Hospital, Ankara, Turkey;Hospices Civils de Lyon, Département Des Maladies Infectieuses Et Tropicales, 69004, Lyon, France;Centre International de Recherche en Infectiologie (CIRI), Inserm 1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ Lyon, 69007, Lyon, France;Infectious Diseases Unit, Internal Medicine Department, La Paz University Hospital, IdiPAZ, Madrid, Spain;Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain;Infectious Diseases Unit, Internal Medicine Department, La Paz University Hospital, Madrid, Spain;Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), IdiPAZ, Madrid, Spain;Institute of Clinical Medicine, University of Oslo, Oslo, Norway;Department of Acute Medicine, Oslo University Hospital, Oslo, Norway;Institute of Clinical Medicine, University of Oslo, Oslo, Norway;Department of Infectious Diseases, Vestfold Hospital Trust, Tønsberg, Norway;Institute of Pharmacology, Hospital Group Gesundheit Nord gGmbH, Bremen, Germany;Intensive Care Medicine Department, Centro Hospitalar Universitário Sao Joao, Porto, Portugal;Faculty of Medicine, University of Porto, Porto, Portugal;Laboratoire de Virologie, Institut Des Agents Infectieux de Lyon, Centre National de Reference Des Virus Des Infections Respiratoires France Sud, Hospices Civils de Lyon, 69317, Lyon, France;Laboratoire de Virologie, Institut Des Agents Infectieux de Lyon, Centre National de Reference Des Virus Respiratoires France Sud, 69317, Hospices Civils de LyonLyon, France;Lille University, Lille, France/CHU Lille - Hôpital Roger Salengro, Lille, France;L’Institut National de La Santé Et de La Recherche Médicale (Inserm), Paris, France;Maladies Infectieuses Emergentes, 75015, Paris, France;Institut National de La Santé Et de La Recherche Médicale, INSERM, 75013, Paris, France;Medical Department, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway;Department of Clinical Science, University of Bergen, Bergen, Norway;Medical University Innsbruck, Innsbruck, Austria;National and Kapodistrian University of Athens, Athens, Greece;University Hospital of Athens Attikon, Athens, Greece;Norwegian Institute of Public Health, Oslo, Norway;Research Institute for Internal Medicine, Oslo University Hospital, Oslo, Norway;Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway;Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway;Institute of Clinical Medicine, University of Oslo, Oslo, Norway;Research support service and Department of Oncology, Oslo University Hospital, Oslo, Norway;Section for Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway;Institute of Clinical Medicine, University of Oslo, Oslo, Norway;Section for Monitoring, Clinical Trial Unit (CTU), Oslo University Hospital, Oslo, Norway;Service de Médecine Intensive-Réanimation, Hôpital de La Croix - Rousse - HCL, Lyon, France;CREATIS INSERM U1206-CNRS UMR 5220, Lyon, France;Service, de Réanimation Médiale, GHRMSA Hopital Emile Muller, Mulhouse, France;Sorbonne Université, INSERM, Institut Pierre Louis d’Épidémiologie Et de Santé Publique (IPLESP), Paris, France;Sorbonne Université, Institut Pierre-Louis d’Épidemiologie Et de Santé Publique, INSERM, 75013, Paris, France;APHP, Hôpital Saint-Antoine, Service de Maladies Infectieuses Et Tropicales, 75012, Paris, France;St. Anne University Hospital, Brno, Czech Republic;Swiss Clinical Trial Organisation and Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland;University College Cork, Cork, Ireland;Université de Paris, IAME, INSERM, 75018, Paris, France;AP-HP, Hôpital Bichat, Service de Maladies Infectieuses Et Tropicales, 75018, Paris, France;Verona University Hospital, Verona, Italy;Division of Infectious Diseases, Department of Diagnostics and Public Health, University of Verona, Verona, Italy;

关键词: COVID-19;    Vaccination;    Safety;    Baricitinib;   

DOI  :  10.1186/s13054-022-04205-8

 received in 2022-10-06, accepted in 2022-10-13,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundBaricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants.MethodsBari-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.ResultsTwo 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.ConclusionThis 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).

【 授权许可】

CC BY   
© The Author(s) 2023

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