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Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial.
Declercq, Jozefien; Van Damme, Karel F A; De Leeuw, Elisabeth; Maes, Bastiaan; Bosteels, Cedric; Tavernier, Simon J; De Buyser, Stefanie; Colman, Roos; Hites, Maya; Verschelden, Gil; Fivez, Tom; Moerman, Filip; Demedts, Ingel K; Dauby, Nicolas; De Schryver, Nicolas; Govaerts, Elke; Vandecasteele, Stefaan J; Van Laethem, Johan; Anguille, Sebastien; van der Hilst, Jeroen; Misset, Benoit; Slabbynck, Hans; Wittebole, Xavier; Liénart, Fabienne; Legrand, Catherine; Buyse, Marc; Stevens, Dieter; Bauters, Fre; Seys, Leen J M; Aegerter, Helena; Smole, Ursula; Bosteels, Victor; Hoste, Levi; Naesens, Leslie; Haerynck, Filomeen; Vandekerckhove, Linos; Depuydt, Pieter; van Braeckel, Eva; Rottey, Sylvie; Peene, Isabelle; Van Der Straeten, Catherine; Hulstaert, Frank; Lambrecht, Bart N.
  • Declercq J; Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghe
  • Van Damme KFA; Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghe
  • De Leeuw E; Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghe
  • Maes B; Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghe
  • Bosteels C; Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghe
  • Tavernier SJ; Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Primary Immunodeficiency Research Laboratory, Faculty of Medicin
  • De Buyser S; Biostatistics Unit, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
  • Colman R; Biostatistics Unit, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
  • Hites M; Clinic of Infectious Diseases, Cliniques Universitaires de Bruxelles, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
  • Verschelden G; Clinic of Infectious Diseases, Cliniques Universitaires de Bruxelles, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
  • Fivez T; Intensive Care Unit, ZOL Genk General Hospital, Genk, Belgium.
  • Moerman F; Department of Infectious Diseases, CHR de La Citadelle General Hospital, Liège, Belgium.
  • Demedts IK; Department of Pulmonary Medicine, AZ Delta General Hospital, Roeselare, Belgium.
  • Dauby N; Institute for Medical Immunology, Université Libre de Bruxelles and CHU Saint-Pierre University Hospital, Brussels, Belgium.
  • De Schryver N; Intensive Care Unit, Clinique Saint-Pierre, Ottignies, Belgium.
  • Govaerts E; Department of Pulmonary Medicine, AZ Sint-Lucas General Hospital, Ghent, Belgium.
  • Vandecasteele SJ; Department of Infectious Diseases, AZ Sint-Jan Brugge-Oostende, Brugge, Belgium.
  • Van Laethem J; Department of Internal Medicine, Universitair Ziekenhuis Brussel, Brussels, Belgium.
  • Anguille S; Department of Hematology, University Hospital Antwerp, Antwerp, Belgium.
  • van der Hilst J; Department of Infectious Diseases and Immune Pathology, Jessa General Hospital and Limburg Clinical Research Center, Hasselt University, Hasselt, Belgium.
  • Misset B; Department of Intensive Care Medicine, University Hospital, Liège, Belgium.
  • Slabbynck H; Department of Pulmonary Medicine, ZNA General Hospital, Antwerp, Belgium.
  • Wittebole X; Intensive Care Unit, Saint Luc University Hospital, UC Louvain, Brussels, Belgium.
  • Liénart F; Department of Internal Medicine, CHU Tivoli University Hospital, La Louvière, Belgium.
  • Legrand C; Institute of Statistics, Biostatistics and Actuarial Sciences (ISBA), Louvain Institute for Data Analysis and Modeling, Louvain-la-Neuve, Belgium.
  • Buyse M; (22)IDDI, Louvain-la-Neuve, and Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt, Belgium.
  • Stevens D; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium.
  • Bauters F; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium.
  • Seys LJM; Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
  • Aegerter H; Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
  • Smole U; Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
  • Bosteels V; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Laboratory of ER Stress and Inflammation, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium.
  • Hoste L; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Primary Immunodeficiency Research Laboratory, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
  • Naesens L; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Primary Immunodeficiency Research Laboratory, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
  • Haerynck F; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Primary Immunodeficiency Research Laboratory, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
  • Vandekerckhove L; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Infectious Diseases, University Hospital Ghent, Ghent, Belgium.
  • Depuydt P; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Intensive Care Unit, University Hospital Ghent, Ghent, Belgium.
  • van Braeckel E; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium.
  • Rottey S; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Drug Research Unit, Ghent University, Ghent, Belgium.
  • Peene I; Department of Rheumatology, AZ Sint-Jan Brugge-Oostende, Brugge, Belgium.
  • Van Der Straeten C; Health Innovation Research, University Hospital Ghent, Ghent, Belgium.
  • Hulstaert F; Belgian Health Care Knowledge Centre, Brussels, Belgium.
  • Lambrecht BN; Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghe
Lancet Respir Med ; 9(12): 1427-1438, 2021 12.
Article in English | MEDLINE | ID: covidwho-1621131
ABSTRACT

BACKGROUND:

Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome.

METHODS:

We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO2FiO2) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 µg/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 µg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria an increasing ferritin concentration of more than 700 µg/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 × 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (12). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (111). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete.

FINDINGS:

Between April 4, and Dec 6, 2020, 342 patients were randomly assigned to IL-1 blockade (n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54-73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2-4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10-16) in the IL-1 blockade group versus 12 days (10-15) in the no IL-1 blockade group (hazard ratio [HR] 0·94 [95% CI 0·73-1·21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10-16) versus 12 days (11-16) in the no IL-6 blockade group (HR 1·00 [0·78-1·29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups.

INTERPRETATION:

Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk.

FUNDING:

Belgian Health Care Knowledge Center and VIB Grand Challenges program.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Respiratory Insufficiency / Antibodies, Monoclonal, Humanized / Cytokine Release Syndrome / COVID-19 Drug Treatment / Antibodies, Monoclonal Type of study: Cohort study / Experimental Studies / Observational study / Prognostic study / Randomized controlled trials / Systematic review/Meta Analysis Topics: Vaccines / Variants Limits: Aged / Female / Humans / Male / Middle aged Country/Region as subject: Europa Language: English Journal: Lancet Respir Med Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Respiratory Insufficiency / Antibodies, Monoclonal, Humanized / Cytokine Release Syndrome / COVID-19 Drug Treatment / Antibodies, Monoclonal Type of study: Cohort study / Experimental Studies / Observational study / Prognostic study / Randomized controlled trials / Systematic review/Meta Analysis Topics: Vaccines / Variants Limits: Aged / Female / Humans / Male / Middle aged Country/Region as subject: Europa Language: English Journal: Lancet Respir Med Year: 2021 Document Type: Article