Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial
MD Jozefien Declercq, Karel F A Van Damme, MD Elisabeth De Leeuw, MD Bastiaan Maes, PhD Cedric Bosteels, PhD Simon J Tavernier, Stefanie De Buyser, Roos Colman, Prof Maya Hites, Gil Verschelden, Tom Fivez, Filip Moerman, Ingel K Demedts, Nicolas Dauby, Nicolas De Schryver, MD Elke Govaerts, PhD Stefaan J Vandecasteele, Johan Van Laethem, Sebastien Anguille, Prof Jeroen Van Der Hilst, Benoit Misset, Hans Slabbynck, Xavier Wittebole, Fabienne Liénart, Catherine Legrand, Marc Buyse, MD Dieter Stevens, Prof Fre Bauters, Leen J M Seys, Helena Aegerter, Ursula Smole, Victor Bosteels, Levi Hoste, Leslie Naesens, Filomeen Haerynck, Linos Vandekerckhove, Pieter Depuydt, Eva Van Braeckel, Sylvie Rottey, Isabelle Peene, Catherine Van Der Straeten, Frank Hulstaert, Bart N Lambrecht
The Lancet Respiratory Medicine, doi:10.1016/s2213-2600(21)00377-5
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 (PaO 2 :FiO 2 ) 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 (1:2). 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 (1:1:1). 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..
Causes of death COVID Acute kidney injury
Data sharing De-identified individual participant data will be available on approval of a proposal. The shared data can be used for the analyses mentioned in the approved proposal. The study protocol has been published before. 33 Proposals should be directed to the corresponding author.
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