Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial

• Published in: Nature medicine Vol. 27; no. 10; pp. 1752 - 1760
• Main Authors: Kyriazopoulou, Evdoxia, Poulakou, Garyfallia, Milionis, Haralampos, Metallidis, Simeon, Adamis, Georgios, Tsiakos, Konstantinos, Fragkou, Archontoula, Rapti, Aggeliki, Damoulari, Christina, Fantoni, Massimo, Kalomenidis, Ioannis, Chrysos, Georgios, Angheben, Andrea, Kainis, Ilias, Alexiou, Zoi, Castelli, Francesco, Serino, Francesco Saverio, Tsilika, Maria, Bakakos, Petros, Nicastri, Emanuele, Tzavara, Vassiliki, Kostis, Evangelos, Dagna, Lorenzo, Koufargyris, Panagiotis, Dimakou, Katerina, Savvanis, Spyridon, Tzatzagou, Glykeria, Chini, Maria, Cavalli, Giulio, Bassetti, Matteo, Katrini, Konstantina, Kotsis, Vasileios, Tsoukalas, George, Selmi, Carlo, Bliziotis, Ioannis, Samarkos, Michael, Doumas, Michael, Ktena, Sofia, Masgala, Aikaterini, Papanikolaou, Ilias, Kosmidou, Maria, Myrodia, Dimitra-Melia, Argyraki, Aikaterini, Cardellino, Chiara Simona, Koliakou, Katerina, Katsigianni, Eleni-Ioanna, Rapti, Vassiliki, Giannitsioti, Efthymia, Cingolani, Antonella, Micha, Styliani, Akinosoglou, Karolina, Liatsis-Douvitsas, Orestis, Symbardi, Styliani, Gatselis, Nikolaos, Mouktaroudi, Maria, Ippolito, Giuseppe, Florou, Eleni, Kotsaki, Antigone, Netea, Mihai G., Eugen-Olsen, Jesper, Kyprianou, Miltiades, Panagopoulos, Periklis, Dalekos, George N., Giamarellos-Bourboulis, Evangelos J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2021; Nature Publishing Group
• Subjects: 692/308; 692/308/2779/777; Aged; Biomedical and Life Sciences; Biomedicine; Cancer Research; Clinical trials; Confidence intervals; Coronaviruses; COVID-19; COVID-19 - virology; COVID-19 Drug Treatment; Dexamethasone; Double-Blind Method; Double-blind studies; Failure; Female; Humans; Infectious Diseases; Inhibitors; Interleukin 1 receptor antagonist; Interleukin 1 Receptor Antagonist Protein - adverse effects; Interleukin 1 Receptor Antagonist Protein - therapeutic use; Male; Metabolic Diseases; Middle Aged; Molecular Medicine; Neurosciences; Patients; Placebos; Plasma levels; Receptors; Receptors, Urokinase Plasminogen Activator - blood; Respiratory failure; SARS-CoV-2 - isolation & purification; Serum levels; Testing; Thrombolytic drugs; U-Plasminogen activator; Urokinase; Viral diseases; Greece
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-021-01499-z

Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/β inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml −1 , 85.9% ( n  = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26–0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P  < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter. The SAVE-MORE phase 3 study demonstrates the efficacy of anakinra, an IL-1α/β inhibitor, in patients with COVID-19 and high serum levels of soluble plasminogen activator receptor.