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

Nat Med. 2021 Oct;27(10):1752-1760. doi: 10.1038/s41591-021-01499-z. | PubMed

Evdoxia Kyriazopoulou¹, Garyfallia Poulakou², Haralampos Milionis³, Simeon Metallidis⁴, Georgios Adamis⁵, Konstantinos Tsiakos⁶, Archontoula Fragkou⁷, Aggeliki Rapti⁶, Christina Damoulari¹, Massimo Fantoni⁸, Ioannis Kalomenidis⁹, Georgios Chrysos¹⁰, Andrea Angheben¹¹, Ilias Kainis¹², Zoi Alexiou¹³, Francesco Castelli¹⁴, Francesco Saverio Serino¹⁵, Maria Tsilika¹, Petros Bakakos¹⁶, Emanuele Nicastri¹⁷, Vassiliki Tzavara¹⁸, Evangelos Kostis¹⁹, Lorenzo Dagna²⁰, Panagiotis Koufargyris¹, Katerina Dimakou²¹, Spyridon Savvanis⁷, Glykeria Tzatzagou²², Maria Chini²³, Giulio Cavalli²⁰, Matteo Bassetti²⁴, Konstantina Katrini¹, Vasileios Kotsis²⁵, George Tsoukalas²⁶, Carlo Selmi²⁷, Ioannis Bliziotis²⁸, Michael Samarkos²⁹, Michael Doumas³⁰, Sofia Ktena¹, Aikaterini Masgala³¹, Ilias Papanikolaou³², Maria Kosmidou³, Dimitra-Melia Myrodia², Aikaterini Argyraki³³, Chiara Simona Cardellino¹¹, Katerina Koliakou³⁴, Eleni-Ioanna Katsigianni³⁴, Vassiliki Rapti², Efthymia Giannitsioti¹⁰, Antonella Cingolani⁸, Styliani Micha³⁴, Karolina Akinosoglou³⁵, Orestis Liatsis-Douvitsas³⁴, Styliani Symbardi³⁶, Nikolaos Gatselis³⁷, Maria Mouktaroudi^1,34, Giuseppe Ippolito¹⁷, Eleni Florou³⁴, Antigone Kotsaki¹, Mihai G Netea^38,39, Jesper Eugen-Olsen⁴⁰, Miltiades Kyprianou³⁴, Periklis Panagopoulos⁴¹, George N Dalekos³⁷, Evangelos J Giamarellos-Bourboulis^42,43

1. 4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
2. 3rd Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
3. 1st Department of Internal Medicine, University of Ioannina, Medical School, Ioannina, Greece.
4. 1st Department of Internal Medicine, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.
5. 1st Department of Internal Medicine, G. Gennimatas General Hospital of Athens, Athens, Greece.
6. 2nd Department of Pulmonary Medicine, Sotiria General Hospital of Chest Diseases, Athens, Greece.
7. Department of Internal Medicine, Elpis General Hospital, Athens, Greece.
8. Dipartimento Scienze di Laboratorio e Infettivologiche - Fondazione Policlinico Gemelli IRCCS, Roma, Italy.
9. 1st Department of Critical Care and Pulmonary Medicine, Medical School, National and Kapodistrian University of Athens, Evangelismos General Hospital, Athens, Greece.
10. 2nd Department of Internal Medicine, Tzaneio General Hospital of Piraeus, Athens, Greece.
11. Department of Infectious Tropical Diseases and Microbiology, IRCSS Sacro Cuore Hospital, Negrar, Verona, Italy.
12. 10th Department of Pulmonary Medicine, Sotiria General Hospital of Chest Diseases of Athens, Athens, Greece.
13. 2nd Department of Internal Medicine, Thriasio General Hospital of Eleusis, Athens, Greece.
14. Spedali Civili, Brescia ASST Spedali Civili Hospital, University of Brescia, Brescia, Italy.
15. Department of Internal Medicine, Hospital of Jesolo, Jesolo, Italy.
16. 1st Department of Chest Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
17. Department of Internal Medicine, Spallanzani Institute of Rome, Rome, Italy.
18. 1st Department of Internal Medicine, Korgialeneion-Benakeion General Hospital, Athens, Greece.
19. Department of Therapeutics, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
20. Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS Ospedale San Raffaele & Vita-Salute San Raffaele University, Milan, Italy.
21. 5th Department of Pulmonary Medicine, Sotiria General Hospital of Chest Diseases, Athens, Greece.
22. 1st Department of Internal Medicine, Papageorgiou General Hospital of Thessaloniki, Thessaloniki, Greece.
23. 3rd Department of Internal Medicine and Infectious Diseases Unit, Korgialeneion-Benakeion General Hospital, Athens, Greece.
24. Infectious Diseases Clinic, Ospedale Policlinico San Martino IRCCS and Department of Health Sciences, University of Genova, Genova, Italy.
25. 3rd Department of Internal Medicine, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.
26. 4th Department of Pulmonary Medicine, Sotiria General Hospital of Chest Diseases, Athens, Greece.
27. Department of Biomedical Sciences, Humanitas University, Milan, Italy & IRCCS Humanitas Research Hospital, Milan, Italy.
28. 1st Department of Internal Medicine, Asklepieio General Hospital of Voula, Athens, Greece.
29. 1st Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
30. 2nd Department of Propedeutic Medicine, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.
31. 2nd Department of Internal Medicine, Konstantopouleio General Hospital, Athens, Greece.
32. Department of Pulmonary Medicine, General Hospital of Kerkyra, Corfu, Greece.
33. Department of Internal Medicine, Sotiria General Hospital of Chest Diseases, Athens, Greece.
34. Hellenic Institute for the Study of Sepsis, Athens, Greece.
35. Department of Internal Medicine, University of Patras, Rion, Greece.
36. 1st Department of Internal Medicine, Thriasio General Hospital of Eleusis, Athens, Greece.
37. Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece.
38. Department of Internal Medicine and Center for Infectious Diseases, Radboud University, Nijmegen, The Netherlands.
39. Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
40. Department of Clinical Research, Copenhagen University Hospital, Amager and Hvidovre, Denmark.
41. 2nd Department of Internal Medicine, Democritus University of Thrace, Medical School, Alexandroupolis, Greece.
42. 4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece. egiamarel@med.uoa.gr.
43. Hellenic Institute for the Study of Sepsis, Athens, Greece. egiamarel@med.uoa.gr.

Abstract

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.