Early suPAR-Guided Anakinra Treatment in COVID-19 Pneumonia: Subgroup Analyses and 90-Day Outcomes of the SAVE-MORE Trial

Background: The SAVE-MORE trial demo that anakinra treatment in COVID-19 pneumonia with plasma suPAR (soluble urokinase plasminogen activator) 6ng/ml or more was associated with 0.36 odds for worse outcome compared to placebo as expressed by the WHO-CPS (Clinical Progression Scale) at day 28. Subgroup analyses and long-term outcomes are reported.Methods: SAVE-MORE was a prospective, double-blind randomized clinical trial that was designed following advice from the Emergency task Force for COVID-19 of the European Medicines Agency. Pre-defined subgroups according to the Charlson’s comorbidity index (CCI), gender, age, level of suPAR and time from symptoms onset were analyzed for the primary and main secondary endpoints at day 28. WHO-CPS score at days 60 and 90 and the cost of hospitalization were also compared. Findings: Multivariate analysis showed that anakinra treatment was accompanied by significantly less odds for worse outcome compared to placebo at day 28 for all studied subgroups (odds ratio 0.34 when CCI ≥2 or more; 0.38 when CCI 9 ng/ml; 0.35 with suPAR ≤9 ng/ml; 0.39 for patients ≥ 65 years old; and 0.29 for patients < 65 years). The benefit was uniform irrespective of the time from start of symptoms until the start of the study drug. Similar benefit was shown for most of the secondary outcomes within subgroups. At day 60, anakinra treatment had 0.40 odds for worse outcome compared to placebo; this was 0.50 at day 90. The costs of general ward stay, ICU stay, and drugs were decreased with anakinra treatment. Interpretation: Benefit from anakinra was found in all subgroups and irrespective of timing of administration. Benefit was prolonged until day 90.Trial Registration: EudraCT number, 2020-005828-11; ClinicalTrials.gov NCT04680949)Funding: Hellenic Institute for the Study of Sepsis; Swedish Orphan Biovitrum ABDeclaration of Interest: Andrea Angheben is partly funded by the Italian Ministry of Health under "Fondi Ricerca Corrente" - L1P1. L. Dagna had received consultation honoraria from SOBI. M. Bassetti has received funds for research grants and/or advisor/consultant and/or speaker/chairman from Angelini, Astellas, Bayer, Biomerieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer, Roche, Shionogi and Nabriva. Mihai G. Netea was supported by an ERC Advanced Grant (833247) and a Spinoza Grant of the Netherlands Organization for Scientific Research. P. Panagopoulos has received honoraria from GILEAD Sciences, Janssen, and MSD. H. Milionis reports receiving honoraria, consulting fees and non-financial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier. G. N. Dalekos is an advisor or lecturer for Ipsen, Pfizer, Genkyotex, Novartis, Sobi, received research grants from Abbvie, Gilead and has served as PI in studies for Abbvie, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana 19 Life Sciences, Bayer, Astellas, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics Inc., Sobi and Intercept Pharmaceuticals. E. J. Giamarellos-Bourboulis has received honoraria from Abbott CH, bioMérieux, Brahms GmbH, GSK, InflaRx GmbH, Sobi and XBiotech Inc; independent educational grants from Abbott CH, AxisShield, bioMérieux Inc, InflaRx GmbH, Johnson & Johnson, MSD, Sobi and XBiotech Inc.; and funding from the Horizon2020 Marie Skłodowska- Curie International Training Network “the European Sepsis Academy” (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grants ImmunoSep and RISCinCOVID (granted to the Hellenic Institute for the Study of Sepsis). The other authors do not disclose any conflict of interest.Ethical Approval: The protocol was approved by the National Ethics Committee of Greece (approval 161/20) and by the Ethics Committee of the National Institute for Infectious Diseases Lazzaro Spallanzani, IRCCS in Rome (01.02.2021)