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Clinical Trial
. 2021 Oct;27(10):1752-1760.
doi: 10.1038/s41591-021-01499-z. Epub 2021 Sep 3.

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

Evdoxia Kyriazopoulou  1 , Garyfallia Poulakou  2 , Haralampos Milionis  3 , Simeon Metallidis  4 , Georgios Adamis  5 , Konstantinos Tsiakos  6 , Archontoula Fragkou  7 , Aggeliki Rapti  6 , Christina Damoulari  1 , Massimo Fantoni  8 , Ioannis Kalomenidis  9 , Georgios Chrysos  10 , Andrea Angheben  11 , Ilias Kainis  12 , Zoi Alexiou  13 , Francesco Castelli  14 , Francesco Saverio Serino  15 , Maria Tsilika  1 , Petros Bakakos  16 , Emanuele Nicastri  17 , Vassiliki Tzavara  18 , Evangelos Kostis  19 , Lorenzo Dagna  20 , Panagiotis Koufargyris  1 , Katerina Dimakou  21 , Spyridon Savvanis  7 , Glykeria Tzatzagou  22 , Maria Chini  23 , Giulio Cavalli  20 , Matteo Bassetti  24 , Konstantina Katrini  1 , Vasileios Kotsis  25 , George Tsoukalas  26 , Carlo Selmi  27 , Ioannis Bliziotis  28 , Michael Samarkos  29 , Michael Doumas  30 , Sofia Ktena  1 , Aikaterini Masgala  31 , Ilias Papanikolaou  32 , Maria Kosmidou  3 , Dimitra-Melia Myrodia  2 , Aikaterini Argyraki  33 , Chiara Simona Cardellino  11 , Katerina Koliakou  34 , Eleni-Ioanna Katsigianni  34 , Vassiliki Rapti  2 , Efthymia Giannitsioti  10 , Antonella Cingolani  8 , Styliani Micha  34 , Karolina Akinosoglou  35 , Orestis Liatsis-Douvitsas  34 , Styliani Symbardi  36 , Nikolaos Gatselis  37 , Maria Mouktaroudi  1   34 , Giuseppe Ippolito  17 , Eleni Florou  34 , Antigone Kotsaki  1 , Mihai G Netea  38   39 , Jesper Eugen-Olsen  40 , Miltiades Kyprianou  34 , Periklis Panagopoulos  41 , George N Dalekos  37 , Evangelos J Giamarellos-Bourboulis  42   43
Affiliations
Clinical Trial

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

Evdoxia Kyriazopoulou et al. Nat Med. 2021 Oct.

Erratum in

  • Author Correction: Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial.
    Kyriazopoulou E, Poulakou G, Milionis H, Metallidis S, Adamis G, Tsiakos K, Fragkou A, Rapti A, Damoulari C, Fantoni M, Kalomenidis I, Chrysos G, Angheben A, Kainis I, Alexiou Z, Castelli F, Serino FS, Tsilika M, Bakakos P, Nicastri E, Tzavara V, Kostis E, Dagna L, Koufargyris P, Dimakou K, Savvanis S, Tzatzagou G, Chini M, Cavalli G, Bassetti M, Katrini K, Kotsis V, Tsoukalas G, Selmi C, Bliziotis I, Samarkos M, Doumas M, Ktena S, Masgala A, Papanikolaou I, Kosmidou M, Myrodia DM, Argyraki A, Cardellino CS, Koliakou K, Katsigianni EI, Rapti V, Giannitsioti E, Cingolani A, Micha S, Akinosoglou K, Liatsis-Douvitsas O, Symbardi S, Gatselis N, Mouktaroudi M, Ippolito G, Florou E, Kotsaki A, Netea MG, Eugen-Olsen J, Kyprianou M, Panagopoulos P, Dalekos GN, Giamarellos-Bourboulis EJ. Kyriazopoulou E, et al. Nat Med. 2021 Oct;27(10):1850. doi: 10.1038/s41591-021-01569-2. Nat Med. 2021. PMID: 34625750 Free PMC article. No abstract available.

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.

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Conflict of interest statement

G.P. has received independent educational grants from Pfizer, MSD, Angelini and Bio-Rad. H.M. reports receiving honoraria, consulting fees and non-financial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer and Servier. L.D. received consultation honoraria from Sobi. M.B. has received funds for research grants and/or advisor/consultant and/or speaker/chairman from Angelini, Astellas, Bayer, bioMérieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer, Roche, Shionogi and Nabriva. M.G.N. is supported by an ERC Advanced Grant (no. 833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. He has also received independent educational grants from TTxD, GSK and ViiV Healthcare. J.E.-O. is a co-founder, shareholder and CSO of ViroGates, Denmark, and is a named inventor on patients on suPAR owned by Copenhagen University Hospital Hvidovre, Denmark. P.P. has received honoraria from Gilead, Janssen and MSD. G.N.D. is an advisor or lecturer for Ipsen, Pfizer, Genkyotex, Novartis and Sobi, has received research grants from Abbvie and Gilead and has served as principal investigator in studies for Abbvie, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics, Tiziana Life Sciences, Bayer, Astellas, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics, Sobi and Intercept Pharmaceuticals. E.J.G.-B. has received honoraria from Abbott, bioMérieux, Brahms, GSK, InflaRx, Sobi and XBiotech; independent educational grants from Abbott, AxisShield, bioMérieux, InflaRx, Johnson & Johnson, MSD, Sobi and XBiotech; and funding from the Horizon 2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens) and the Horizon 2020 European Grants ImmunoSep and RISKinCOVID (granted to the Hellenic Institute for the Study of Sepsis). The other authors do not have any competing interests to declare.

Figures

Fig. 1
Fig. 1. Study flow chart.
IV, intravenous. Source data
Fig. 2
Fig. 2. Study primary endpoint.
a, Distribution of the WHO-CPS scores at day 28 of patients allocated to treatment with placebo and to treatment with anakinra. Comparison is done by unadjusted ordinal regression analysis; the ORs of the 95% CIs are provided. The exact P value of the unadjusted ordinal regression analysis is 3.6 × 10−10. The two tests of the assumptions of the ordinal regression analysis are also provided. b, Univariate and multivariate ordinal regression analysis of the WHO-CPS scores at day 28. The exact P value of the effect of anakinra versus placebo treatment in the multivariate analysis is 7.7 × 10−10. Covariates entered in the multivariate model were those used for stratified randomization according to advice received from the COVID-ETF. ECMO, extracorporeal membrane oxygenation; P/F, respiratory ratio. Source data
Fig. 3
Fig. 3. Levels of lymphocytes, IL-6 and CRP over days of follow-up.
Day 1 sampling was done before start of administration of the study drug. The two-sided P values of comparisons for each day of follow-up are provided. The comparisons were performed by the Mann–Whitney U test. The lower whisker indicates the 95% lower CI; the lower bound of the box indicates the first quartile; the center of the box indicates the median; the upper bound of the box indicates the third quartile; and the upper whisker indicates the 95% upper CI. Circles represent outliers. a, The respective number of measurements of the absolute lymphocyte count of day 1 for placebo and anakinra were for 184 and 387 patients; minimum values were 782 and 799 per mm3 and maximum values were 1,008 and 1,238 per mm3. The respective number of measurements of the absolute lymphocyte count of day 4 for placebo and anakinra were for 176 and 386 patients; minimum values were 1,008 and 1,114 per mm3 and maximum values were 1,183 and 1,938 per mm3. The respective number of measurements of the absolute lymphocyte count of day 7 for placebo and anakinra were for 171 and 377 patients; minimum values were 1,216 and 1,386 per mm3 and maximum values were 1,446 and 1,551 per mm3. b, The respective number of measurements of IL-6 of day 1 for placebo and anakinra were for 182 and 394 patients; minimum values were 1.4 and 0.4 pg ml−1 and maximum values were 6,263.0 and 418.9 pg ml−1. The respective number of measurements of IL-6 of day 4 for placebo and anakinra were for 176 and 381 patients; minimum values were 1.4 and 1.4 pg ml−1 and maximum values were 1,352.0 and 1,209.0 pg ml−1. The respective number of measurements of IL-6 of day 7 for placebo and anakinra were for 167 and 376 patients; minimum values were 1.4 and 1.4 pg ml−1 and maximum values were 1,900.0 and 867.5 pg ml−1. c, The respective number of measurements of CRP of day 1 for placebo and anakinra were for 183 and 404 patients; minimum values were 0.9 and 0.8 mg L−1 and maximum values were 328.8 and 411.9 mg L−1. The respective number of measurements of CRP of day 4 for placebo and anakinra were for 180 and 393 patients; minimum values were 0.40 and 0.41 mg L−1 and maximum values were 272.3 and 274.0 mg L−1. The respective number of measurements of CRP of day 7 for placebo and anakinra were for 174 and 381 patients; minimum values were 0.5 and 0.1 mg L−1 and maximum values were 226.5 and 145.1 mg L−1. Source data
Extended Data Fig. 1
Extended Data Fig. 1. First supporting analysis of the study primary endpoint.
Distribution of the World Health Organization (WHO) Clinical Progression Scale (CPS) at day 14 of patients allocated to treatment with placebo and to treatment with anakinra. Comparison is done by the unadjusted ordinal regression analysis; the odds ratio (OR) and the 95% confidence intervals (CIs) are provided. The exact P value is 3.9 ×10-4. The two tests of the assumptions of the ordinal regression analysis are also provided. Abbreviations CI: confidence interval; ECMO: extracorporeal membrane oxygenation; HFO: high flow oxygen; MV: mechanical ventilation; NIV: non-invasive ventilation; OR: odds ratio; PCR: polymerase chain reaction; P/F: respiratory ratio. Source data
Extended Data Fig. 2
Extended Data Fig. 2. Time to progression into severe respiratory failure.
Severe respiratory failure is defined as respiratory ratio-PF < 150 necessitating high flow oxygen/non-invasive ventilation/mechanical ventilation or death) by day 14. Comparison is done by univariate Cox regression analysis. The hazard ratio (HR) and the 95% confidence intervals (CIs) are provided. Abbreviations HFO: high flow oxygen; MV: mechanical ventilation; n: number; P/F: respiratory ratio; SoC; standard-of-care. Source data
Extended Data Fig. 3
Extended Data Fig. 3. Survival analysis of enrolled patients.
Comparison is done by univariate Cox regression analysis. Abbreviations: CI: confidence intervals; HR: hazard ratio; n: number. Source data
Extended Data Fig. 4
Extended Data Fig. 4. Time to hospital discharge.
Comparison is done by univariate Cox regression analysis. Abbreviations: CI: confidence intervals; HR: hazard ratio; n: number. Source data
Extended Data Fig. 5
Extended Data Fig. 5. Time to discharge from the intensive care unit.
Analysis involves only patients who were admitted in the intensive care unit. Comparison is done by univariate Cox regression analysis. Abbreviations: CI: confidence intervals; HR: hazard ratio; n: number. Source data
Extended Data Fig. 6
Extended Data Fig. 6. Survival analysis among patients who score 2 or more points of the COVID-associated hyperinflammation syndrome score.
Comparison is done by univariate Cox regression analysis. Abbreviations: CI: confidence intervals; HR: hazard ratio; n: number. Source data
Extended Data Fig. 7
Extended Data Fig. 7. Survival analysis among patients who score positive for the criteria of prediction of cytokine storm in COVID-19.
Comparison is done by univariate Cox regression analysis. Abbreviations: CI: confidence intervals; HR: hazard ratio; n: number. Source data
Extended Data Fig. 8
Extended Data Fig. 8. AST, NLR, CRP and ferritin for prediction of response to anakinra.
A, C, E, and G) Receiver operator characteristics (ROC) curves of AST, NLR, CRP and ferritin to predict progression into severe respiratory failure (SRF) or death the first 14 days. The exact P-value of the ROC analysis in panel A is 9.3 ×10-8; in panel C is 5.1 ×10-5; in panel E is 2.7 ×10-7; and in panel G is 1.6 ×10-7. B, D, G and H) Diagnostic performance of AST > 44U/l, NLR > 5.5, CRP > 50 mg/l and ferritin > 700 ng/ml for prognostication of progression into SRF or death by day 14. The selected cut-offs are the Youden indexes for the best trade-off of sensitivity and specificity for each variable. Analysis involved patients for whom all four variables were available at baseline before start of the study drug. Comparisons are done by Mantel-Haenszel test estimating the odds ratio and 95% confidence intervals. The exact P value of the test in panel B is 4.1 ×10-5; in panel F 5.0 ×10-6; and in H 6.5 ×10-4. Abbreviations AUC: area under the curve; AST: aspartate aminotransferase; CI: confidence intervals; CRP: C-reactive protein; n: number of patients; NLR: neutrophil to lymphocyte ratio; NPV: negative predictive value; OR: odds ratio; PPV: positive predictive value. Source data
See this image and copyright information in PMC

Comment in

  • Calming the cytokine storm in COVID-19.
    Cron RQ, Caricchio R, Chatham WW. Cron RQ, et al. Nat Med. 2021 Oct;27(10):1674-1675. doi: 10.1038/s41591-021-01500-9. Nat Med. 2021. PMID: 34480126 No abstract available.

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