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; Garyfallia Poulakou; Haralampos Milionis; Simeon Metallidis; Georgios Adamis; Konstantinos Tsiakos; Archontoula Fragkou; Aggeliki Rapti; Christina Damoulari; Massimo Fantoni; Ioannis Kalomenidis; Georgios Chrysos; Andrea Angheben; Ilias Kainis; Zoi Alexiou; Francesco Castelli; Francesco Saverio Serino; Maria Tsilika; Petros Bakakos; Emanuele Nicastri; Vassiliki Tzavara; Evangelos Kostis; Lorenzo Dagna; Panagiotis Koufargyris; Katerina Dimakou; Spyridon Savvanis; Glykeria Tzatzagou; Maria Chini; Giulio Cavalli; Matteo Bassetti; Konstantina Katrini; Vasileios Kotsis; George Tsoukalas; Carlo Selmi; Ioannis Bliziotis; Michael Samarkos; Michael Doumas; Sofia Ktena; Aikaterini Masgala; Ilias Papanikolaou; Maria Kosmidou; Dimitra Melia Myrodia; Aikaterini Argyraki; Chiara Simona Cardellino; Katerina Koliakou; Eleni Ioanna Katsigianni; Vassiliki Rapti; Efthymia Giannitsioti; Antonella Cingolani; Styliani Micha; Karolina Akinosoglou; Orestis Liatsis-Douvitsas; Styliani Symbardi; Nikolaos Gatselis; Maria Mouktaroudi; Giuseppe Ippolito; Eleni Florou; Antigone Kotsaki; Mihai G. Netea; Jesper Eugen-Olsen; Miltiades Kyprianou; Periklis Panagopoulos; George N. Dalekos; Evangelos J. Giamarellos-Bourboulis

doi:10.1038/s41591-021-01499-z

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, Garyfallia Poulakou, Haralampos Milionis, Simeon Metallidis, Georgios Adamis, Konstantinos Tsiakos, Archontoula Fragkou, Aggeliki Rapti, Christina Damoulari, Massimo Fantoni, Ioannis Kalomenidis, Georgios Chrysos, Andrea Angheben, Ilias Kainis, Zoi Alexiou, Francesco Castelli, Francesco Saverio Serino, Maria Tsilika, Petros Bakakos, Emanuele NicastriVassiliki Tzavara, Evangelos Kostis, Lorenzo Dagna, Panagiotis Koufargyris, Katerina Dimakou, Spyridon Savvanis, Glykeria Tzatzagou, Maria Chini, Giulio Cavalli, Matteo Bassetti, Konstantina Katrini, Vasileios Kotsis, George Tsoukalas, Carlo Selmi, Ioannis Bliziotis, Michael Samarkos, Michael Doumas, Sofia Ktena, Aikaterini Masgala, Ilias Papanikolaou, Maria Kosmidou, Dimitra Melia Myrodia, Aikaterini Argyraki, Chiara Simona Cardellino, Katerina Koliakou, Eleni Ioanna Katsigianni, Vassiliki Rapti, Efthymia Giannitsioti, Antonella Cingolani, Styliani Micha, Karolina Akinosoglou, Orestis Liatsis-Douvitsas, Styliani Symbardi, Nikolaos Gatselis, Maria Mouktaroudi, Giuseppe Ippolito, Eleni Florou, Antigone Kotsaki, Mihai G. Netea, Jesper Eugen-Olsen, Miltiades Kyprianou, Periklis Panagopoulos, George N. Dalekos, Evangelos J. Giamarellos-Bourboulis

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	Nature Medicine
DOIs	https://doi.org/10.1038/s41591-021-01499-z
Publication status	Accepted/In press - 2021

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1038/s41591-021-01499-z

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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, F. S., Tsilika, M., Bakakos, P., ... Giamarellos-Bourboulis, E. J. (Accepted/In press). Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial. Nature Medicine. https://doi.org/10.1038/s41591-021-01499-z

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 2021, 'Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial', Nature Medicine. https://doi.org/10.1038/s41591-021-01499-z

@article{293ba561053c4e7484d4832d40662f59,

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

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.",

author = "Evdoxia Kyriazopoulou and Garyfallia Poulakou and Haralampos Milionis and Simeon Metallidis and Georgios Adamis and Konstantinos Tsiakos and Archontoula Fragkou and Aggeliki Rapti and Christina Damoulari and Massimo Fantoni and Ioannis Kalomenidis and Georgios Chrysos and Andrea Angheben and Ilias Kainis and Zoi Alexiou and Francesco Castelli and Serino, {Francesco Saverio} and Maria Tsilika and Petros Bakakos and Emanuele Nicastri and Vassiliki Tzavara and Evangelos Kostis and Lorenzo Dagna and Panagiotis Koufargyris and Katerina Dimakou and Spyridon Savvanis and Glykeria Tzatzagou and Maria Chini and Giulio Cavalli and Matteo Bassetti and Konstantina Katrini and Vasileios Kotsis and George Tsoukalas and Carlo Selmi and Ioannis Bliziotis and Michael Samarkos and Michael Doumas and Sofia Ktena and Aikaterini Masgala and Ilias Papanikolaou and Maria Kosmidou and Myrodia, {Dimitra Melia} and Aikaterini Argyraki and Cardellino, {Chiara Simona} and Katerina Koliakou and Katsigianni, {Eleni Ioanna} and Vassiliki Rapti and Efthymia Giannitsioti and Antonella Cingolani and Styliani Micha and Karolina Akinosoglou and Orestis Liatsis-Douvitsas and Styliani Symbardi and Nikolaos Gatselis and Maria Mouktaroudi and Giuseppe Ippolito and Eleni Florou and Antigone Kotsaki and Netea, {Mihai G.} and Jesper Eugen-Olsen and Miltiades Kyprianou and Periklis Panagopoulos and Dalekos, {George N.} and Giamarellos-Bourboulis, {Evangelos J.}",

note = "Funding Information: 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, bioM{\'e}rieux, 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, bioM{\'e}rieux, Brahms, GSK, InflaRx, Sobi and XBiotech; independent educational grants from Abbott, AxisShield, bioM{\'e}rieux, 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. Funding Information: The authors wish to express their gratitude to the members of the Data Monitoring and Safety Committee and to M. Niederman, J. W. M. van der Meer and K. Reinhart for their valuable contributions and for their critical review of the submitted manuscript. This trial was sponsored by the Hellenic Institute for the Study of Sepsis (HISS) and funded, in part, by HISS and, in part, by Swedish Orphan Biovitrum (Sobi). HISS was responsible for the conceptualization and design of the study, data collection, analysis, decision to publish and preparation of the manuscript. Sobi had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

doi = "10.1038/s41591-021-01499-z",

language = "English",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial

AU - Kyriazopoulou, Evdoxia

AU - Poulakou, Garyfallia

AU - Milionis, Haralampos

AU - Metallidis, Simeon

AU - Adamis, Georgios

AU - Tsiakos, Konstantinos

AU - Fragkou, Archontoula

AU - Rapti, Aggeliki

AU - Damoulari, Christina

AU - Fantoni, Massimo

AU - Kalomenidis, Ioannis

AU - Chrysos, Georgios

AU - Angheben, Andrea

AU - Kainis, Ilias

AU - Alexiou, Zoi

AU - Castelli, Francesco

AU - Serino, Francesco Saverio

AU - Tsilika, Maria

AU - Bakakos, Petros

AU - Nicastri, Emanuele

AU - Tzavara, Vassiliki

AU - Kostis, Evangelos

AU - Dagna, Lorenzo

AU - Koufargyris, Panagiotis

AU - Dimakou, Katerina

AU - Savvanis, Spyridon

AU - Tzatzagou, Glykeria

AU - Chini, Maria

AU - Cavalli, Giulio

AU - Bassetti, Matteo

AU - Katrini, Konstantina

AU - Kotsis, Vasileios

AU - Tsoukalas, George

AU - Selmi, Carlo

AU - Bliziotis, Ioannis

AU - Samarkos, Michael

AU - Doumas, Michael

AU - Ktena, Sofia

AU - Masgala, Aikaterini

AU - Papanikolaou, Ilias

AU - Kosmidou, Maria

AU - Myrodia, Dimitra Melia

AU - Argyraki, Aikaterini

AU - Cardellino, Chiara Simona

AU - Koliakou, Katerina

AU - Katsigianni, Eleni Ioanna

AU - Rapti, Vassiliki

AU - Giannitsioti, Efthymia

AU - Cingolani, Antonella

AU - Micha, Styliani

AU - Akinosoglou, Karolina

AU - Liatsis-Douvitsas, Orestis

AU - Symbardi, Styliani

AU - Gatselis, Nikolaos

AU - Mouktaroudi, Maria

AU - Ippolito, Giuseppe

AU - Florou, Eleni

AU - Kotsaki, Antigone

AU - Netea, Mihai G.

AU - Eugen-Olsen, Jesper

AU - Kyprianou, Miltiades

AU - Panagopoulos, Periklis

AU - Dalekos, George N.

AU - Giamarellos-Bourboulis, Evangelos J.

N1 - Funding Information: 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. Funding Information: The authors wish to express their gratitude to the members of the Data Monitoring and Safety Committee and to M. Niederman, J. W. M. van der Meer and K. Reinhart for their valuable contributions and for their critical review of the submitted manuscript. This trial was sponsored by the Hellenic Institute for the Study of Sepsis (HISS) and funded, in part, by HISS and, in part, by Swedish Orphan Biovitrum (Sobi). HISS was responsible for the conceptualization and design of the study, data collection, analysis, decision to publish and preparation of the manuscript. Sobi had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: © 2021, The Author(s).

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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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U2 - 10.1038/s41591-021-01499-z

DO - 10.1038/s41591-021-01499-z

M3 - Article

AN - SCOPUS:85114635853

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

ER -

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

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