An open label trial of anakinra to prevent respiratory failure in COVID-19

  1. Evdoxia Kyriazopoulou
  2. Periklis Panagopoulos
  3. Symeon Metallidis
  4. George N Dalekos
  5. Garyphallia Poulakou
  6. Nikolaos Gatselis
  7. Eleni Karakike
  8. Maria Saridaki
  9. Georgia Loli
  10. Aggelos Stefos
  11. Danai Prasianaki
  12. Sarah Georgiadou
  13. Olga Tsachouridou
  14. Vasileios Petrakis
  15. Konstantinos Tsiakos
  16. Maria Kosmidou
  17. Vassiliki Lygoura
  18. Maria Dareioti
  19. Haralampos Milionis
  20. Ilias C Papanikolaou
  21. Karolina Akinosoglou
  22. Dimitra-Melia Myrodia
  23. Areti Gravvani
  24. Aliki Stamou
  25. Theologia Gkavogianni
  26. Konstantina Katrini
  27. Theodoros Marantos
  28. Ioannis P Trontzas
  29. Konstantinos Syrigos
  30. Loukas Chatzis
  31. Stamatios Chatzis
  32. Nikolaos Vechlidis
  33. Christina Avgoustou
  34. Stamatios Chalvatzis
  35. Miltiades Kyprianou
  36. Jos WM van der Meer
  37. Jesper Eugen-Olsen
  38. Mihai G Netea
  39. Evangelos J Giamarellos-Bourboulis  Is a corresponding author
  1. National and Kapodistrian University of Athens, Medical School, Greece
  2. Democritus University of Thrace, Medical School, Greece
  3. Aristotle University of Thessaloniki, Medical School, Greece
  4. National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece
  5. Univeristy of Ioannina School of Medicine, Greece
  6. University of Ioannina, School of Health Sciences, Faculty of Medicine, Greece
  7. General Hospital of Kerkyra, Greece
  8. University of Patras, Greece
  9. Radboud University Medical Centre, Netherlands
  10. Copenhagen University Hospital Hvidovre, Denmark
  11. Radboud University Nijmegen Medical Centre, Netherlands

Abstract

Background It was studied if early suPAR-guided anakinra treatment can prevent severe respiratory failure (SRF) of COVID-19.

Methods 130 patients with suPAR ≥6 ng/ml were assigned to subcutaneous anakinra 100mg once daily for 10 days. Primary outcome was SRF incidence by day 14 defined as any respiratory ratio below 150 mmHg necessitating mechanical or non-invasive ventilation. Main secondary outcomes were 30-day mortality and inflammatory mediators; 28-day WHO-CPS was explored. Propensity-matched standard-of care comparators were studied.

Results 22.3% with anakinra treatment and 59.2% comparators (hazard ratio, 0.30; 95%CI, 0.20-0.46) progressed into SRF; 30-day mortality was 11.5% and 22.3% respectively (hazard ratio 0.49; 95% CI 0.25-0.97). Anakinra was associated with decrease in circulating interleukin (IL)-6, sCD163 and sIL2-R; IL-10/IL-6 ratio on day 7 was inversely associated with SOFA score; patients were allocated to less severe WHO-CPS strata.

Conclusions Early suPAR-guided anakinra decreased SRF and restored the pro-/anti-inflammatory balance.

Trial Registration: ClinicalTrials.gov, NCT04357366

Data availability

Data of this submission are anticipated to be part of a submission package to the European Medicines Agency for the request of approval of Anakinra for the management of COVID-19 guided by the biomarker suPAR. Once this is finalized, the data will be made publicly available upon request. Requests will require signing contract with the sponsor of the study which is the Hellenic Institute for the Study of Sepsis. The responsible official is Ms Leda Efstratiou who is the DPO responsible for GDPR. Interested researchers should contact Ms Efstratiou at le.efstrat@gmail.com and headed@sepsis.gr to request access to the data.

Article and author information

Author details

  1. Evdoxia Kyriazopoulou

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9585-517X
  2. Periklis Panagopoulos

    2nd Department of Internal Medicine, Democritus University of Thrace, Medical School, Alexandroupolis, Greece
    Competing interests
    Periklis Panagopoulos, honoraria from GILEAD Sciences, Janssen, and MSD.
  3. Symeon Metallidis

    1st Department of Internal Medicine, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
    Competing interests
    No competing interests declared.
  4. George N Dalekos

    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
    Competing interests
    George N Dalekos, Advisor/Lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Novartis, Roche, Amgen, MSD, Janssen, Ipsen and Pfizer, has received Grant support from Bristol-Myers Squib, Gilead, Roche, Janssen, Abbvie and Bayer and was or is currently PI in National & International Protocols sponsored by Abbvie, Bristol-Myers Squibb, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana Life Sciences, Bayer, Astellas, Ipsen, Pfizer and Roche.
  5. Garyphallia Poulakou

    3rd Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    Garyphallia Poulakou, independent educational grants from Pfizer, MSD, Angelini, and Biorad.
  6. Nikolaos Gatselis

    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
    Competing interests
    No competing interests declared.
  7. Eleni Karakike

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  8. Maria Saridaki

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  9. Georgia Loli

    1st Department of Internal Medicine, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
    Competing interests
    No competing interests declared.
  10. Aggelos Stefos

    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
    Competing interests
    No competing interests declared.
  11. Danai Prasianaki

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  12. Sarah Georgiadou

    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
    Competing interests
    No competing interests declared.
  13. Olga Tsachouridou

    1st Department of Internal Medicine, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
    Competing interests
    No competing interests declared.
  14. Vasileios Petrakis

    2nd Department of Internal Medicine, Democritus University of Thrace, Medical School, Alexandroupolis, Greece
    Competing interests
    No competing interests declared.
  15. Konstantinos Tsiakos

    3rd Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  16. Maria Kosmidou

    1st Department of Internal Medicine, Univeristy of Ioannina School of Medicine, Ioannina, Greece
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8618-9435
  17. Vassiliki Lygoura

    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
    Competing interests
    No competing interests declared.
  18. Maria Dareioti

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  19. Haralampos Milionis

    1st Department of Internal Medicine, University of Ioannina, School of Health Sciences, Faculty of Medicine, Ioannina, Greece
    Competing interests
    Haralampos Milionis, honoraria, consulting fees and non-financial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier.
  20. Ilias C Papanikolaou

    Department of Pulmonary Medicine, General Hospital of Kerkyra, Corfou, Greece
    Competing interests
    No competing interests declared.
  21. Karolina Akinosoglou

    University of Patras, Rion, Greece
    Competing interests
    No competing interests declared.
  22. Dimitra-Melia Myrodia

    3rd Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  23. Areti Gravvani

    3rd Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  24. Aliki Stamou

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  25. Theologia Gkavogianni

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  26. Konstantina Katrini

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  27. Theodoros Marantos

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  28. Ioannis P Trontzas

    3rd Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  29. Konstantinos Syrigos

    3rd Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  30. Loukas Chatzis

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2832-0116
  31. Stamatios Chatzis

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  32. Nikolaos Vechlidis

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  33. Christina Avgoustou

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  34. Stamatios Chalvatzis

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  35. Miltiades Kyprianou

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    Competing interests
    No competing interests declared.
  36. Jos WM van der Meer

    Internal Medicine, Radboud University Medical Centre, Nijmegen, Netherlands
    Competing interests
    Jos WM van der Meer, Senior editor, eLife.
  37. Jesper Eugen-Olsen

    Clinical Research Centre, Copenhagen University Hospital Hvidovre, Copenhagen, Denmark
    Competing interests
    Jesper Eugen-Olsen, cofounder, shareholder and CSO of ViroGates A7S, Denmark and is named inventor on patents on suPAR owned by Copenhagen University Hospital Hvidovre, Denmark.
  38. Mihai G Netea

    Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    Competing interests
    Mihai G Netea, supported by an ERC Advanced Grant (#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.
  39. Evangelos J Giamarellos-Bourboulis

    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
    For correspondence
    egiamarel@med.uoa.gr
    Competing interests
    Evangelos J Giamarellos-Bourboulis, Reviewing editor, eLifehonoraria from Abbott CH, Angelini Italy, InflaRx GmbH, MSD Greece, XBiotech Inc., and B·R·A·H·M·S GmbH (Thermo Fisher Scientific); independent educational grants from AbbVie Inc, Abbott CH, Astellas Pharma Europe, AxisShield, bioMérieux Inc, Novartis, InflaRx GmbH, and XBiotech Inc; and funding from the FrameWork 7 program HemoSpec (granted to the National and Kapodistrian University of Athens), the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grant ImmunoSep (granted to the Hellenic Institute for the Study of Sepsis)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4713-3911

Funding

Hellenic Institute for the Study of Sepsis (NA)

  • Evangelos J Giamarellos-Bourboulis

Technomar Shipping Inc (NA)

  • Evangelos J Giamarellos-Bourboulis

Swedish Orphan Biovitrum AB (NA)

  • Evangelos J Giamarellos-Bourboulis

Horizon 2020 (RISKinCOVID)

  • Evangelos J Giamarellos-Bourboulis

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Approved in Greece by National Ethics Committee approval 38/20; National Organization for Medicines approval ISO 28/20.Written informed consent was provided by the patient or legal representative before screening.

Reviewing Editor

  1. Arduino A Mangoni, Flinders Medical Centre, Australia

Publication history

  1. Received: December 29, 2020
  2. Accepted: March 4, 2021
  3. Accepted Manuscript published: March 8, 2021 (version 1)
  4. Version of Record published: April 9, 2021 (version 2)

Copyright

© 2021, Kyriazopoulou et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Evdoxia Kyriazopoulou
  2. Periklis Panagopoulos
  3. Symeon Metallidis
  4. George N Dalekos
  5. Garyphallia Poulakou
  6. Nikolaos Gatselis
  7. Eleni Karakike
  8. Maria Saridaki
  9. Georgia Loli
  10. Aggelos Stefos
  11. Danai Prasianaki
  12. Sarah Georgiadou
  13. Olga Tsachouridou
  14. Vasileios Petrakis
  15. Konstantinos Tsiakos
  16. Maria Kosmidou
  17. Vassiliki Lygoura
  18. Maria Dareioti
  19. Haralampos Milionis
  20. Ilias C Papanikolaou
  21. Karolina Akinosoglou
  22. Dimitra-Melia Myrodia
  23. Areti Gravvani
  24. Aliki Stamou
  25. Theologia Gkavogianni
  26. Konstantina Katrini
  27. Theodoros Marantos
  28. Ioannis P Trontzas
  29. Konstantinos Syrigos
  30. Loukas Chatzis
  31. Stamatios Chatzis
  32. Nikolaos Vechlidis
  33. Christina Avgoustou
  34. Stamatios Chalvatzis
  35. Miltiades Kyprianou
  36. Jos WM van der Meer
  37. Jesper Eugen-Olsen
  38. Mihai G Netea
  39. Evangelos J Giamarellos-Bourboulis
(2021)
An open label trial of anakinra to prevent respiratory failure in COVID-19
eLife 10:e66125.
https://doi.org/10.7554/eLife.66125
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