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COVID-19Phase 2SAVENCT04357366

suPAR-guided Anakinra Treatment for Validation of the Risk and Management of Respiratory Failure by COVID-19 (SAVE)

A Phase 2 study testing Anakinra in people with COVID-19 and Virus Diseases, run by Hellenic Institute for the Study of Sepsis at 28 sites in Greece.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

In the SAVE study patients with lower respiratory tract infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at high risk for progression to serious respiratory failure will be detected using the suPAR biomarker. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
COVID-19, Virus Diseases, Corona Virus Infection
What is being tested?
Anakinra
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,000 participants
Where
28 sitesGreece
Study dates
15 Apr 2020to 15 Apr 2022
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age equal to or above 18 years
  • Male or female gender
  • In case of women, unwillingness to remain pregnant during the study period.
  • Written informed consent provided by the patient or by one first-degree relative/spouse in case of patients unable to consent
  • Confirmed infection by SARS-CoV-2 virus using molecular techniques as defined by the World Health Organization
  • Findings in chest-X-ray or in chest computed tomography compatible with lower respiratory tract infection
  • Plasma suPAR ≥6ng/ml

Who cannot join

  • Age below 18 years
  • Denial for written informed consent
  • Any stage IV malignancy
  • Any do not resuscitate decision
  • Any primary immunodeficiency
  • Less than 1,500 neutrophils/mm3
Show all 14Show fewer
  • Known hypersensitivity to anakinra
  • Oral or IV intake of corticosteroids at a daily dose equal or greater than 0.4 mg prednisone for a greater period than the last 15 days.
  • Any anti-cytokine biological treatment the last one month
  • Pregnancy or lactation. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study
  • Severe hepatic failure
  • Severe renal failure
  • Any need for CPAP or mechanical ventilation
  • Any pO2/FiO2 ratio less than 150

Trial locations and contacts

28 sites in 1 country.

28 sites in 1 country

Greece28 sites

  • 2nd Department of Internal Medicine, University General Hospital of Alexandroupolis

    Alexandroupoli, 68100

  • Department of Internal Medicine, I PAMMAKARISTOS Hospital

    Athens, 11144

  • 1st Department of InternalMedicine, General Hospital of Athens KORGIALENIO-BENAKIO E.E.S.

    Athens, 11526

  • 1st Department of Internal Medicine, General Hospital of Athens G. GENNIMATAS

    Athens, 11527

  • 1st University Department of Internal Medicine, General Hospital of Athens LAIKO

    Athens, 11527

  • 1st University Departmentof Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseasesof Athens

    Athens, 11527

  • 2nd University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens

    Athens, 11527

  • 3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA

    Athens, 11527

  • Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA

    Athens, 11527

  • Department of Clinical Therapeutics, ALEXANDRA General Hospital of Athens

    Athens, 11528

  • 1st Department of Internal Medicine Amalia Fleming General Hospital

    Athens

  • 1st Department of Internal Medicine, General Hospital of Eleusis THRIASIO

    Athens

  • 1st Department of Internal Medicine, General Hospital of Nea Ionia CONSTANTOPOULIO-PATISION

    Athens

  • 1st Department of Internal Medicine, General Hospital of Voula ASKLEPIEIO

    Athens

  • 2nd Department of Internal Medicine, 251 Air Force General Hospital

    Athens

  • 2nd Department of Internal Medicine, General Hospital of Eleusis THRIASIO

    Athens

  • 3rd Department of Internal Medicine, General Hospital of Athens KORGIALENEIO-BENAKEIO E.E.S.

    Athens

  • 5th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens

    Athens

  • Department of Internal Medicine, General Hospital of Athens ELPIS

    Athens

  • Department of Infectious Diseases, General Hospital of Kerkira

    Corfu, 49100

  • 1st Department of Internal Medicine, General University Hospital of Ioannina

    Ioannina, 45500

  • Department of Internal Medicine, General Hospital of Katerini

    Katerini, 60100

  • Department of Internal Medicine, University General Hospital of Larissa

    Larissa, 41334

  • Department of Internal Medicine, General Hospital of Larisa KOUTLIMBANEIO & ΤΡΙΑΝΤΑFΥLLΕΙΟ

    Larissa

  • COVID-19 Department, General Hospital of Attica SISMANOGLEIO-AMALIA FLEMING

    Marousi, Athens, 15126

  • Department of Internal Medicine, University General Hospital of Patras PANAGIA I VOITHIA

    Pátrai, 26504

  • 2nd Department of Internal Medicine, General Hospital of Piraeus TZANEIO

    Piraeus

  • 1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki

    Thessaloniki, 54621

Other trials in Greece

About this study

Official title: suPAR-guided Anakinra Treatment for Validation of the Risk and Early Management of Severe Respiratory Failure by COVID-19: The SAVE Open-label, Non-randomized Single-arm Trial

In the SAVE study patients with lower respiratory tract infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at high risk for progression to serious respiratory failure will be detected using the suPAR biomarker. They will begin early treatment with anakinra in the effort to prevent progression in serious respiratory failure.

Read the detailed description

The major hurdle of Coronavirus disease 2019 (COVID-19) is the early recognition of the patients at high risk for the development of severe respiratory failure (SRF). If this can be achieved early, then appropriate immunomodulatory treatment may be administered to prevent development of SRF. This scenario is extremely visionary since it prevents the development of the major fatal consequence of COVID-19 but also alleviates the heavy medical and financial burden of Intensive Care Unit (ICU) admission.

Current evidence suggests that SARS-CoV-2 activates endothelial function which leads to over-production of D-dimers. Urokinase plasminogen activator receptor (uPAR) is anchored to the cell membranes of the lung endothelial cells. As result of the activation of kallikrein, uPAR is cleaved and enters the systemic circulation as the soluble counterpart suPAR. Preliminary unpublished data from 57 Greek patients hospitalized after March 1st, 2020 in Greek hospitals due to pneumonia by confirmed SARS-CoV-2 infection showed that those with suPAR admission levels ≥ 6 ng/ml had greater risk for the development of SRF within 14 days than patients with suPAR less than 6ng/ml. The sensitivity of suPAR to detect these patients was 85.9% and the positive predictive value 85.9%. It needs to be underlined that all 21 Greek patients with suPAR≥ 6ng/ml were under treatment with hydroxychloroquine and azithromycin. These data were confirmed in 15 patients hospitalized for pneumonia by SARS-CoV-2 in Rush Medical Center at Chicago.

This prognostic ability of suPAR for unfavourable outcome is not presented for the first time; in the TRIAGE III trial that was conducted among 4,420 admissions in the emergency department in Denmark the interquartile range of suPAR was between 2.6 and 4.7 ng/ml in 30-day survivors and between 6.7 and 11.8 ng/ml in 30-day non-survivors. Previous data from the Hellenic Sepsis Study Group on 1,914 patients clearly shows a high prognostic utility of admission suPAR for 28-day mortality.

It is obvious that suPAR can early identify the start of such a type of inflammatory process in the lung parenchyma that has will soon be intensified. A recent publication has shown that this is due to the early release of interleukin-1α (IL-1α) from lung epithelial cells that are infected by the virus. This IL-1α acts as a promoting factor that stimulates the production of IL-1β and of a further cytokine storm from alveolar macrophages.

Anakinra is the only marketed product that inhibits both IL-1β and IL-1α and hence it is able to block an inflammatory response early on and to prevent the downstream inflammatory cascade. suPAR can be used as the biomarker tool to indicate patients with COVID-19 pneumonia in risk of SRF and for whom early start of anakinra may prevent development of SRF.

Anakinra is a safe drug that has been licensed for chronic subcutaneous administration in rheumatoid arthritis, refractory gout and chronic auto-inflammatory disorders. The safety profile was further proven when it was administered in two randomized clinical trials where more than 1,500 critically ill patients with severe sepsis were intravenously treated.

Being tested
Anakinra
Keywords
COVID-19, SARS-CoV-2, Anakinra, suPAR
Medical subject headings
COVID-19, Virus Diseases, Coronavirus Infections

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AnakinraDrug

    Also called Kineret

    Treatment with 100mg Anakinra subcutaneously (sc) once daily for ten days

Study groups in NCT04357366
Study groupRoleWhat they receive
AnakinraExperimentalPatients will receive 100mg of anakinra subcutaneously once daily for ten days. The drugs should be administered on the same time ± 2 hours every day. All other administered drugs are allowed. In case the patient is discharged home before the completion of 10 days of treatment, it is at the discretion of the investigator to suggest treatment continuation at home. In case such a decision is taken, the patient will be provided the required number of pre-filled syringes for daily self-injection. In this case, the patient should return the empty used syringes within 30 days.
Receives: Drug: Anakinra

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. The ratio of patients who will develop serious respiratory failure (SRF)

    The primary study endpoint is the ratio of patients who will develop serious respiratory failure SRF until day 14. Patients dying before study visit of day 14 are considered achieving the primary endpoint.

    Measured: Visit study day 14

Secondary outcomes (15)

  1. Comparison of the rate of patients who will develop serious respiratory failure (SRF) until day 14 with comparators from Hellenic Sepsis Study Group Database receiving standard-of-care treatment

    Evaluation of clinical data (pO2/FiO2 and need of mechanical ventilation) between baseline and study visit day 14 will be compared with comparators from Hellenic Sepsis Study Group Database

    Measured: Visit study day 14

  2. Change of scoring for respiratory symptoms in enrolled subjects between days 1 and 7

    Change of scoring for respiratory symptoms (evaluation of cough, chest pain, shortness of breath and sputum) in enrolled subjects between days 1 and 7

    Measured: Visit study day 1, visit study day 7

  3. Change of scoring for respiratory symptoms in enrolled subjects between days 1 and 14

    Change of scoring for respiratory symptoms (evaluation of cough, chest pain, shortness of breath and sputum) in enrolled subjects between days 1 and 14

    Measured: Visit study day 1, visit study day 14

  4. Change of SOFA score in enrolled subjects between days 1 and 7

    Change of Sequential organ failure assessment (SOFA) score of enrolled subjects between days 1 and 7 (Sequential organ failure assessment range 0-24, high score associated with worst outcome)

    Measured: Visit study day 1, visit study day 7

  5. Change of Sequential organ failure assessment (SOFA) score in enrolled subjects between days 1 and 14

    Change of Sequential organ failure assessment (SOFA) score of enrolled subjects between days 1 and 14 (Sequential organ failure assessment range 0-24, high score associated with worst outcome)

    Measured: Visit study day 1, visit study day 14

  6. Change of peripheral mononuclear blood cells' (PBMCs) functionality between days 1 and 7

    Change of peripheral mononuclear blood cells' (PBMCs) functionality of enrolled subjects will be compared between days 1 and 7

    Measured: Visit study day 1, visit study day 7

  7. Change of plasma inflammatory mediators levels between days 1 and 7

    Change of plasma inflammatory mediators measured levels will be compared between days 1 and 7

    Measured: Visit study day 1, visit study day 7

  8. Rate of Mortality

    Mortality on day 30

    Measured: Visit study day 30

  9. Rate of Mortality

    Mortality on day 90

    Measured: Visit study day 90

  10. Change of gene expression between days 1 nad 7

    Transcriptional, proteomic and metabolomic change will be compared between days 1 and 7

    Measured: days 1 and 7

  11. Safety of anakinra

    Safety of anakinra

    Measured: Last patients visit, Day 90

  12. Association between the time interval from hospital admission until start of anakinra and the incidence of SRF

    Association between the time interval from hospital admission until start of anakinra and the incidence of SRF

    Measured: Visit day 14

  13. Correlation between time interval and the occurrence of SAA under treatment with anakinra

    Correlation between time interval and the occurrence of SAA under treatment with anakinra

    Measured: Visit day 14

  14. Association between radiological opacities in chest computed tomography and the incidence of SRF under anakinra treatment

    Association between radiological opacities in chest computed tomography and the incidence of SRF under anakinra treatment

    Measured: Visit day 14

  15. Association of the efficacy of anakinra for subgroups of patients; the studied subgroups will be the quartiles of the respiratory ratio (pO2/FiO2) at admission; the main comorbidities; the WHO classification

    Association of the efficacy of anakinra for subgroups of patients; the studied subgroups will be the quartiles of the respiratory ratio (pO2/FiO2) at admission; the main comorbidities; the WHO classification

    Measured: Visit day 14

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Apr 2020
  2. Study start15 Apr 2020
  3. Primary completion29 Jan 2022
  4. Study completion15 Apr 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Prevention
Allocation
Not applicable
Intervention model
Single group
Model description
Treatment with anakinra
Masking
None (open label)
Enrolment
1,000 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04357366
Sponsor's protocol ID
SAVE
Other IDs
2020-001466-11
Acronym
SAVE
Status last verified
Jul 2023
First submitted
20 Apr 2020
Last updated
13 Jul 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Rapti V, Foutadakis S, Kakavoulis N, Skorda L, Giamarellos-Bourboulis EJ, Poulakou G. The Divergent Metabolomic Landscape of COVID-19 and Community-Acquired Pneumonia. Crit Care Explor. 2026 Sep 4;8(9):e1473. doi: 10.1097/CCE.0000000000001473. eCollection 2026 Sep 1.

    PubMed 42704050

  • Kyriazopoulou E, Akinosoglou K, Florou E, Kouriannidi E, Bogosian A, Tsachouridou O, Syrigos KN, Gatselis N, Milionis H, Papanikolaou IC, Sympardi S, Dafni M, Alevizou A, Amvrazi AV, Alexandrou E, Archontoulis K, Argyraki K, Alexiou Z, Georgiou Y, Gkogka D, Kyrailidi F, Kalyva V, Nikolopoulou T, Ioannou S, Bakakos P, Karathanassiou G, Koklanos K, Miletis DN, Tili AM, Vakkas L, Vila I, Panagopoulos P, Samarkos M, Chrysos G, Dalekos GN, Poulakou G, Metallidis S, Giamarellos-Bourboulis EJ. Anakinra efficacy in COVID-19 pneumonia guided by soluble urokinase plasminogen activator receptor: Association with the inflammatory burden of the host. Int J Antimicrob Agents. 2025 Jan;65(1):107405. doi: 10.1016/j.ijantimicag.2024.107405. Epub 2024 Dec 6.

    PubMed 39647797

  • Kyriazopoulou E, Dalekos GN, Metallidis S, Poulakou G, Papanikolaou IC, Tzavara V, Argyraki K, Alexiou Z, Panagopoulos P, Samarkos M, Chrysos G, Tseliou A, Milionis H, Sympardi S, Vasishta A, Giamarellos-Bourboulis EJ. HEPARIN-BINDING PROTEIN LEVELS PREDICT UNFAVORABLE OUTCOME IN COVID-19 PNEUMONIA: A POST HOC ANALYSIS OF THE SAVE TRIAL. Shock. 2024 Mar 1;61(3):395-399. doi: 10.1097/SHK.0000000000002315. Epub 2024 Jan 19.

    PubMed 38517242

  • Keur N, Saridaki M, Ricano-Ponce I, Netea MG, Giamarellos-Bourboulis EJ, Kumar V. Analysis of inflammatory protein profiles in the circulation of COVID-19 patients identifies patients with severe disease phenotypes. Respir Med. 2023 Oct;217:107331. doi: 10.1016/j.rmed.2023.107331. Epub 2023 Jun 25.

    PubMed 37364721

  • Samaras C, Kyriazopoulou E, Poulakou G, Reiner E, Kosmidou M, Karanika I, Petrakis V, Adamis G, Gatselis NK, Fragkou A, Rapti A, Taddei E, Kalomenidis I, Chrysos G, Bertoli G, Kainis I, Alexiou Z, Castelli F, Saverio Serino F, Bakakos P, Nicastri E, Tzavara V, Kostis E, Dagna L, Koukidou S, Tzatzagou G, Chini M, Bassetti M, Trakatelli C, Tsoukalas G, Selmi C, Samarkos M, Pyrpasopoulou A, Masgala A, Antonakis E, Argyraki A, Akinosoglou K, Sympardi S, Panagopoulos P, Milionis H, Metallidis S, Syrigos KN, Angel A, Dalekos GN, Netea MG, Giamarellos-Bourboulis EJ. Interferon gamma-induced protein 10 (IP-10) for the early prognosis of the risk for severe respiratory failure and death in COVID-19 pneumonia. Cytokine. 2023 Feb;162:156111. doi: 10.1016/j.cyto.2022.156111. Epub 2022 Dec 14.

    PubMed 36529030

  • Renieris G, Karakike E, Gkavogianni T, Droggiti DE, Stylianakis E, Andriopoulou T, Spanou VM, Kafousopoulos D, Netea MG, Eugen-Olsen J, Simard J, Giamarellos-Bourboulis EJ. IL-1 Mediates Tissue-Specific Inflammation and Severe Respiratory Failure in COVID-19. J Innate Immun. 2022;14(6):643-656. doi: 10.1159/000524560. Epub 2022 May 11.

    PubMed 35545011

  • Kyriazopoulou E, Panagopoulos P, Metallidis S, Dalekos GN, Poulakou G, Gatselis N, Karakike E, Saridaki M, Loli G, Stefos A, Prasianaki D, Georgiadou S, Tsachouridou O, Petrakis V, Tsiakos K, Kosmidou M, Lygoura V, Dareioti M, Milionis H, Papanikolaou IC, Akinosoglou K, Myrodia DM, Gravvani A, Stamou A, Gkavogianni T, Katrini K, Marantos T, Trontzas IP, Syrigos K, Chatzis L, Chatzis S, Vechlidis N, Avgoustou C, Chalvatzis S, Kyprianou M, van der Meer JW, Eugen-Olsen J, Netea MG, Giamarellos-Bourboulis EJ. An open label trial of anakinra to prevent respiratory failure in COVID-19. Elife. 2021 Mar 8;10:e66125. doi: 10.7554/eLife.66125.

    PubMed 33682678

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Anakinra in people with COVID-19 and Virus Diseases, run by Hellenic Institute for the Study of Sepsis at 28 sites in Greece.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 28 sites in Greece. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The ratio of patients who will develop serious respiratory failure (SRF) (time frame: Visit study day 14). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04357366, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jul 2023.

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