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

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.

Study Overview

• Status: Completed
• Conditions: Virus Diseases; COVID-19; Corona Virus Infection; Lower Respiratory Tract Infection Viral
• Intervention / Treatment: Drug: Anakinra

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 Preliminary unpublished data from 57 Greek patients hospitalized after March 1st, 2020 in Greek hospitals due to pneumonia by confirmed SARS-CoV-2 infection showed that those with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.

• Study Type: Interventional
• Enrollment (Actual): 1000
• Phase: Phase 2

Contacts and Locations

Study Locations

• Greece
  • Alexandroupolis, Greece, 68100
    • 2nd Department of Internal Medicine, University General Hospital of Alexandroupolis
  • Athens, Greece, 11527
    • 2nd University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens
  • Athens, Greece, 11527
    • 3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA
  • Athens, Greece
    • 1st Department of Internal Medicine, General Hospital of Eleusis THRIASIO
  • Athens, Greece
    • 1st Department of Internal Medicine, General Hospital of Nea Ionia CONSTANTOPOULIO-PATISION
  • Athens, Greece
    • 1st Department of Internal Medicine, General Hospital of Voula ASKLEPIEIO
  • Athens, Greece
    • 2nd Department of Internal Medicine, General Hospital of Eleusis THRIASIO
  • Athens, Greece
    • 3rd Department of Internal Medicine, General Hospital of Athens KORGIALENEIO-BENAKEIO E.E.S.
  • Athens, Greece
    • 5th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
  • Athens, Greece
    • Department of Internal Medicine, General Hospital of Athens ELPIS
  • Athens, Greece, 11527
    • 1st Department of Internal Medicine, General Hospital of Athens G. GENNIMATAS
  • Athens, Greece, 11144
    • Department of Internal Medicine, I PAMMAKARISTOS Hospital
  • Athens, Greece, 11526
    • 1st Department of InternalMedicine, General Hospital of Athens KORGIALENIO-BENAKIO E.E.S.
  • Athens, Greece, 11527
    • 1st University Department of Internal Medicine, General Hospital of Athens LAIKO
  • Athens, Greece, 11527
    • 1st University Departmentof Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseasesof Athens
  • Athens, Greece, 11527
    • Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA
  • Athens, Greece, 11528
    • Department of Clinical Therapeutics, ALEXANDRA General Hospital of Athens
  • Athens, Greece
    • 2nd Department of Internal Medicine, 251 Air Force General Hospital
  • Athens, Greece
    • 1st Department of Internal Medicine Amalia Fleming General Hospital
  • Corfu, Greece, 49100
    • Department of Infectious Diseases, General Hospital of Kerkira
  • Ioánnina, Greece, 45500
    • 1st Department of Internal Medicine, General University Hospital of Ioannina
  • Kateríni, Greece, 60100
    • Department of Internal Medicine, General Hospital of Katerini
  • Larissa, Greece, 41334
    • Department of Internal Medicine, University General Hospital of Larissa
  • Larissa, Greece
    • Department of Internal Medicine, General Hospital of Larisa KOUTLIMBANEIO & ΤΡΙΑΝΤΑFΥLLΕΙΟ
  • Patra, Greece, 26504
    • Department of Internal Medicine, University General Hospital of Patras PANAGIA I VOITHIA
  • Piraeus, Greece
    • 2nd Department of Internal Medicine, General Hospital of Piraeus TZANEIO
  • Thessaloníki, Greece, 54621
    • 1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki
  • Athens
    • Marousi, Athens, Greece, 15126
      • COVID-19 Department, General Hospital of Attica SISMANOGLEIO-AMALIA FLEMING

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Anakinra; Patients 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.

Drug: Anakinra; Treatment with 100mg Anakinra subcutaneously (sc) once daily for ten days; Other Names: Kineret

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Visit study day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Visit study day 14
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	Visit study day 1, visit study day 7
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	Visit study day 1, visit study day 14
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)	Visit study day 1, visit study day 7
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)	Visit study day 1, visit study day 14
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	Visit study day 1, visit study day 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	Visit study day 1, visit study day 7
Rate of Mortality	Mortality on day 30	Visit study day 30
Rate of Mortality	Mortality on day 90	Visit study day 90
Change of gene expression between days 1 nad 7	Transcriptional, proteomic and metabolomic change will be compared between days 1 and 7	days 1 and 7
Safety of anakinra	Safety of anakinra	Last patients visit, Day 90
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	Visit day 14
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	Visit day 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	Visit day 14
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	Visit day 14

Collaborators and Investigators

• Sponsor: Hellenic Institute for the Study of Sepsis
• Investigators: Principal Investigator: Simeon Metallidis, MD, PhD, Aristotle University of Thessaloniki, Medical School

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2020
• Primary Completion (Actual): January 29, 2022
• Study Completion (Actual): April 15, 2022

Study Registration Dates

• First Submitted: April 20, 2020
• First Submitted That Met QC Criteria: April 21, 2020
• First Posted (Actual): April 22, 2020

Study Record Updates

• Last Update Posted (Actual): July 13, 2023
• Last Update Submitted That Met QC Criteria: July 12, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: SARS-CoV-2; COVID-19; Anakinra; suPAR
• Additional Relevant MeSH Terms: Pathologic Processes; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; COVID-19; Coronavirus Infections; Infections; Communicable Diseases; Virus Diseases; Respiratory Insufficiency; Respiratory Tract Infections; Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: SAVE; 2020-001466-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No