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

• ClinicalTrials.gov Identifier: NCT04357366
• Recruitment Status: Completed
• First Posted: April 22, 2020
• Last Update Posted: July 13, 2023
• Sponsor: Hellenic Institute for the Study of Sepsis
• Information provided by (Responsible Party): Hellenic Institute for the Study of Sepsis

Tracking Information

• First Submitted Date: April 20, 2020
• First Posted Date: April 22, 2020
• Last Update Posted Date: July 13, 2023
• Actual Study Start Date: April 15, 2020
• Actual Primary Completion Date: January 29, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 26, 2020)

The ratio of patients who will develop serious respiratory failure (SRF) [ Time Frame: Visit study day 14 ]

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.

Original Primary Outcome Measures (submitted: April 21, 2020)

The ratio of patients who will not develop serious respiratory failure (SRF) [ Time Frame: Visit study day 14 ]

The primary study endpoint is the ratio of patients who will not develop serious respiratory failure SRF until day 14. Patients dying before study visit of day 14 are considered non-achieving the primary endpoint.

Current Secondary Outcome Measures (submitted: July 12, 2023)

• 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 [ Time Frame: Visit study day 14 ]
  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
• Change of scoring for respiratory symptoms in enrolled subjects between days 1 and 7 [ Time Frame: Visit study day 1, visit study day 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
• Change of scoring for respiratory symptoms in enrolled subjects between days 1 and 14 [ Time Frame: Visit study day 1, visit study day 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
• Change of SOFA score in enrolled subjects between days 1 and 7 [ Time Frame: Visit study day 1, visit study day 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)
• Change of Sequential organ failure assessment (SOFA) score in enrolled subjects between days 1 and 14 [ Time Frame: Visit study day 1, visit study day 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)
• Change of peripheral mononuclear blood cells' (PBMCs) functionality between days 1 and 7 [ Time Frame: Visit study day 1, visit study day 7 ]
  Change of peripheral mononuclear blood cells' (PBMCs) functionality of enrolled subjects will be compared between days 1 and 7
• Change of plasma inflammatory mediators levels between days 1 and 7 [ Time Frame: Visit study day 1, visit study day 7 ]
  Change of plasma inflammatory mediators measured levels will be compared between days 1 and 7
• Rate of Mortality [ Time Frame: Visit study day 30 ]
  Mortality on day 30
• Rate of Mortality [ Time Frame: Visit study day 90 ]
  Mortality on day 90
• Change of gene expression between days 1 nad 7 [ Time Frame: days 1 and 7 ]
  Transcriptional, proteomic and metabolomic change will be compared between days 1 and 7
• Safety of anakinra [ Time Frame: Last patients visit, Day 90 ]
  Safety of anakinra
• Association between the time interval from hospital admission until start of anakinra and the incidence of SRF [ Time Frame: Visit day 14 ]
  Association between the time interval from hospital admission until start of anakinra and the incidence of SRF
• Correlation between time interval and the occurrence of SAA under treatment with anakinra [ Time Frame: Visit day 14 ]
  Correlation between time interval and the occurrence of SAA under treatment with anakinra
• Association between radiological opacities in chest computed tomography and the incidence of SRF under anakinra treatment [ Time Frame: Visit day 14 ]
  Association between radiological opacities in chest computed tomography and the incidence of SRF under anakinra treatment
• 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 [ Time Frame: 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

Original Secondary Outcome Measures (submitted: April 21, 2020)

• Comparison of the rate of patients who will not develop serious respiratory failure (SRF) until day 14 with historical comparators from Hellenic Sepsis Study Group Database [ Time Frame: Visit study day 14 ]
  Evaluation of clinical data (pO2/FiO2 and need of mechanical ventilation) between baseline and study visit day 14 will be compared with historical comparators from Hellenic Sepsis Study Group Database
• Change of scoring for respiratory symptoms in enrolled subjects between days 1 and 7 [ Time Frame: Visit study day 1, visit study day 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
• Change of scoring for respiratory symptoms in enrolled subjects between days 1 and 14 [ Time Frame: Visit study day 1, visit study day 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
• Change of SOFA score in enrolled subjects between days 1 and 7 [ Time Frame: Visit study day 1, visit study day 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)
• Change of Sequential organ failure assessment (SOFA) score in enrolled subjects between days 1 and 14 [ Time Frame: Visit study day 1, visit study day 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)
• Cytokine of cytikine production between days 1 and 7 [ Time Frame: Visit study day 1, visit study day 7 ]
  Change of cytokine stimulation from peripheral blood mononuclear cells of enrolled subjects will be compared between days 1 and 7
• Change of plasma inflammatory mediators levels between days 1 and 7 [ Time Frame: Visit study day 1, visit study day 7 ]
  Change of plasma inflammatory mediators measured levels will be compared between days 1 and 7

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: suPAR-guided Anakinra Treatment for Validation of the Risk and Management of Respiratory Failure by COVID-19 (SAVE)
• 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
• Brief 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. They will begin early treatment with anakinra in the effort to prevent progression in serious respiratory failure.

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
• Study Phase: Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

Treatment with anakinra

Masking: None (Open Label)
Primary Purpose: Prevention

Condition

• COVID-19
• Virus Diseases
• Corona Virus Infection
• Lower Respiratory Tract Infection Viral

Intervention

Drug: Anakinra

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

Other Name: Kineret

Study Arms

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.

Intervention: Drug: Anakinra

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 12, 2021): 1000
• Original Estimated Enrollment (submitted: April 21, 2020): 100
• Actual Study Completion Date: April 15, 2022
• Actual Primary Completion Date: January 29, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Greece

Administrative Information

• NCT Number: NCT04357366
• Other Study ID Numbers: SAVE; 2020-001466-11 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Hellenic Institute for the Study of Sepsis
• Original Responsible Party: Same as current
• Current Study Sponsor: Hellenic Institute for the Study of Sepsis
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Simeon Metallidis, MD, PhD; Aristotle University of Thessaloniki, Medical School

• PRS Account: Hellenic Institute for the Study of Sepsis
• Verification Date: July 2023