Clinical trial NCT04357366: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19
Virus Diseases
Corona Virus Infection
Lower Respiratory Tract Infection Viral
Keywords: COVID-19
SARS-CoV-2
Anakinra
suPAR
Lead sponsor: Hellenic Institute for the Study of Sepsis
Sponsor class: OTHER
First posted: 2020-04-22
Enrollment: 1000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Treatment with anakinra
Primary purpose: PREVENTION

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 Preliminary unpublished data from 57 Greek patients hospitalized after March 1st, 2020 in Greek hospitals due to pneumonia by confirmed SARS-CoV-2 infection showed that those with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

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

Primary outcomes:
measure: The ratio of patients who will develop serious respiratory failure (SRF)
timeFrame: Visit study day 14
Secondary outcomes:
measure: 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
timeFrame: Visit study day 14
measure: Change of scoring for respiratory symptoms in enrolled subjects between days 1 and 7
timeFrame: Visit study day 1, visit study day 7
measure: Change of scoring for respiratory symptoms in enrolled subjects between days 1 and 14
timeFrame: Visit study day 1, visit study day 14
measure: Change of SOFA score in enrolled subjects between days 1 and 7
timeFrame: Visit study day 1, visit study day 7
measure: Change of Sequential organ failure assessment (SOFA) score in enrolled subjects between days 1 and 14
timeFrame: Visit study day 1, visit study day 14
measure: Change of peripheral mononuclear blood cells' (PBMCs) functionality between days 1 and 7
timeFrame: Visit study day 1, visit study day 7
measure: Change of plasma inflammatory mediators levels between days 1 and 7
timeFrame: Visit study day 1, visit study day 7
measure: Rate of Mortality
timeFrame: Visit study day 30
measure: Rate of Mortality
timeFrame: Visit study day 90
measure: Change of gene expression between days 1 nad 7
timeFrame: days 1 and 7
measure: Safety of anakinra
timeFrame: Last patients visit, Day 90
measure: Association between the time interval from hospital admission until start of anakinra and the incidence of SRF
timeFrame: Visit day 14
measure: Correlation between time interval and the occurrence of SAA under treatment with anakinra
timeFrame: Visit day 14
measure: Association between radiological opacities in chest computed tomography and the incidence of SRF under anakinra treatment
timeFrame: Visit day 14
measure: 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
timeFrame: Visit day 14
Other outcomes:
Locations:
city: Marousi
country: Greece
facility: COVID-19 Department, General Hospital of Attica SISMANOGLEIO-AMALIA FLEMING
state: Athens
city: Alexandroupolis
country: Greece
facility: 2nd Department of Internal Medicine, University General Hospital of Alexandroupolis
city: Athens
country: Greece
facility: Department of Internal Medicine, I PAMMAKARISTOS Hospital
city: Athens
country: Greece
facility: 1st Department of InternalMedicine, General Hospital of Athens KORGIALENIO-BENAKIO E.E.S.
city: Athens
country: Greece
facility: 1st Department of Internal Medicine, General Hospital of Athens G. GENNIMATAS
city: Athens
country: Greece
facility: 1st University Department of Internal Medicine, General Hospital of Athens LAIKO
city: Athens
country: Greece
facility: 1st University Departmentof Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseasesof Athens
city: Athens
country: Greece
facility: 2nd University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens
city: Athens
country: Greece
facility: 3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA
city: Athens
country: Greece
facility: Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA
city: Athens
country: Greece
facility: Department of Clinical Therapeutics, ALEXANDRA General Hospital of Athens
city: Athens
country: Greece
facility: 1st Department of Internal Medicine Amalia Fleming General Hospital
city: Athens
country: Greece
facility: 1st Department of Internal Medicine, General Hospital of Eleusis THRIASIO
city: Athens
country: Greece
facility: 1st Department of Internal Medicine, General Hospital of Nea Ionia CONSTANTOPOULIO-PATISION
city: Athens
country: Greece
facility: 1st Department of Internal Medicine, General Hospital of Voula ASKLEPIEIO
city: Athens
country: Greece
facility: 2nd Department of Internal Medicine, 251 Air Force General Hospital
city: Athens
country: Greece
facility: 2nd Department of Internal Medicine, General Hospital of Eleusis THRIASIO
city: Athens
country: Greece
facility: 3rd Department of Internal Medicine, General Hospital of Athens KORGIALENEIO-BENAKEIO E.E.S.
city: Athens
country: Greece
facility: 5th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
city: Athens
country: Greece
facility: Department of Internal Medicine, General Hospital of Athens ELPIS
city: Corfu
country: Greece
facility: Department of Infectious Diseases, General Hospital of Kerkira
city: Ioánnina
country: Greece
facility: 1st Department of Internal Medicine, General University Hospital of Ioannina
city: Kateríni
country: Greece
facility: Department of Internal Medicine, General Hospital of Katerini
city: Larissa
country: Greece
facility: Department of Internal Medicine, University General Hospital of Larissa
city: Larissa
country: Greece
facility: Department of Internal Medicine, General Hospital of Larisa KOUTLIMBANEIO & ΤΡΙΑΝΤΑFΥLLΕΙΟ
city: Patra
country: Greece
facility: Department of Internal Medicine, University General Hospital of Patras PANAGIA I VOITHIA
city: Piraeus
country: Greece
facility: 2nd Department of Internal Medicine, General Hospital of Piraeus TZANEIO
city: Thessaloníki
country: Greece
facility: 1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki
Study officials:
affiliation: Aristotle University of Thessaloniki, Medical School
name: Simeon Metallidis, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.