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

COVID-19 Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04357366
• Other study ID #: SAVE
• Secondary ID: 2020-001466-11
• Status: Completed
• Phase: Phase 2
• Start date: April 15, 2020
• Est. completion date: April 15, 2022

Study information

• Verified date: July 2023
• Source: Hellenic Institute for the Study of Sepsis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. They will begin early treatment with anakinra in the effort to prevent progression in serious respiratory failure.

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 Preliminary unpublished data from 57 Greek patients hospitalized after March 1st, 2020 in Greek hospitals due to pneumonia by confirmed SARS-CoV-2 infection showed that those with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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1000
• Est. completion date: April 15, 2022
• Est. primary completion date: January 29, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Communicable Diseases
• Corona Virus Infection
• Coronavirus Infections
• COVID-19
• Infections
• Lower Respiratory Tract Infection Viral
• Respiratory Insufficiency
• Respiratory Tract Infections
• Virus Diseases

Intervention

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

Locations

Country	Name	City	State
Greece	2nd Department of Internal Medicine, University General Hospital of Alexandroupolis	Alexandroupolis
Greece	1st Department of Internal Medicine Amalia Fleming General Hospital	Athens
Greece	1st Department of Internal Medicine, General Hospital of Athens G. GENNIMATAS	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	1st Department of InternalMedicine, General Hospital of Athens KORGIALENIO-BENAKIO E.E.S.	Athens
Greece	1st University Department of Internal Medicine, General Hospital of Athens LAIKO	Athens
Greece	1st University Departmentof Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseasesof Athens	Athens
Greece	2nd Department of Internal Medicine, 251 Air Force General Hospital	Athens
Greece	2nd Department of Internal Medicine, General Hospital of Eleusis THRIASIO	Athens
Greece	2nd University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens	Athens
Greece	3rd Department of Internal Medicine, General Hospital of Athens KORGIALENEIO-BENAKEIO E.E.S.	Athens
Greece	3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA	Athens
Greece	5th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens	Athens
Greece	Department of Clinical Therapeutics, ALEXANDRA General Hospital of Athens	Athens
Greece	Department of Internal Medicine, General Hospital of Athens ELPIS	Athens
Greece	Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA	Athens
Greece	Department of Internal Medicine, I PAMMAKARISTOS Hospital	Athens
Greece	Department of Infectious Diseases, General Hospital of Kerkira	Corfu
Greece	1st Department of Internal Medicine, General University Hospital of Ioannina	Ioánnina
Greece	Department of Internal Medicine, General Hospital of Katerini	Kateríni
Greece	Department of Internal Medicine, General Hospital of Larisa KOUTLIMBANEIO & ???????F?LL???	Larissa
Greece	Department of Internal Medicine, University General Hospital of Larissa	Larissa
Greece	COVID-19 Department, General Hospital of Attica SISMANOGLEIO-AMALIA FLEMING	Marousi	Athens
Greece	Department of Internal Medicine, University General Hospital of Patras PANAGIA I VOITHIA	Patra
Greece	2nd Department of Internal Medicine, General Hospital of Piraeus TZANEIO	Piraeus
Greece	1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki	Thessaloníki

Sponsors (1)

Lead Sponsor	Collaborator
Hellenic Institute for the Study of Sepsis

Country where clinical trial is conducted

Greece, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Rate of Mortality	Mortality on day 30	Visit study day 30
Secondary	Rate of Mortality	Mortality on day 90	Visit study day 90
Secondary	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
Secondary	Safety of anakinra	Safety of anakinra	Last patients visit, Day 90
Secondary	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
Secondary	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
Secondary	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
Secondary	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