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

Sponsor

Hellenic Institute for the Study of Sepsis (Other)

Overall Status

Recruiting

CT.gov ID

NCT04357366

Collaborator

(none)

1,000

Enrollment

Locations

Arm

Anticipated Duration (Months)

Patients Per Site

1.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
COVID-19 Virus Diseases Corona Virus Infection Lower Respiratory Tract Infection Viral	Drug: Anakinra	Phase 2

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 Preliminary unpublished data from 57 Greek patients hospitalized after March 1st, 2020 in Greek hospitals due to pneumonia by confirmed SARS-CoV-2 infection showed that those with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

Study Type:

Interventional

Anticipated Enrollment :

1000 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Treatment with anakinraTreatment with anakinra

Masking:

None (Open Label)

Primary Purpose:

Prevention

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

Actual Study Start Date :

Apr 15, 2020

Anticipated Primary Completion Date :

Apr 15, 2022

Anticipated Study Completion Date :

Apr 15, 2022

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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 [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 [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 [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 [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 [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 [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 [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 [Visit study day 30]
Mortality on day 30
Rate of Mortality [Visit study day 90]
Mortality on day 90
Change of gene expression between days 1 nad 7 [days 1 and 7]
Transcriptional, proteomic and metabolomic change will be compared between days 1 and 7

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	COVID-19 Department, General Hospital of Attica SISMANOGLEIO-AMALIA FLEMING	Marousi	Athens	Greece	15126
2	2nd Department of Internal Medicine, University General Hospital of Alexandroupolis	Alexandroupolis		Greece	68100
3	Department of Internal Medicine, I PAMMAKARISTOS Hospital	Athens		Greece	11144
4	1st Department of InternalMedicine, General Hospital of Athens KORGIALENIO-BENAKIO E.E.S.	Athens		Greece	11526
5	1st Department of Internal Medicine, General Hospital of Athens G. GENNIMATAS	Athens		Greece	11527
6	1st University Department of Internal Medicine, General Hospital of Athens LAIKO	Athens		Greece	11527
7	1st University Departmentof Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseasesof Athens	Athens		Greece	11527
8	2nd University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens	Athens		Greece	11527
9	3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA	Athens		Greece	11527
10	Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA	Athens		Greece	11527
11	Department of Clinical Therapeutics, ALEXANDRA General Hospital of Athens	Athens		Greece	11528
12	1st Department of Internal Medicine, General Hospital of Eleusis THRIASIO	Athens		Greece
13	1st Department of Internal Medicine, General Hospital of Nea Ionia CONSTANTOPOULIO-PATISION	Athens		Greece
14	1st Department of Internal Medicine, General Hospital of Voula ASKLEPIEIO	Athens		Greece
15	2nd Department of Internal Medicine, 251 Air Force General Hospital	Athens		Greece
16	2nd Department of Internal Medicine, General Hospital of Eleusis THRIASIO	Athens		Greece
17	3rd Department of Internal Medicine, General Hospital of Athens KORGIALENEIO-BENAKEIO E.E.S.	Athens		Greece
18	5th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens	Athens		Greece
19	Department of Internal Medicine, General Hospital of Athens ELPIS	Athens		Greece
20	Department of Infectious Diseases, General Hospital of Kerkira	Corfu		Greece	49100
21	1st Department of Internal Medicine, General University Hospital of Ioannina	Ioánnina		Greece	45500
22	Department of Internal Medicine, General Hospital of Katerini	Kateríni		Greece	60100
23	Department of Internal Medicine, University General Hospital of Larissa	Larissa		Greece	41334
24	Department of Internal Medicine, General Hospital of Larisa KOUTLIMBANEIO & ΤΡΙΑΝΤΑFΥLLΕΙΟ	Larissa		Greece
25	Department of Internal Medicine, University General Hospital of Patras PANAGIA I VOITHIA	Patra		Greece	26504
26	2nd Department of Internal Medicine, General Hospital of Piraeus TZANEIO	Piraeus		Greece
27	1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki	Thessaloníki		Greece	54621