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

NCT ID: NCT04357366

Last Updated: 2023-07-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 1000 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-04-15
• Study Completion Date: 2022-04-15

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 Preliminary unpublished data from 57 Greek patients hospitalized after March 1st, 2020 in Greek hospitals due to pneumonia by confirmed SARS-CoV-2 infection showed that those with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

Conditions

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Anakinra

Intervention Type: DRUG

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

Interventions

Anakinra

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

Intervention Type: DRUG

Other Intervention Names

Kineret

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hellenic Institute for the Study of Sepsis

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Simeon Metallidis, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Aristotle University of Thessaloniki, Medical School

Locations

COVID-19 Department, General Hospital of Attica SISMANOGLEIO-AMALIA FLEMING

Marousi, Athens, Greece

2nd Department of Internal Medicine, University General Hospital of Alexandroupolis

Alexandroupoli, , Greece

Department of Internal Medicine, I PAMMAKARISTOS Hospital

Athens, , Greece

1st Department of InternalMedicine, General Hospital of Athens KORGIALENIO-BENAKIO E.E.S.

Athens, , Greece

1st Department of Internal Medicine, General Hospital of Athens G. GENNIMATAS

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 University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens

Athens, , Greece

3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA

Athens, , Greece

Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA

Athens, , Greece

Department of Clinical Therapeutics, ALEXANDRA General Hospital of Athens

Athens, , Greece

1st Department of Internal Medicine Amalia Fleming General Hospital

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, 251 Air Force General Hospital

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

Department of Infectious Diseases, General Hospital of Kerkira

Corfu, , Greece

1st Department of Internal Medicine, General University Hospital of Ioannina

Ioannina, , Greece

Department of Internal Medicine, General Hospital of Katerini

Katerini, , Greece

Department of Internal Medicine, University General Hospital of Larissa

Larissa, , Greece

Department of Internal Medicine, General Hospital of Larisa KOUTLIMBANEIO & ΤΡΙΑΝΤΑFΥLLΕΙΟ

Larissa, , Greece

Department of Internal Medicine, University General Hospital of Patras PANAGIA I VOITHIA

Pátrai, , Greece

2nd Department of Internal Medicine, General Hospital of Piraeus TZANEIO

Piraeus, , Greece

1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki

Thessaloniki, , Greece

Countries

Greece

References

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Other Identifiers

2020-001466-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

SAVE

Identifier Type: -

Identifier Source: org_study_id