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

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ClinicalTrials.gov Identifier: NCT04357366
Recruitment Status : Recruiting
First Posted : April 22, 2020
Last Update Posted : April 27, 2020
Sponsor:
Information provided by (Responsible Party):
Hellenic Institute for the Study of Sepsis

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. Also due to the potential co-existing immunodysfunction in the context of SARS-CoV-2 infection patients will also receive trimethoprim/sulfamethoxazole as part of chemoprophylaxis.

Condition or disease Intervention/treatment Phase
COVID-19 Virus Diseases Corona Virus Infection Lower Respiratory Tract Infection Viral Drug: Anakinra Drug: trimethoprim/sulfamethoxazole 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 Preliminary unpublished data from 57 Greek patients hospitalized after March 1st, 2020 in Greek hospitals due to pneumonia by confirmed SARS-CoV-2 infection showed that those with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.

Chemoprophylaxis in HIV-free patients with some form of immunosuppression is considered effective. Given the active inflammatory process in the pulmonary parenchyma, hypercytokinemia, co-existing lymphopenia and the dysregulation of the immune response accompanying COVID-19 disease patients will also receive trimethoprim / sulfamethoxazole as part of chemoprophylaxis.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Treatment with anakinra and trimethoprim/sulfamethoxazole
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 : April 15, 2020
Estimated Primary Completion Date : April 15, 2022
Estimated Study Completion Date : April 15, 2022


Arm Intervention/treatment
Experimental: Anakinra and trimethoprim/sulfamethoxazole
Patients will receive 100mg of anakinra subcutaneously and a tablet of 80mg/400mg trimethoprim/sulfamethoxazole orally as antimicrobial prophylaxis 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 and the required number of oral tablets of trimethoprim/sulfamethoxazole in a cartridge format respectively. In this case, the patient should return the empty used syringes and the empty cartridges within 30 days.
Drug: Anakinra
Treatment with 100mg Anakinra subcutaneously (sc) once daily for ten days
Other Name: Kineret

Drug: trimethoprim/sulfamethoxazole
Treatment with 80/400 mgTrimethoprime/sulfamethoxazole orally once daily for ten days
Other Name: Bactrimel




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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)

  5. 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)

  6. Change of cytokine 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

  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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • Evident respiratory failure
  • Any primary immunodeficiency
  • Less than 1,500 neutrophils/mm3
  • Known hypersensitivity to anakinra
  • Known hypersensitivity to trimethoprim/sulfamethoxazole
  • Known glucose 6 phosphate dehydrogenase (G-6PD) enzyme deficiency
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04357366


Contacts
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Contact: Evangelos Giamarellos-Bourboulis, MD, PhD +302107480662 egiamarel@med.uoa.gr
Contact: Antigoni Kotsaki, MD, PhD +306946637164 antigonebut@yahoo.com

Locations
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Greece
COVID-19 Department, General Hospital of Attica SISMANOGLEIO-AMALIA FLEMING Recruiting
Marousi, Athens, Greece, 15126
Contact: Malvina Lada, MD    +30 2132058360    malvinalada@gmail.com   
2nd Department of Internal Medicine, University General Hospital of Alexandroupolis Recruiting
Alexandroupolis, Greece, 68100
Contact: Periklis Panagopoulos, MD, PhD    +30 2551351592    ppanago@med.duth.gr   
Department of Internal Medicine, I PAMMAKARISTOS Hospital Recruiting
Athens, Greece, 11144
Contact: Ioannis Baraboutis, MD    +30 2132042100    ioannisbaraboutis@gmail.com   
1st Department of Internal Medicine, General Hospital of Athens G. GENNIMATAS Recruiting
Athens, Greece, 11527
Contact: Georgios Adamis, MD    +30 2107768534    geo.adamis@gmail.com   
1st University Department of Internal Medicine, General Hospital of Athens LAIKO Recruiting
Athens, Greece, 11527
Contact: Michael Samarkos, MD, PhD    +30 2132061643    msamarkos@gmail.com   
2nd University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens Recruiting
Athens, Greece, 11527
Contact: Helen Sambatakou    +30 6977476385    helensambatakou@msn.com   
3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA Recruiting
Athens, Greece, 11527
Contact: Garyfallia Poulakou, MD, PhD    +30 2107719975    gpoulakou@gmail.com   
Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA Recruiting
Athens, Greece, 11527
Contact: Aikaterini Argyraki, MD    +30 2107763467    katrin.argyraki@gmail.com   
Department of Clinical Therapeutics, ALEXANDRA General Hospital of Athens Recruiting
Athens, Greece, 11528
Contact: Evangelos Kostis, MD    +30 6945067742    ekostis@otenet.gr   
Department of Infectious Diseases, General Hospital of Kerkira Recruiting
Corfu, Greece, 49100
Contact: Ilias Papanikolaou, MD    +30 2661360694    icpapanikolaou@hotmail.com   
1st Department of Internal Medicine, General University Hospital of Ioannina Recruiting
Ioánnina, Greece, 45500
Contact: Charalambos Milionis, MD, PhD    +30 2651362736    hmilioni@uoi.gr   
Department of Internal Medicine, University General Hospital of Larissa Recruiting
Larissa, Greece, 41334
Contact: George Dalekos, MD, PhD    +30 2413501557    georgedalekos@gmail.com   
Department of Internal Medicine, University General Hospital of Patras PANAGIA I VOITHIA Recruiting
Patra, Greece, 26504
Contact: Charalambos Gogos, MD, PhD    +30 2610999582    cgogos@med.upatras.gr   
1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki Recruiting
Thessaloníki, Greece, 54621
Contact: Simeon Metallidis, MD, PhD    +30 2313303214    metallidissimeon@yahoo.gr   
Sponsors and Collaborators
Hellenic Institute for the Study of Sepsis
Investigators
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Principal Investigator: Simeon Metallidis, MD, PhD Aristotle University of Thessaloniki, Medical School
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Responsible Party: Hellenic Institute for the Study of Sepsis
ClinicalTrials.gov Identifier: NCT04357366    
Other Study ID Numbers: SAVE
2020-001466-11 ( EudraCT Number )
First Posted: April 22, 2020    Key Record Dates
Last Update Posted: April 27, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hellenic Institute for the Study of Sepsis:
COVID-19
SARS-CoV-2
Anakinra
Trimethoprim/Sulfamethoxazole
Co-trimoxazole
suPAR
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Respiratory Tract Infections
Coronavirus Infections
Severe Acute Respiratory Syndrome
Respiratory Insufficiency
Virus Diseases
Respiration Disorders
Respiratory Tract Diseases
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Trimethoprim
Sulfamethoxazole
Interleukin 1 Receptor Antagonist Protein
Anti-Infective Agents, Urinary
Anti-Infective Agents
Renal Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Folic Acid Antagonists
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Dyskinesia Agents
Cytochrome P-450 CYP2C8 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Antirheumatic Agents