suPAR-Guided Anakinra Treatment for Management of Severe Respiratory Failure by COVID-19

NCT ID: NCT04680949

Last Updated: 2022-09-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 606 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-12-23
• Study Completion Date: 2022-02-06

Brief Summary

The SAVE-MORE is a pivotal, confirmatory, phase III randomized clinical trial (RCT) aiming to evaluate the efficacy and safety of early start of anakinra guided by suPAR in patients with LRTI by SARS-CoV-2 in improving the clinical state of COVID-19 over 28 days as measured by the ordinal scale of the 11-point World Health Organization (WHO) clinical progression scale (CPS).

Detailed Description

Since March 2020 when the COVID-19 pandemic started in Europe, the Hellenic Institute for the Study of Sepsis has launched in Greece the SAVE clinical trial (suPAR-guided Anakinra treatment for Validation of the risk and Early management of severe respiratory failure by COVID-19) (EudraCT number 2020-001466-11; approval 38/20 of the National Ethics Committee of Greece, approval IS 028/20 of the National Organization for Medicine of Greece, ClinicalTrials.gov identifier, NCT04357366). The concept of the SAVE trial was that early recognition of the risk for the progression of patients with lower respiratory tract infection (LRTI) by the new coronavirus SARS-CoV-2 into severe respiratory failure (SRF) may guide anakinra therapy to prevent SRF. The tool that was used for the diagnosis of risk for SRF is the biomarker suPAR (soluble urokinase plasminogen activator receptor) at measurable concentrations in the blood ≥6 ng/ml. The trial was designed to be open-label non-randomized and the idea was το the start of treatment well before any sign of respiratory failure emerges. Patients hospitalized at tertiary hospitals during the same time period as the SAVE trial was ongoing and who were receiving the same standard-of-care (SOC) treatment were studied as comparators. An interim analysis was submitted to the National Organization for Medicines; number 108002/23.10/2020. In this interim analysis, 130 patients receiving anakinra treatment and SOC were analysed and they were compared to 130 patients receiving SOC. The 130 SOC parallel comparators were selected by propensity score matching to be fully matched to the anakinra-treated patients for age, comorbidities, severity scores on the day of hospital admission, i.e. APACHE II score, Pneumonia Severity Index (PSI), Sequential Organ Failure Assessment (SOFA) and WHO severity, and for the intake of azithromycin, hydroxychloroquine and dexamethasone. SRF was defined as any respiratory ratio (pO2/FiO2) less than 150 mmHg necessitating mechanical ventilation or non-invasive ventilation (NIV). The results of this analysis may be summarized as follows:

• The incidence of SRF was significantly decreased from 59.2% in the parallel standard-of-care (SOC) comparators (n= 130) to 22.3% among the 130 anakinra-treated patients; hazard ratio, 0.30; 95% confidence intervals 0.20-0.46; P: 4.6 x 10-8.
• 30-day mortality was decreased from 22.3% in the SOC comparators to 11.5% among anakinra-treated patients; hazard ratio 0.49; 95% confidence intervals 0.25-0.97%; P: 0.041.
• Duration of stay at the intensive care unit was shortened with anakinra treatment compared to the SOC comparators for the patients who eventually developed SRF
• The median cost of hospitalization was significantly reduced from €2.398,40 among SOC comparators to €1.291,40 among anakinra-treated patients
• No safety concerns were raised.

Conditions

Covid19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo

Patients receiving standard-of-care (SOC) and placebo. Placebo is injected subcutaneously once daily for 10 days

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Standard-of-care and placebo. Placebo is injected subcutaneously once daily for 10 days

Anakinra

Patients receiving SOC and anakinra. Anakinra is injected subcutaneously as 100 mg once daily for 10 days

Group Type: EXPERIMENTAL

Anakinra

Intervention Type: DRUG

Standard-of-care and anakinra. Anakinra is injected subcutaneously as 100 mg once daily for 10 days

Interventions

Anakinra

Standard-of-care and anakinra. Anakinra is injected subcutaneously as 100 mg once daily for 10 days

Intervention Type: DRUG

Placebo

Standard-of-care and placebo. Placebo is injected subcutaneously once daily for 10 days

Intervention Type: DRUG

Other Intervention Names

Kineret

Eligibility Criteria

Inclusion Criteria

1. Age equal to or above 18 years

2. Male or female gender

3. In case of women, unwillingness to remain pregnant during the study period.

4. Written informed consent provided by the patient. For subjects without decision-making capacity, informed consent must be obtained from a legally designated representative following the national legislation in the Member State where the trial is planned.

5. Confirmed infection by SARS-CoV-2 virus

6. Findings in chest-X-ray or in chest computed tomography compatible with lower respiratory tract infection

7. Need for hospitalization for COVID-19. The need for hospitalization is defined by the attending physician taking into consideration clinical presentation, requirement for supportive care, potential risk factors for severe disease, and conditions at home, including the presence of vulnerable persons in the household.

8. Plasma suPAR ≥6ng/ml

Exclusion Criteria

• Age below 18 years
• Denial for written informed consent
• Any stage IV malignancy
• Any do not resuscitate decision
• Αny pO2/FiO2 (partial oxygen pressure to fraction of inspired oxygen) ratio less than 150 mmHg irrespective if the patient is under mechanical ventilation (MV) / non-invasive ventilation (NIV) / extracorporeal membrane oxygenation (ECMO) or not
• Patient under MV or NIV or ECMO
• Any primary immunodeficiency
• Less than 1,500 neutrophils/mm3
• Plasma suPAR less than 6 ng/ml
• Known hypersensitivity to anakinra
• Oral or IV intake of corticosteroids at a daily dose equal or greater than 0.4 mg/kg prednisone for a period greater than the last 15 days.
• Any anti-cytokine biological treatment the last one month
• Severe hepatic failure defined as Child-Pugh stage of 3
• End-stage renal failure necessitating hemofiltration or peritoneal hemodialysis
• Pregnancy or lactation. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study
• Participation in any other interventional trial

• 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

Evangelos Giamarellos-Bourboulis, MD, PhD

Role: STUDY_CHAIR

Hellenic Institute for the Study of Sepsis

Locations

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

Alexandroupoli, , Greece

10th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens

Athens, , Greece

1st Department of Internal Medicine, AMALIA FLEMING Prefecture General Hospital of Melissia

Athens, , Greece

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

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 University Department of Internal Medicine, General Hospital of Athens LAIKO

Athens, , Greece

1st University Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens

Athens, , Greece

2nd Department of Internal Medicine, General Hospital of Eleusis THRIASIO

Athens, , Greece

2nd Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens

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 SOTIRIA

Athens, , Greece

4th Department of Internal Medicine, ATTIKON University General Hospital

Athens, , Greece

4th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens

Athens, , Greece

5th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens

Athens, , Greece

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

Athens, , Greece

Department of Clinical Therapeutics, ALEXANDRA General Hospital of Athens

Athens, , Greece

Department of COVID-19, Evangelismos General Hospital

Athens, , Greece

Department of Internal Medicine, General Hospital of Athens Elpis

Athens, , Greece

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

Athens, , Greece

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

Athens, , Greece

Department of Pulmonary Medicine, General Hospital of Kerkyra

Corfu, , Greece

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

Ioannina, , Greece

Department of Internal Medicine, University General Hospital of Larissa,

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

1st Department of Internal Medicine, PAPAGEORGIOU General Hospital of Thessaloniki

Thessaloniki, , Greece

2nd Department of Propedeutic Medicine, Ippokrateion University General Hospital of Thessaloniki

Thessaloniki, , Greece

3rd University Department of Internal Medicine, PAPAGEORGIOU General Hospital of Thessaloniki

Thessaloniki, , Greece

Dipartimento di Medicina Dipartimento di Malattie Infettive, ASST Spedali civili

Brescia, , Italy

Unità Operativa Clinica Malattie Infettive, Ospedale Policlinico San Martino

Genova, , Italy

Dipartimento di Medicina Interna, Istituto Clinico Humanitas

Milan, , Italy

Medicina Interna, Reumatologia, Immunologia, IRCCS San Raffaele

Milan, , Italy

Dipartimento di Malattie Infettive e Tropicali e Microbiologia, IRCCS Ospedale Sacro Cuore Don Calabria

Negrar, , Italy

Dipartimento di Malattie Infettive ad alta Intensità di cura ed altamente contagiose, IRCCS Lazzaro Spallanzani

Roma, , Italy

Dipartimento Scienze di laboratorio e infettivologiche, Policlinico Universitario Agostino Gemelli

Roma, , Italy

Dipartimento di Malattie infettive e tropicali-Università dell'Insubria, ASST dei Sette Laghi

Varese, , Italy

Countries

Greece; Italy

References

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Other Identifiers

SAVE-MORE

Identifier Type: -

Identifier Source: org_study_id