Clinical trial NCT04680949: suPAR-Guided Anakinra Treatment for Management of Severe Respiratory Failure by COVID-19
Official title: suPAR-Guided Anakinra Treatment for Validation of the Risk and Early Management of Severe Respiratory Failure by COVID-19: The SAVE-MORE Double-blind, Randomized, Phase III Confirmatory Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Covid19
Keywords: SARS-CoV 2
anakinra
Lead sponsor: Hellenic Institute for the Study of Sepsis
Sponsor class: OTHER
First posted: 2020-12-23
Enrollment: 606
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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 WHO clinical progression scale (CPS).
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Comparison of the distribution of frequencies of each score of a 5-scale patient state evaluated from the 11-point WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment
timeFrame: 28 days
Secondary outcomes:
measure: Absolute change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)
timeFrame: 28 days
measure: Relative change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)
timeFrame: 28 days
measure: Absolute change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)
timeFrame: 14 days
measure: Relative change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)
timeFrame: 14 days
measure: Absolute change of the SOFA score
timeFrame: 14 days
measure: Relative change of the SOFA score
timeFrame: 14 days
measure: Absolute change of the SOFA score
timeFrame: 7 days
measure: Relative change of the SOFA score
timeFrame: 7 days
measure: Time until hospital discharge
timeFrame: 90 days
measure: Time until discharge from the intensive care unit
timeFrame: 90 days
measure: Comparison of the rate of serious and non-serious adverse events between the two arms of treatment
timeFrame: 90 days
measure: Comparison of the rate of serious and non-serious adverse events between the two arms of treatment
timeFrame: 60 days
measure: Relative changes of circulating concentrations of suPAR (μg/liter), D-dimers (μg/liter), ferritin (μg/liter), and Interleukin-6 (μg/liter) by Day 7 from baseline Day 1
timeFrame: 7 days
measure: Relative changes of circulating concentrations of C-reactive protein (mg/liter) by Day 7 from baseline Day 1
timeFrame: 7 days
measure: Relative changes of circulating concentrations of suPAR (μg/liter),D-dimers (μg/liter), ferritin (μg/liter), and Interleukin-6 (μg/liter) by Day 4 from baseline Day 1
timeFrame: 4 days
measure: Relative changes of circulating concentrations of C-reactive protein (mg/liter) by Day 4 from baseline Day 1
timeFrame: 4 days
measure: Absolute change of the viral load by Day 7 from baseline Day 1
timeFrame: 7 days
measure: Relative change of the viral load by Day 7 from baseline Day 1
timeFrame: 7 days
measure: Absolute change of the viral load by Day 4 from baseline Day 1
timeFrame: 4 days
measure: relative change of the viral load by Day 4 from baseline Day 1
timeFrame: 4 days
measure: Transcriptomic analysis
timeFrame: 7 days
measure: Proteomic analysis
timeFrame: 7 days
Other outcomes:
measure: Cost of hospitalization
timeFrame: 90 days
measure: Comparison of the distribution of frequencies of each score of a 5-scale patient state
timeFrame: 60 days
measure: Comparison of the distribution of frequencies of each score of a 5-scale patient state
timeFrame: 90 days
Locations:
city: Alexandroupolis
country: Greece
facility: 2nd Department of Internal Medicine, University General Hospital of Alexandroupolis
city: Athens
country: Greece
facility: 10th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
city: Athens
country: Greece
facility: 1st Department of Internal Medicine, AMALIA FLEMING Prefecture General Hospital of Melissia
city: Athens
country: Greece
facility: 1st Department of Internal Medicine, General Hospital of Athens KORGIALENIO-BENAKIO E.E.S.
city: Athens
country: Greece
facility: 1st Department of Internal Medicine, General Hospital of Eleusis THRIASIO
city: Athens
country: Greece
facility: 1st Department of Internal Medicine, General Hospital of Nea Ionia CONSTANTOPOULIO-PATISION
city: Athens
country: Greece
facility: 1st Department of Internal Medicine, General Hospital of Voula ASKLEPIEIO
city: Athens
country: Greece
facility: 1st University Department of Internal Medicine, General Hospital of Athens LAIKO
city: Athens
country: Greece
facility: 1st University Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
city: Athens
country: Greece
facility: 2nd Department of Internal Medicine, General Hospital of Eleusis THRIASIO
city: Athens
country: Greece
facility: 2nd Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
city: Athens
country: Greece
facility: 2nd University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens
city: Athens
country: Greece
facility: 3rd Department of Internal Medicine, General Hospital of Athens KORGIALENEIO-BENAKEIO E.E.S.
city: Athens
country: Greece
facility: 3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens SOTIRIA
city: Athens
country: Greece
facility: 4th Department of Internal Medicine, ATTIKON University General Hospital
city: Athens
country: Greece
facility: 4th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
city: Athens
country: Greece
facility: 5th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
city: Athens
country: Greece
facility: COVID-19 Department, General Hospital of Attica SISMANOGLEIO-AMALIA FLEMING
city: Athens
country: Greece
facility: Department of Clinical Therapeutics, ALEXANDRA General Hospital of Athens
city: Athens
country: Greece
facility: Department of COVID-19, Evangelismos General Hospital
city: Athens
country: Greece
facility: Department of Internal Medicine, General Hospital of Athens Elpis
city: Athens
country: Greece
facility: • 1st Department of Internal Medicine, General Hospital of Athens G. GENNIMATAS
city: Athens
country: Greece
facility: • Department of Internal Medicine, General Hospital of Chest Diseases of Athens SOTIRIA
city: Corfu
country: Greece
facility: Department of Pulmonary Medicine, General Hospital of Kerkyra
city: Ioánnina
country: Greece
facility: 1st Department of Internal Medicine, General University Hospital of Ioannina
city: Larissa
country: Greece
facility: Department of Internal Medicine, University General Hospital of Larissa,
city: Patra
country: Greece
facility: Department of Internal Medicine, University General Hospital of Patras PANAGIA I VOITHIA
city: Piraeus
country: Greece
facility: 2nd Department of Internal Medicine, General Hospital of Piraeus TZANEIO
city: Thessaloníki
country: Greece
facility: 1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki
city: Thessaloníki
country: Greece
facility: 1st Department of Internal Medicine, PAPAGEORGIOU General Hospital of Thessaloniki
city: Thessaloníki
country: Greece
facility: 2nd Department of Propedeutic Medicine, Ippokrateion University General Hospital of Thessaloniki
city: Thessaloníki
country: Greece
facility: 3rd University Department of Internal Medicine, PAPAGEORGIOU General Hospital of Thessaloniki
city: Brescia
country: Italy
facility: Dipartimento di Medicina Dipartimento di Malattie Infettive, ASST Spedali civili
city: Genova
country: Italy
facility: Unità Operativa Clinica Malattie Infettive, Ospedale Policlinico San Martino
city: Milano
country: Italy
facility: Dipartimento di Medicina Interna, Istituto Clinico Humanitas
city: Milano
country: Italy
facility: Medicina Interna, Reumatologia, Immunologia, IRCCS San Raffaele
city: Negrar
country: Italy
facility: Dipartimento di Malattie Infettive e Tropicali e Microbiologia, IRCCS Ospedale Sacro Cuore Don Calabria
city: Roma
country: Italy
facility: Dipartimento di Malattie Infettive ad alta Intensità di cura ed altamente contagiose, IRCCS Lazzaro Spallanzani
city: Roma
country: Italy
facility: Dipartimento Scienze di laboratorio e infettivologiche, Policlinico Universitario Agostino Gemelli
city: Varese
country: Italy
facility: Dipartimento di Malattie infettive e tropicali-Università dell'Insubria, ASST dei Sette Laghi
Study officials:
affiliation: Hellenic Institute for the Study of Sepsis
name: Evangelos Giamarellos-Bourboulis, MD, PhD
role: STUDY_CHAIR
References: