suPAR-Guided Anakinra Treatment for Management of Severe Respiratory Failure by COVID-19 (SAVE-MORE)

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

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).

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Drug: Placebo; Drug: Anakinra

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.

• Study Type: Interventional
• Enrollment (Actual): 606
• Phase: Phase 3

Contacts and Locations

Study Locations

• Greece
  • Alexandroupolis, Greece
    • 2nd Department of Internal Medicine, University General Hospital of Alexandroupolis
  • Athens, 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
  • Corfu, Greece
    • Department of Pulmonary Medicine, General Hospital of Kerkyra
  • Ioánnina, Greece
    • 1st Department of Internal Medicine, General University Hospital of Ioannina
  • Larissa, Greece
    • Department of Internal Medicine, University General Hospital of Larissa,
  • Patra, Greece
    • Department of Internal Medicine, University General Hospital of Patras PANAGIA I VOITHIA
  • Piraeus, Greece
    • 2nd Department of Internal Medicine, General Hospital of Piraeus TZANEIO
  • Thessaloníki, Greece
    • 1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki
  • Thessaloníki, Greece
    • 1st Department of Internal Medicine, PAPAGEORGIOU General Hospital of Thessaloniki
  • Thessaloníki, Greece
    • 2nd Department of Propedeutic Medicine, Ippokrateion University General Hospital of Thessaloniki
  • Thessaloníki, Greece
    • 3rd University Department of Internal Medicine, PAPAGEORGIOU General Hospital of Thessaloniki
• Italy
  • Brescia, Italy
    • Dipartimento di Medicina Dipartimento di Malattie Infettive, ASST Spedali civili
  • Genova, Italy
    • Unità Operativa Clinica Malattie Infettive, Ospedale Policlinico San Martino
  • Milano, Italy
    • Dipartimento di Medicina Interna, Istituto Clinico Humanitas
  • Milano, Italy
    • Medicina Interna, Reumatologia, Immunologia, IRCCS San Raffaele
  • Negrar, Italy
    • Dipartimento di Malattie Infettive e Tropicali e Microbiologia, IRCCS Ospedale Sacro Cuore Don Calabria
  • Roma, 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
  • Varese, Italy
    • Dipartimento di Malattie infettive e tropicali-Università dell'Insubria, ASST dei Sette Laghi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Patients receiving standard-of-care (SOC) and placebo. Placebo is injected subcutaneously once daily for 10 days	Drug: Placebo; Standard-of-care and placebo. Placebo is injected subcutaneously once daily for 10 days
Experimental: Anakinra; Patients receiving SOC and anakinra. Anakinra is injected subcutaneously as 100 mg once daily for 10 days	Drug: Anakinra; Standard-of-care and anakinra. Anakinra is injected subcutaneously as 100 mg once daily for 10 days; Other Names: Kineret

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Comparison of the distribution of frequencies of each score of the 5-scale patient state evaluated from the 11-point WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment by Day 28. This will be expressed as the distribution of the frequencies of each score of the scale in each arm of treatment by Day 28. The scale ranges from 0 (best outcome-asymptomatic) to 11 (worst outcome-death).	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)	Comparison of the absolute change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment. The scale ranges from 0 (best outcome-asymptomatic) to 11 (worst outcome-death).	28 days
Relative change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)	Comparison of the relative change (%) of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment. The scale ranges from 0 (best outcome-asymptomatic) to 11 (worst outcome-death).	28 days
Absolute change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)	Comparison of the absolute change of the measure of the 11-point of WHO Clinical Progression nordinal Scale (CPS) between the two arms of treatment. The scale ranges from 0 (best outcome-asymptomatic) to 11 (worst outcome-death).	14 days
Relative change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)	Comparison of the relative (%) change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment. The scale ranges from 0 (best outcome-asymptomatic) to 11 (worst outcome-death).	14 days
Absolute change of the SOFA score	Comparison of the absolute change of the SOFA score (in points) between the two arms of treatment	14 days
Relative change of the SOFA score	Comparison of the relative (%) change of the SOFA score (in points) between the two arms of treatment	14 days
Absolute change of the SOFA score	Comparison of the absolute change of the SOFA score between the two arms of treatment	7 days
Relative change of the SOFA score	Comparison of the relative (%) change of the SOFA score between the two arms of treatment	7 days
Time until hospital discharge	Comparison of the time until hospital discharge between the two arms of treatment	90 days
Time until discharge from the intensive care unit	Comparison of the time until discharge from the intensive care unit between the two arms of treatment	90 days
Comparison of the rate of serious and non-serious adverse events between the two arms of treatment	Comparison of the rate of serious and non-serious adverse events between the two arms of treatment	90 days
Comparison of the rate of serious and non-serious adverse events between the two arms of treatment	Comparison of the rate of serious and non-serious adverse events between the two arms of treatment	60 days
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	Comparison of the relative changes of circulating concentrations of suPAR (μg/liter),D-dimers (μg/liter), ferritin (μg/liter), and Interleukin-6 (μg/liter) between the two arms of treatment	7 days
Relative changes of circulating concentrations of C-reactive protein (mg/liter) by Day 7 from baseline Day 1	Comparison of the relative changes of circulating concentrations of C-reactive protein (mg/liter) between the two arms of treatment	7 days
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	Comparison of the relative changes of circulating concentrations of suPAR (μg/liter),D-dimers (μg/liter), ferritin (μg/liter), and Interleukin-6 (μg/liter) between the two arms of treatment	4 days
Relative changes of circulating concentrations of C-reactive protein (mg/liter) by Day 4 from baseline Day 1	Comparison of the relative changes of circulating concentrations of C-reactive protein (mg/liter) between the two arms of treatment	4 days
Absolute change of the viral load by Day 7 from baseline Day 1	Comparison of the absolute change of the viral load (in copies) between the two arms of treatment	7 days
Relative change of the viral load by Day 7 from baseline Day 1	Comparison of the relative (%) change of the viral load between the two arms of treatment	7 days
Absolute change of the viral load by Day 4 from baseline Day 1	Comparison of the absolute change of the viral load (in copies) between the two arms of treatment	4 days
relative change of the viral load by Day 4 from baseline Day 1	Comparison of the relative change (%) of the viral load between the two arms of treatment	4 days
Transcriptomic analysis	Expression of messenger Ribonucleic Acid (mRNA) will be compared between the two arms of treatment	7 days
Proteomic analysis	Protein composition will be compared between the two arms of treatment	7 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cost of hospitalization	Comparison of the cost of hospitalization between the two arms of treatment	90 days
Comparison of the distribution of frequencies of each score of a 5-scale patient state	Comparison of the distribution of frequencies of each score of the 5-scale patient state evaluated from the 11-point WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment by Day 28. This will be expressed as the distribution of the frequencies of each score of the scale in each arm of treatment by Day 60. The scale ranges from 0 (best outcome outpatients) to 5 (worst outcome-death)	60 days
Comparison of the distribution of frequencies of each score of a 5-scale patient state	Comparison of the distribution of frequencies of each score of the 5-scale patient state evaluated from the 11-point WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment by Day 28. This will be expressed as the distribution of the frequencies of each score of the scale in each arm of treatment by Day 90. The scale ranges from ) (best outcome-outpatients) to 5 (worst outcome-death)	90 days

Collaborators and Investigators

• Sponsor: Hellenic Institute for the Study of Sepsis
• Investigators: Study Chair: Evangelos Giamarellos-Bourboulis, MD, PhD, Hellenic Institute for the Study of Sepsis

Study record dates

Study Major Dates

• Study Start (Actual): December 23, 2020
• Primary Completion (Actual): March 31, 2021
• Study Completion (Actual): February 6, 2022

Study Registration Dates

• First Submitted: December 18, 2020
• First Submitted That Met QC Criteria: December 22, 2020
• First Posted (Actual): December 23, 2020

Study Record Updates

• Last Update Posted (Actual): September 6, 2022
• Last Update Submitted That Met QC Criteria: September 2, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: SARS-CoV 2; anakinra
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Respiratory Insufficiency; Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: SAVE-MORE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No