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

Covid19 Clinical Trial

— SAVE-MORE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04680949
• Other study ID #: SAVE-MORE
• Status: Completed
• Phase: Phase 3
• Start date: December 23, 2020
• Est. completion date: February 6, 2022

Study information

• Verified date: September 2022
• Source: Hellenic Institute for the Study of Sepsis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 606
• Est. completion date: February 6, 2022
• Est. primary completion date: March 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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
• ?ny 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

Related Conditions & MeSH terms

• COVID-19
• Covid19
• Respiratory Insufficiency

Intervention

Drug:
• Anakinra
Standard-of-care and anakinra. Anakinra is injected subcutaneously as 100 mg once daily for 10 days
• Placebo
Standard-of-care and placebo. Placebo is injected subcutaneously once daily for 10 days

Locations

Country	Name	City	State
Greece	2nd Department of Internal Medicine, University General Hospital of Alexandroupolis	Alexandroupolis
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	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	Department of Pulmonary Medicine, General Hospital of Kerkyra	Corfu
Greece	1st Department of Internal Medicine, General University Hospital of Ioannina	Ioánnina
Greece	Department of Internal Medicine, University General Hospital of Larissa,	Larissa
Greece	Department of Internal Medicine, University General Hospital of Patras PANAGIA I VOITHIA	Patra
Greece	2nd Department of Internal Medicine, General Hospital of Piraeus TZANEIO	Piraeus
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	Thessaloníki
Italy	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	Milano
Italy	Medicina Interna, Reumatologia, Immunologia, IRCCS San Raffaele	Milano
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

Sponsors (1)

Lead Sponsor	Collaborator
Hellenic Institute for the Study of Sepsis

Countries where clinical trial is conducted

Greece,  Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Cost of hospitalization	Comparison of the cost of hospitalization between the two arms of treatment	90 days
Other	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
Other	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Absolute change of the SOFA score	Comparison of the absolute change of the SOFA score between the two arms of treatment	7 days
Secondary	Relative change of the SOFA score	Comparison of the relative (%) change of the SOFA score between the two arms of treatment	7 days
Secondary	Time until hospital discharge	Comparison of the time until hospital discharge between the two arms of treatment	90 days
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Transcriptomic analysis	Expression of messenger Ribonucleic Acid (mRNA) will be compared between the two arms of treatment	7 days
Secondary	Proteomic analysis	Protein composition will be compared between the two arms of treatment	7 days