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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Covid19

Intervention / Treatment
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* Drug: Anakinra
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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. 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. Confirmed infection by SARS-CoV-2 virus Findings in chest-X-ray or in chest computed tomography compatible with lower respiratory tract infection 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. 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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).
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV 2, anakinra