Personalised Immunotherapy for SARS-CoV-2 (COVID-19) Associated With Organ Dysfunction

Study Overview
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Brief Summary
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Our aim is to conduct one trial of personalized immunotherapy in patients with SARS-CoV-2 (COVID-19) associated with organ dysfunction and with laboratory findings of macrophage activation syndrome or immune dysregulation. These patients will be selected by the use of a panel of biomarkers and laboratory findings and they will be allocated to immunotherapy treatment according to their needs.

Detailed Description
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Humanity is experiencing since November 2019 a new pandemic by the novel SARS Coronavirus-19 (SARS-CoV-2). As of March 16 2020 170,191 documented case were reported worldwide of which 6,526 died1. The analysis of the clinical characteristics of these patients showed that among those who were critically ill with acute respiratory failure the risk of death was as high as 60%2. Main clinical feature is the presence of comorbidities and age more than 60 years whereas main laboratory findings are leukopenia and lymphopenia with hepatic dysfunction and increase of D-dimers3,4. It is also reported that these patients suffer from intense pro-inflammation where hyper-cytokinemia predominates5,6. The above characteristics lead to consider two main mechanisms of pathogenesis of this critical condition: macrophage activation syndrome (MAS) and immune dysregulation. Early and correct understanding of the mechanism and management are of prime importance. This can be achieved only through a therapeutic protocol where the early recognition of the immune state can be done with the use of biomarkers and with the delivery of the precise treatment aiming to the correction of the immune dysregulation. Data of the Hellenic Sepsis Study Group indicate that MAS can be diagnosed with reliability using serum ferritin7. Concentrations greater than 4,420ng/ml possess diagnostic specificity 97.3% and negative predictive value 98%. According to these data, the risk of developing MAS is greater among patients with comorbidities like type 2 diabetes mellitus and heart failure who are prone to hyper-production of interleukin (IL)-1β by tissue macrophages8. A recent retrospective analysis of patients with severe sepsis and MAS showed that the administration of anakinra decreased 28-day mortality by 30%9. Anakinra is the recombinant antagonist of human IL-1β receptor. IL-1β over-production is the hallmark of the pathogenesis of MAS. Results of a phase III study in 906 patients showed that anakinra was a very safe drug: there was neither excess mortality nor increased susceptibility to secondary infections9. Since November 2017 the randomized clinical trial entitled A trial of validation and restoration of immune dysfunction in severe infections and sepsis, PROVIDE (EudraCT number: 2017-002171-26, approval 78/17 by the National Ethics Committee, approval IS 75/17 by the National Organization for Medicines, ClinicalTrials.gov NCT03332225). In this study patients with sepsis and laboratory diagnosis of MAS are randomized to treatment with placebo or anakinra for seven days. Enrolment was completed in December 2019 and no drug related adverse events have been reported. Recent unpublished data of the Hellenic Sepsis Study Group demonstrate that patients with immune dysregulation have profound lymphopenia associated with elevated IL-6. This is in accordance with evidence of the H1N1 pandemic where patients with pneumonia had substantial lymphopenia and increased Τ regulatory lymphocytes (Treg). This increase of Τreg was prominent among patients with comorbidities like diabetes mellitus, chronic heart failure and chronic obstructive pulmonary disease10,11. The IL-6 blocker tocilizumab is a promising candidate for the reversal of this immune dysregulation. ESCAPE is an address to the personalized management of life-threatening organ dysfunction by SARS-CoV-2. More precisely, patients infected by SARS-CoV-2 associated with MAS and immune dysregulation will be administered treatment with anakinra and tocilizumab respectively.

Official Title
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Efficiency in Management of Organ Dysfunction Associated With Infection by the Novel SARS-CoV-2 Virus (COVID-19) Through a Personalized Immunotherapy Approach: the ESCAPE Clinical Trial

Conditions
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COVID-19, Virus Diseases, Macrophage Activation Syndrome, Corona Virus Infection

Intervention / Treatment
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* Drug: Anakinra
* Drug: Tocilizumab


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 or by one first-degree relative/spouse in case of patients unable to consent Confirmed infection by SARS-CoV-2 virus using molecular techniques as defined by the World Health Organization11 Organ dysfunction defined as the presence of at least one of the following conditions: Total SOFA score greater than or equal to 2; Involvement of the lower respiratory tract Laboratory documentation of MAS or immune dysregulation. MAS is documented by the findings of any serum ferritin greater than 4,420ng/ml. immune dysregulation is documented by the combination of two findings: a) serum ferritin equal to or lower than 4,420ng/ml; and b) less than 5,000 receptors of the membrane molecule of HLA-DR on the cell membrane of blood CD14-monocytes or less than 30 MFI of HLA-DR on the cell membrane of blood CD14-monocytes as counted by flow cytometry Exclusion Criteria: Age below 18 years Denial for written informed consent Any stage IV malignancy Any do not resuscitate decision Active tuberculosis (TB) as defined by the co-administration of drugs for the treatment of TB Infection by the human immunodeficiency virus (HIV) Any primary immunodeficiency Oral or IV intake of corticosteroids at a daily dose equal or greater than 0.4 mg prednisone or greater the last 15 days. Any anti-cytokine biological treatment the last one month Medical history of systemic lupus erythematosus Medical history of multiple sclerosis or any other demyelinating disorder. Pregnancy or lactation. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study

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: Non-Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Treatment with tocilizumab or anakinra
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: anakinra<br>In case of diagnosis of MAS, IV anakinra 200mg three times daily (every eight hours) for 7 days. Patients who will receive anakinra treatment and who suffer from kidney dysfunction will receive 50% of the dose i.e. 100mg anakinra three times daily for 15 days | Drug: Anakinra<br>* In case of diagnosis of MAS treatment with anakinra<br>* Other names: kineret;|
| Experimental: tocilizumab<br>In case of diagnosis of immune dysregulation IV tocilizumab 8mg/kg body weight once up to a maximum of 800mg. These patients will receive anakinra at the above dose in case they meet one of the following contra-indications for tocilizumab: absolute neutrophil count less than 2,500/mm3; absolute platelet count less than 100,000/mm3; and AST or ALT more than 1.5 x the upper normal limit | Drug: Tocilizumab<br>* In case of diagnosis of immune dysregulation treatment with tocilizumab<br>* Other names: RoActemra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of baseline total sequential organ failure assessment (SOFA) score | At least 25% decrease between baseline sequential organ failure assessment SOFA score and measured sequential organ failure assessment SOFA score at Study Day 8 | Visit study day 8 | 
| Improvement of lung involvement measurements | Resolution of all criteria of lower respiratory tract involvemed that led to study inclusion (except findings from imaging studies) at Study Day 8 | Visit study day 8 | 
| Increase of pO2/FiO2 ratio | At least 50% increase of pO2/FiO2 ratio between baseline and study visit Day 8 | Visit Study Day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of change of baseline total sequential organ failure assessment (SOFA) score in enrolled subjects towards historical comparators | Change of total sequential organ failure assessment (SOFA) score between baseline and study visit day 8 will be compared with historical comparators from Hellenic Sepsis Study Group Database (Sequential organ failure assessment range 0-24, high score associated with worst outcome) | Screening, Day 8 | 
| Comparison of change of lung involvement measurements in enrolled subjects towards historical comparators | Change of lung involvement measurements between baseline and study visit day 8 will be compared with historical comparators from Hellenic Sepsis Study Group Database | Screening, Day 8 | 
| Comparison of pO2/FiO2 ratio in enrolled subjects towards historical comparators | Comparison of increase in pO2/FiO2 ratio towards historical comparators from Hellenic Sepsis Study Group Database | Screening, Day 8 | 
| Change of sequential organ failure assessment (SOFA) score | Change of Sequential organ failure assessment (SOFA) score on day 28 (Sequential organ failure assessment range 0-24, high score associated with worst outcome) | Day 28 | 
| Rate of Mortality | Mortality on day 28 | Day 28 | 
| Rate of Mortality | Mortality on day 90 | Day 90 | 
| Cytokine stimulation | Cytokine stimulation from peripheral blood mononuclear cells will be compared between days 0 and 4 | Screening, Day 4 | 
| Gene expression | Gene expression of peripheral blood mononuclear cells will be compared between days 0 and 4 | Screening, Day 4 | 
| Serum/plasma proteins | Change of serum/plasma proteins between days 0 and 4 | Screening, Day 4 | 
| Classification of the immune function | Classification of immune function of screened patients who are not enrolled in study drug since they are not characterized with MAS or immune dysregulation | Screening | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, SARS-CoV-2, MAS, Anakinra, Tocilizumab