Interleukin-6 Antagonists in Critically-ill Covid-19 Patients

Study Overview
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Brief Summary
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The emerging SARS-COV2 virus has shed a new light on the cross-talks between the immune and the hemostatic system. In this study we aim to evaluate the dynamic change in coagulation caused by the modulation of the inflammatory response by interleukin-6 antagonist as assessed by viscoelastic methods in critically ill COVID-19 patients. Furthermore we try to draw attention to possible associations between the endothelial cell injury, inflammation and coagulation.

Detailed Description
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The emerging SARS-COV2 virus has shed new light on the cross-talk between the immune and the hemostatic system. Pathophysiologically in COVID-19 infection the thrombo-inflammatory process is initiated by the host's exaggerated systemic inflammatory response, also called dysregulated immune response that activates both the inflammatory and the coagulation cascade directly by inflammatory mediators and indirectly by causing endothelial cell injury. These mechanisms altogether contribute to the imbalance of the hemostasis that is characterized by a procoagulant state. In this multicenter prospective observational study, we aim to evaluate the dynamic change in coagulation as a result of immunomodulation by interleukin-6 antagonists in critically ill COVID-19 patients. We will assess the hemostatic system by a viscoelastic hemostasis assay (Clotpro, Haemonetics Corporation, Boston). Furthermore, we try to draw attention to possible associations between endothelial cell injury, inflammation, and coagulation. To compare these parameters we will draw blood for analysis before administration of IL-6 antagonist then 24h after, 48h after, and 7 days after.

Official Title
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Effects of Immunomodulation With Interleukin-6 Antagonists on the Coagulation System in Critically-ill Covid-19 Patients

Conditions
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COVID-19, Critical Illness

Intervention / Treatment
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* Drug: IL6 Antagonist


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (>18 years old) Clinical diagnosis of SARS-CoV2 infection with rtPCR confirmation Disease severity with the indication of immunomodulation therapy with interleukin-6 antagonist: acute respiratory failure that requires invasive, noninvasive ventilation , or high flow nasal oxygen therapy with the following parameters: FiO2 > 0,4, flow > 30L/min and C Reactive Protein > 75 mg/L Exclusion Criteria: The patient had previously been administered one of the following immunomodulating drug: anakinra, tocilizumab, sarilumab Presence of any condition or drug in the medical history that can lead to immunosuppression Suspicion of infection (active tuberculosis, bacterial, viral, fungal) or level of procalcitonine higher than 0,5 ng/ml at the enrollment of the patient Number of thrombocyte lower than 50 x 109 / L More than >120 hours passed between the admission to the ICU and the administration of interleukin-6 antagonist Administration of any of the following drugs the week before or during the study: fibrinolytic therapy, factor products (PCC, ATIII, FVIIa, FXIII), fibrinogen, desmopressin, tranexamic acid, blood products (FFP, thrombocyte concentrate) Pregnancy The patient or his legal guardian does not sign the consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Critically ill COVID-19 patients<br>Patients in ICU due to critical COVID-19 infection, who receive early (within the first 24 hours, but no later than 48 hours after intubation) IL-6 antagonist therapy at the consultant's discretion. | Drug: IL6 Antagonist<br>* Patients will receive IL-6 antagonist therapy at the consultant's discretion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the lysis time | Change of the fibrinolytic system before (T0) and after immunomodulation therapy, measured by the lysis time (LT). | 48 hours | 
| Change in the lysis onset time | Change of the fibrinolytic system before (T0) and after immunomodulation therapy, measured by the lysis onset time (LOT). | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the lysis time | Change of the fibrinolytic system before (T0) and after immunomodulation therapy, measured by the lysis time (LT). | 24 hours and 7 days | 
| Change in the lysis onset time | Change of the fibrinolytic system before (T0) and after immunomodulation therapy, measured by the lysis onset time (LOT). | 24 hours and 7 days | 
| Change in Clotpro assay | Change in blood coagulation parameters which evaluate hypercoagulable state before (T0) and after immunomodulation therapy (T1,2,3) measured by Clotpro device assays. | 24 hours, 48 hours, and 7 days | 
| Correlation between procalcitonin and Clotpro | Correlation between inflammatory and blood coagulation parameters. For the assessment of this endpoint, we will use the results of the inflammatory laboratory parameters as procalcitonin and the blood coagulation parameters measured by the Clotpro. | 24 hours, 48 hours, and 7 days | 
| Correlation between C reactive protein and Clotpro | Correlation between inflammatory and blood coagulation parameters. For the assessment of this endpoint, we will use the results of the inflammatory laboratory parameters as C reactive protein and the blood coagulation parameters measured by the Clotpro. | 24 hours, 48 hours, and 7 days | 
| Correlation between ferritin and Clotpro | Correlation between inflammatory and blood coagulation parameters. For the assessment of this endpoint, we will use the results of the inflammatory laboratory parameters as ferritin and the blood coagulation parameters measured by the Clotpro. | 24 hours, 48 hours, and 7 days | 
| Correlation between lactate dehydrogenase and Clotpro | Correlation between inflammatory and blood coagulation parameters. For the assessment of this endpoint, we will use the results of the inflammatory laboratory parameters as lactate dehydrogenase and the blood coagulation parameters measured by the Clotpro. | 24 hours, 48 hours, and 7 days | 
| Correlation between syndecan-1 and Clotpro | Correlation between biomarkers of endothelial injury and blood coagulation parameters. For the assessment of this endpoint, we will use the results of the biomarkers of the endothelial damage as syndecan-1 and the blood coagulation parameters measured by the Clotpro. | 24 hours, 48 hours, and 7 days | 
| Correlation between thrombomodulin and Clotpro | Correlation between biomarkers of endothelial injury and blood coagulation parameters. For the assessment of this endpoint, we will use the results of the biomarkers of the endothelial damage as thrombomodulin and the blood coagulation parameters measured by the Clotpro. | 24 hours, 48 hours, and 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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severe COVID-19, interleukin-6 antagonist, ClotPro, viscoelastic hemostasis assay