Defibrotide as Prevention and Treatment of Respiratory Distress and Cytokine Release Syndrome of Covid 19.

Study Overview
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Brief Summary
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Protection of endothelial dysfunction by intravenous infusion of Defibrotide (Defitelio), expected to decrease inflammation and expression of adhesion molecules in the endothelium, leukocyte tissue infiltration and epithelial destruction, and to promote immune tolerance through a change in the Cytokine balance, which is decisive in preventing multiorgan failure and death in patients with SARS-CoV-2 infection with clinical status grade 4 or 5 according to the WHO classification

Detailed Description
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Protection of endothelial dysfunction by intravenous infusion of Defibrotide (Defitelio), expected to decrease inflammation and expression of adhesion molecules in the endothelium, leukocyte tissue infiltration and epithelial destruction, and to promote immune tolerance through a change in the Cytokine balance, which is decisive in preventing multiorgan failure and death in patients with SARS-CoV-2 infection with clinical status grade 4 or 5 according to the WHO classification

Official Title
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Phase IIb Prospective, Multi-center, Randomized, Parallel, Double Blind, Placebo Controlled Trial to Evaluate Defibrotide Intravenous Infusion in the Prevention and Treatment of COVID-19 Respiratory Distress and Cytokine Release Syndrome

Conditions
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COVID19

Intervention / Treatment
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* Drug: Defibrotide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acceptance of participation in the study by the patient or legal representative. Patients of any gender, 18 years or older. Confirmed diagnosis by PCR+ of SARS-CoV-2 infection. COVID-19 positive patients WHO grades 4, 5 or 6. Grade 4: hospitalized requiring oxygen therapy. Grade 5: hospitalized requiring high-flow oxygen therapy, noninvasive mechanical ventilation, or both. Levels of IL-6 ≥ 3 times the upper limit of normality Exclusion Criteria: Acute bleeding. Thrombolytic treatment and anticoagulant treatment at therapeutic doses. Pregnancy or lactation. Patients with active malignant tumour, other serious systemic or neuropsychiatric diseases. Patients participating in other clinical trials in the last month. Inability to give informed consent or to accomplish the requirements of the diagnostic tests. Patients with hypersensitivity to Defibrotide.

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: Phase IIb prospective, multi-center, randomized, parallel, double blind, placebo controlled
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Defibrotide + standard therapy<br>Defibrotide + standard therapy | Drug: Defibrotide<br>* 6.25 mg/kg every 6 hours in 2 hours infusion for 7 or 15 days<br>|
| Placebo Comparator: Placebo<br>Placebo + standard therapy | Drug: Placebo<br>* Placebo 250 cc every 6 hours for 7 or15 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical improvement. | Number of days that the patient maintains the clinical improvement. The patient achieves a change of al least 1 category on WHO scale. | 7,15, 30 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. Mortality rate | All cause mortality | : up to 30 days | 
| Rate os serious adverse events . | Number of adverse events with possible, probable or definite relationship with the study. | 7, 15, 30 and 60 Day | 
| Clinical improvement by WHO | Decrease ventilation days in grade 6 patients | 7, 15, 30 and 60 Day | 
| Clinical improvement by NEWS2 scales | Decrease the rate of grades 4-5 patients requiring mechanical ventilation. | 7, 15, 30 and 60 Day | 
| Clinical improvement by NEWS2 scales | Decrease ventilation days in grade 6 patients | 7, 15, 30 and 60 Day | 
| Biologic response | Decrease of IL-6 levels with respect to the basal ones > 50%. | 7, 15, 30 and 60 Day | 
| Biologic response | Absolute lymphocytes count: 50% increase with respect to the baseline | 7, 15, 30 and 60 Day | 
| Biologic response | Normal D-dimer (DD) or decrease of 50% with respect to the baseline | 7, 15, 30 and 60 Day | 
| Biologic response | Normal CRP or decrease of 50% with respect to the baseline | 7, 15, 30 and 60 Day | 
| Biologic response | Normal LDH or decrease of 50% with respect to the baseline | 7, 15, 30 and 60 Day | 
| Biologic response | Normal CPK or decrease of 50% with respect to the baseline | 7, 15, 30 and 60 Day | 
| Biologic response | Normal Ferritin or decrease of 50% with respect to the baseline | 7, 15, 30 and 60 Day | 
| Radiological response | Improvement of radiological images by conventional radiology | 7, 15, 30 and 60 Day | 
| Collection and storage of biological samples | improve the knowledge of the disease at the inclusion of the patients | 15,30 days | 
| Clinical improvement by WHO | Decrease the rate of grades 4-5 patients requiring mechanical ventilation. | 7, 15, 30 and 60 Day |