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

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

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

Study Overview

• Status: Completed
• Conditions: COVID19
• Intervention / Treatment: Drug: Defibrotide; Drug: Placebo

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 156
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain
    • Hospital Clínico y Provincial de Barcelona
  • Murcia, Spain, 30120
    • Virgen de la Arrixaca University Clinical Hospital
  • Murcia, Spain
    • Hospital General Universitario Morales Meseguer
  • Murcia, Spain
    • Hospital General Universitario Reina Sofia
  • Salamanca, Spain
    • Hospital Universitario Salamanca
  • Murcia
    • Cartagena, Murcia, Spain
      • Hospital General Universitario Santa Lucía

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Acceptance of participation in the study by the patient or legal representative.
2. Patients of any gender, 18 years or older.
3. Confirmed diagnosis by PCR+ of SARS-CoV-2 infection.

4. 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.
5. Levels of IL-6 ≥ 3 times the upper limit of normality

Exclusion Criteria:

1. Acute bleeding.
2. Thrombolytic treatment and anticoagulant treatment at therapeutic doses.
3. Pregnancy or lactation.
4. Patients with active malignant tumour, other serious systemic or neuropsychiatric diseases.
5. Patients participating in other clinical trials in the last month.
6. Inability to give informed consent or to accomplish the requirements of the diagnostic tests.
7. Patients with hypersensitivity to Defibrotide.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fundacion para la Formacion e Investigacion Sanitarias de la Region de Murcia

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2020
• Primary Completion (Actual): February 28, 2023
• Study Completion (Actual): February 28, 2023

Study Registration Dates

• First Submitted: April 8, 2020
• First Submitted That Met QC Criteria: April 15, 2020
• First Posted (Actual): April 16, 2020

Study Record Updates

• Last Update Posted (Actual): June 7, 2023
• Last Update Submitted That Met QC Criteria: June 6, 2023
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Shock; COVID-19; Cytokine Release Syndrome; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Defibrotide
• Other Study ID Numbers: IMIB-DFC-2020-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No