Back to resultsDefibrotide Therapy for SARS-CoV2 (COVID-19) Acute Respiratory Distress Syndrome (ARDS)
Primary Purpose
COVID, Sars-CoV2, COVID-19
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Defibrotide
Sponsored by
About this trial
This is an interventional treatment trial for COVID
Eligibility Criteria
Inclusion Criteria:
- Presence of SARS-CoV2 infection, confirmed by real-time reverse transcription polymerase chain reaction (RT-PCR) assay from a nasopharyngeal swab specimen or other diagnostic test for SARS-CoV2.
- Serum D-Dimer ≥ 2.0 mcg/ml.
Patients with Acute Respiratory Distress Syndrome (ARDS) as determined by the following criteria (Berlin criteria adaptation):
- Radiographic evidence of bilateral lung disease (opacities or ground glass opacification) on chest radiograph (CXR) or computed tomography (CT), and the opacities not fully explained by pleural effusions, cardiac failure or fluid overload.
- Impairment of oxygenation, as defined by the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2) ≤ 300 mmHg (millimeters of mercury).
- Patients must provide voluntary written informed consent to be eligible for study. For patients who are medically unable to provide consent, their designated proxy or legal guardian will provide informed consent. The consenting process is described in Appendix II.
- Patients actively participating in another clinical trial for the management of SARS-CoV2 are eligible provided those trials do not directly involve an anti-platelet, anti-coagulant or anti-fibrinolytic agent. (Patients enrolled on investigational trials utilizing anti-viral specific agents, cytokine inhibitors, tyrosine kinase inhibitors, or other anti-inflammatory agents are still eligible).
Exclusion Criteria:
- Concomitant use of heparin, systemic anticoagulants, and/or fibrinolytics are not permitted within 12 hours, with the exception of heparin flushes for centrally placed catheters, fibrinolytic instillation for central venous line occlusion, or in the in-flow circuit for patients on continuous veno-venous hemodialysis.
- Clinically significant acute bleeding, including (but not limited to one of the following): pulmonary hemorrhage (diffuse alveolar hemorrhage), intracranial bleed, gastro-intestinal hemorrhage (gross hematemesis or hematochezia), gross hematuria or uncontrolled epistaxis irrespective of the amount of blood loss, within the prior 3 days.
- On mechanical ventilation for > 96 consecutive hours.
- Serum platelet count < 50,000/Microliters (uL). Transfusion of platelets to achieve a level > 50,000/uL is not allowed for eligibility.
- Serum fibrinogen < 150 mg/dl. Transfusion of fresh frozen plasma or cryoprecipitate to achieve a level > 150 mg/dl is not allowed for eligibility.
- Positive blood culture for a bacterial pathogen within the prior 24 hours prior to study entry, and/or the presence of bacterial pneumonia.
- Hemodynamic instability as defined by a requirement for 2 or more vasopressors (not including renal-doses of dopamine).
- Concurrent use of Extracorporeal membrane oxygenation (ECMO).
- Patients with a previously known hypersensitivity reaction to defibrotide, or any of its excipients.
- Females who are pregnant or breastfeeding.
- History of cerebrovascular accident (i.e. thrombotic or hemorrhagic stroke) within 3 months prior to study entry.
Sites / Locations
- University of Michigan
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Defibrotide
Arm Description
Outcomes
Primary Outcome Measures
Number of Major Hemorrhagic Complications Within 14 Days of Initiation of Treatment
Major hemorrhagic complications will be based on the International Society on Thrombosis and Haemostasis Bleeding scale.
Fatal Bleeding, and/or
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome, and/or
Bleeding associated with a decline in hemoglobin level of > 2.0 g/dl, leading to transfusion of two or more units of whole blood or red cells.
In addition, symptomatic alveolar hemorrhage, macroscopic hematuria, uncontrolled menorrhagia or epistaxis or bleeding from any wound site would also be considered a major hemorrhagic event.
Secondary Outcome Measures
Overall Survival
Number of patients who are alive at Day 28 after starting treatment.
Overall Survival
Number of patients who are alive at Day 14 after starting treatment.
Ventilator-free Survival
Day 14 ventilator-free survival will be summarized by the number of patients who are both alive and not using a ventilator at Day 14 after starting treatment.
Number of Ventilator Free Days Within 14 Days of Study Entry
The Time to Improvement in Oxygenation
Improvement in oxygenation defined as an increase in ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) of 50 (or greater) compared to the nadir of PaO2/FiO2.
Mean Change in the WHO COVID-19 Ordinal Scale During Therapy
Ordinal scale:
= Ambulatory, no limitation of activities;
= Ambulatory, Activity LImited;
= Hospitalized, no oxygen therapy;
= Oxygen by mask or nasal cannula;
= Non-invasive ventilation or high-flow oxygen (O2);
= Intubation/mechanical ventilation;
= Intubation/Mechanical ventilation plus one of the following: Pressors, Extracorporeal membrane oxygenation (ECMO) or Dialysis;
= Decased/Death Key: For change in ordinal score, negative values represent a decline in WHO score from baseline to day 14 (improvement of condition); positive values represent an increase (worsening of condition).
Full Information
NCT ID
NCT04530604
First Posted
August 25, 2020
Last Updated
June 28, 2022
Sponsor
Gregory Yanik
Collaborators
Jazz Pharmaceuticals
1. Study Identification
Unique Protocol Identification Number
NCT04530604
Brief Title
Defibrotide Therapy for SARS-CoV2 (COVID-19) Acute Respiratory Distress Syndrome (ARDS)
Official Title
Defibrotide Therapy for SARS-CoV2 Acute Respiratory Distress Syndrome (ARDS)
Study Type
Interventional
2. Study Status
Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
October 1, 2020 (Actual)
Primary Completion Date
March 26, 2021 (Actual)
Study Completion Date
April 9, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Gregory Yanik
Collaborators
Jazz Pharmaceuticals
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
This clinical trial will enroll participants that have pneumonia caused by the COVID-19 virus. During the study patients will receive 7 to up to 14 days of defibrotide. After completing the treatment, participants will have 30 day follow-up check-up to assess for adverse events and clinical status. This final assessment can be done virtually, by telephone or electronically (email) if the patient cannot be contacted by phone. No in-person visit is required.
The hypothesis of this trial is that defibrotide therapy given to patients with severe SARS-CoV2 ARDS will be safe and associated with improved overall survival, within 28 days of therapy initiation.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID, Sars-CoV2, COVID-19, Acute Respiratory Distress Syndrome
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
13 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Defibrotide
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Defibrotide
Other Intervention Name(s)
defitelio
Intervention Description
All patients will receive 25 milligram/kilogram/day (mg/kg/day) of defibrotide, given in 4 divided doses (approximately every 6 hours), each dose infused over 2-hours intravenously (IV).
The planned duration of study therapy is 7 days (while in the hospital), with the following qualifications:
Patients who respond to study therapy prior to day 7 (able to discontinue oxygen) will discontinue study therapy at that earlier time point.
Patients who have not responded to study therapy by day 7 of therapy, evidenced by <20% reduction (or a worsening) of the amount of supplemental oxygen they are receiving, will discontinue study therapy at day 7.
Patients who have evidence of a partial pulmonary response by day 7 (>20% reduction in supplemental oxygen requirement, but still require supplemental oxygen) may elect to continue to receive study drug through an additional 7 days of study (total 14-day therapy course).
Primary Outcome Measure Information:
Title
Number of Major Hemorrhagic Complications Within 14 Days of Initiation of Treatment
Description
Major hemorrhagic complications will be based on the International Society on Thrombosis and Haemostasis Bleeding scale.
Fatal Bleeding, and/or
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome, and/or
Bleeding associated with a decline in hemoglobin level of > 2.0 g/dl, leading to transfusion of two or more units of whole blood or red cells.
In addition, symptomatic alveolar hemorrhage, macroscopic hematuria, uncontrolled menorrhagia or epistaxis or bleeding from any wound site would also be considered a major hemorrhagic event.
Time Frame
14 days
Secondary Outcome Measure Information:
Title
Overall Survival
Description
Number of patients who are alive at Day 28 after starting treatment.
Time Frame
28 days
Title
Overall Survival
Description
Number of patients who are alive at Day 14 after starting treatment.
Time Frame
14 days
Title
Ventilator-free Survival
Description
Day 14 ventilator-free survival will be summarized by the number of patients who are both alive and not using a ventilator at Day 14 after starting treatment.
Time Frame
14 days
Title
Number of Ventilator Free Days Within 14 Days of Study Entry
Time Frame
14 days
Title
The Time to Improvement in Oxygenation
Description
Improvement in oxygenation defined as an increase in ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) of 50 (or greater) compared to the nadir of PaO2/FiO2.
Time Frame
up to 14 days
Title
Mean Change in the WHO COVID-19 Ordinal Scale During Therapy
Description
Ordinal scale:
= Ambulatory, no limitation of activities;
= Ambulatory, Activity LImited;
= Hospitalized, no oxygen therapy;
= Oxygen by mask or nasal cannula;
= Non-invasive ventilation or high-flow oxygen (O2);
= Intubation/mechanical ventilation;
= Intubation/Mechanical ventilation plus one of the following: Pressors, Extracorporeal membrane oxygenation (ECMO) or Dialysis;
= Decased/Death Key: For change in ordinal score, negative values represent a decline in WHO score from baseline to day 14 (improvement of condition); positive values represent an increase (worsening of condition).
Time Frame
up to 14 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Presence of SARS-CoV2 infection, confirmed by real-time reverse transcription polymerase chain reaction (RT-PCR) assay from a nasopharyngeal swab specimen or other diagnostic test for SARS-CoV2.
Serum D-Dimer ≥ 2.0 mcg/ml.
Patients with Acute Respiratory Distress Syndrome (ARDS) as determined by the following criteria (Berlin criteria adaptation):
Radiographic evidence of bilateral lung disease (opacities or ground glass opacification) on chest radiograph (CXR) or computed tomography (CT), and the opacities not fully explained by pleural effusions, cardiac failure or fluid overload.
Impairment of oxygenation, as defined by the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2) ≤ 300 mmHg (millimeters of mercury).
Patients must provide voluntary written informed consent to be eligible for study. For patients who are medically unable to provide consent, their designated proxy or legal guardian will provide informed consent. The consenting process is described in Appendix II.
Patients actively participating in another clinical trial for the management of SARS-CoV2 are eligible provided those trials do not directly involve an anti-platelet, anti-coagulant or anti-fibrinolytic agent. (Patients enrolled on investigational trials utilizing anti-viral specific agents, cytokine inhibitors, tyrosine kinase inhibitors, or other anti-inflammatory agents are still eligible).
Exclusion Criteria:
Concomitant use of heparin, systemic anticoagulants, and/or fibrinolytics are not permitted within 12 hours, with the exception of heparin flushes for centrally placed catheters, fibrinolytic instillation for central venous line occlusion, or in the in-flow circuit for patients on continuous veno-venous hemodialysis.
Clinically significant acute bleeding, including (but not limited to one of the following): pulmonary hemorrhage (diffuse alveolar hemorrhage), intracranial bleed, gastro-intestinal hemorrhage (gross hematemesis or hematochezia), gross hematuria or uncontrolled epistaxis irrespective of the amount of blood loss, within the prior 3 days.
On mechanical ventilation for > 96 consecutive hours.
Serum platelet count < 50,000/Microliters (uL). Transfusion of platelets to achieve a level > 50,000/uL is not allowed for eligibility.
Serum fibrinogen < 150 mg/dl. Transfusion of fresh frozen plasma or cryoprecipitate to achieve a level > 150 mg/dl is not allowed for eligibility.
Positive blood culture for a bacterial pathogen within the prior 24 hours prior to study entry, and/or the presence of bacterial pneumonia.
Hemodynamic instability as defined by a requirement for 2 or more vasopressors (not including renal-doses of dopamine).
Concurrent use of Extracorporeal membrane oxygenation (ECMO).
Patients with a previously known hypersensitivity reaction to defibrotide, or any of its excipients.
Females who are pregnant or breastfeeding.
History of cerebrovascular accident (i.e. thrombotic or hemorrhagic stroke) within 3 months prior to study entry.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gregory Yanik, MD
Organizational Affiliation
University of Michigan
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
35413279
Citation
Frame D, Scappaticci GB, Braun TM, Maliarik M, Sisson TH, Pipe SW, Lawrence DA, Richardson PG, Holinstat M, Hyzy RC, Kaul DR, Gregg KS, Lama VN, Yanik GA. Defibrotide Therapy for SARS-CoV-2 ARDS. Chest. 2022 Aug;162(2):346-355. doi: 10.1016/j.chest.2022.03.046. Epub 2022 Apr 9.
Results Reference
derived
Learn more about this trial
Defibrotide Therapy for SARS-CoV2 (COVID-19) Acute Respiratory Distress Syndrome (ARDS)
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