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Defibrotide Therapy for SARS-CoV2 (COVID-19) Acute Respiratory Distress Syndrome (ARDS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04530604
Recruitment Status : Recruiting
First Posted : August 28, 2020
Last Update Posted : October 14, 2020
Sponsor:
Collaborator:
Jazz Pharmaceuticals
Information provided by (Responsible Party):
Gregory Yanik, University of Michigan

Tracking Information
First Submitted Date  ICMJE August 25, 2020
First Posted Date  ICMJE August 28, 2020
Last Update Posted Date October 14, 2020
Actual Study Start Date  ICMJE October 1, 2020
Estimated Primary Completion Date October 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 26, 2020)
Number of major hemorrhagic complications within 14 days of initiation of treatment [ Time Frame: 14 days ]
Major hemorrhagic complications will be based on the International Society on Thrombosis and Haemostasis Bleeding scale.
  1. Fatal Bleeding, and/or
  2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome, and/or
  3. 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.
  4. 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 26, 2020)
  • Overall survival [ Time Frame: 28 days ]
    Proportion of the twelve patients who are alive at day 28 after starting treatment.
  • Overall survival [ Time Frame: 14 days ]
    Proportion of the twelve patients who are alive at Day 14 after starting treatment.
  • Ventilator free survival [ Time Frame: 14 days ]
    Day 14 ventilator-free survival will be summarized by the proportion of the twelve 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 [ Time Frame: 14 days ]
  • The time to improvement in oxygenation [ Time Frame: up to 14 days ]
    Improvement in oxygenation defined as an increase in atio 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 [ Time Frame: up to 14 days ]
    Ordinal scale: Ambulatory (1) - No limitation of activities (2) - Limitations of activities Hospitalized: (3) no oxygen therapy (4) oxygen by mask or nasal prongs Hospitalized: (5) Non-invasive ventilation or high-flow oxygen (6) Intubation and mechanical ventilation (7) Mechanical ventilation plus additional organs support-pressors, renal replacement therapy (RRT), Extracorporeal membrane oxygenation (ECMO) Dead: (8) Death
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Defibrotide Therapy for SARS-CoV2 (COVID-19) Acute Respiratory Distress Syndrome (ARDS)
Official Title  ICMJE Defibrotide Therapy for SARS-CoV2 Acute Respiratory Distress Syndrome (ARDS)
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • COVID
  • Sars-CoV2
  • COVID-19
  • Acute Respiratory Distress Syndrome
Intervention  ICMJE Drug: Defibrotide

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).
Other Name: defitelio
Study Arms  ICMJE Experimental: Defibrotide
Intervention: Drug: Defibrotide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 26, 2020)
12
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 1, 2021
Estimated Primary Completion Date October 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Mary Maliarik, PhD 734-615-8627 marymali@umich.edu
Contact: Gregory Yanik, MD 734-764-3243 gyanik@umich.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04530604
Other Study ID Numbers  ICMJE HUM00182089
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Gregory Yanik, University of Michigan
Study Sponsor  ICMJE Gregory Yanik
Collaborators  ICMJE Jazz Pharmaceuticals
Investigators  ICMJE
Principal Investigator: Gregory Yanik, MD University of Michigan
PRS Account University of Michigan
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP