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

• ClinicalTrials.gov Identifier: NCT04530604
• Recruitment Status: Recruiting
• First Posted: August 28, 2020
• Last Update Posted: October 14, 2020
• Sponsor: Gregory Yanik
• Collaborator: Jazz Pharmaceuticals
• Information provided by (Responsible Party): Gregory Yanik, University of Michigan

Tracking Information

• First Submitted Date: August 25, 2020
• First Posted Date: August 28, 2020
• Last Update Posted Date: October 14, 2020
• Actual Study Start Date: October 1, 2020
• Estimated Primary Completion Date: October 1, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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)

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: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• COVID
• Sars-CoV2
• COVID-19
• Acute Respiratory Distress Syndrome

Intervention

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

Experimental: Defibrotide

Intervention: Drug: Defibrotide

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 26, 2020): 12
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 1, 2021
• Estimated Primary Completion Date: October 1, 2021 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Mary Maliarik, PhD; 734-615-8627; marymali@umich.edu

Contact: Gregory Yanik, MD; 734-764-3243; gyanik@umich.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04530604
• Other Study ID Numbers: 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

• Plan to Share IPD: No

• Responsible Party: Gregory Yanik, University of Michigan
• Study Sponsor: Gregory Yanik
• Collaborators: Jazz Pharmaceuticals

Investigators

• Principal Investigator: Gregory Yanik, MD; University of Michigan

• PRS Account: University of Michigan
• Verification Date: October 2020