Defibrotide Therapy for SARS-CoV2 (COVID-19) Acute Respiratory Distress Syndrome (ARDS)
Condition: COVID; Sars-CoV2; COVID-19; Acute Respiratory Distress Syndrome
MeSH terms: COVID-19; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Syndrome
Intervention: Defibrotide
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).
Intervention MeSH terms: Defibrotide
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

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.
    

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.