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.
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
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.
University of Michigan
Ann Arbor, Michigan, United States
Gregory Yanik, MD, Principal Investigator
University of Michigan