Clinical trial NCT04530604: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: COVID
Sars-CoV2
COVID-19
Acute Respiratory Distress Syndrome
Lead sponsor: University of Michigan
Sponsor class: OTHER
Collaborators: name: Jazz Pharmaceuticals
First posted: 2020-08-28
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Number of Major Hemorrhagic Complications Within 14 Days of Initiation of Treatment
timeFrame: 14 days
Secondary outcomes:
measure: Overall Survival
timeFrame: 28 days
measure: Overall Survival
timeFrame: 14 days
measure: Ventilator-free Survival
timeFrame: 14 days
measure: Number of Ventilator Free Days Within 14 Days of Study Entry
timeFrame: 14 days
measure: The Time to Improvement in Oxygenation
timeFrame: up to 14 days
measure: Mean Change in the WHO COVID-19 Ordinal Scale During Therapy
timeFrame: up to 14 days
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
Study officials:
affiliation: University of Michigan
name: Gregory Yanik, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.