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

Phase 1

Completed

• Conditions: COVID; COVID-19; Sars-CoV2; Acute Respiratory Distress Syndrome
• Interventions: Drug: Defibrotide

• Registration Number: NCT04530604
• Lead Sponsor: Gregory Yanik

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 available

Study Timeline

• Study First Submitted: 2020-08-25
• Study First Submitted QC: 2020-08-26
• Study First Posted: 2020-08-28
• Study Start: 2020-10-01
• Primary Completion: 2021-03-26
• Study Completion: 2021-04-09
• Status Verified: 2022-06
• Results First Submitted: 2022-06-28
• Results First Submitted QC: 2022-06-28
• Last Update Submitted: 2022-06-28
• Results First Posted: 2023-05-09
• Last Update Posted: 2023-05-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 13

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).

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Defibrotide	Defibrotide	-

Primary Outcome Measures

Name	Time	Method
Number of Major Hemorrhagic Complications Within 14 Days of Initiation of Treatment	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.

Secondary Outcome Measures

Name	Time	Method
Ventilator-free Survival	14 days	Day 14 ventilator-free survival will be summarized by the number of 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	14 days
The Time to Improvement in Oxygenation	up to 14 days	Improvement in oxygenation defined as an increase in ratio 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	up to 14 days	Ordinal scale: 1. = Ambulatory, no limitation of activities; 2. = Ambulatory, Activity LImited; 3. = Hospitalized, no oxygen therapy; 4. = Oxygen by mask or nasal cannula; 5. = Non-invasive ventilation or high-flow oxygen (O2); 6. = Intubation/mechanical ventilation; 7. = Intubation/Mechanical ventilation plus one of the following: Pressors, Extracorporeal membrane oxygenation (ECMO) or Dialysis; 8. = Decased/Death Key: For change in ordinal score, negative values represent a decline in WHO score from baseline to day 14 (improvement of condition); positive values represent an increase (worsening of condition).
Overall Survival	14 days	Number of patients who are alive at Day 14 after starting treatment.

Trial Locations

Locations (1)

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States