Acute Respiratory Distress Syndrome, COVID, COVID-19, Sars-CoV2
Conditions
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.
Interventions
DRUGDefibrotide
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).
Sponsors
Jazz Pharmaceuticals
Gregory Yanik
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 28 days | Number of patients who are alive at Day 28 after starting treatment. |
| 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). |
Countries
United States
Participant flow
Pre-assignment details
Of 13 enrolled, 1 participant was screen failed and did not receive any defibrotide.
Participants by arm
| Arm | Count |
|---|---|
| Defibrotide Defibrotide: All patients received 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 was 7 days (while in the hospital), with the following qualifications:
* Patients who responded to study therapy prior to day 7 (able to discontinue oxygen) discontinued study therapy at that earlier time point.
* Patients who did not respond to study therapy by day 7 of therapy, evidenced by \<20% reduction (or a worsening) of the amount of supplemental oxygen they were receiving, discontinued study therapy at day 7.
* Patients who had evidence of a partial pulmonary response by day 7 (\>20% reduction in supplemental oxygen requirement, but still requiring supplemental oxygen) could elect to continue to receive study drug through an additional 7 days of study (total 14-day therapy course). | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Defibrotide |
|---|---|
| Age, Customized 18-29 years | 0 Participants |
| Age, Customized 30-39 years | 2 Participants |
| Age, Customized 40-49 years | 1 Participants |
| Age, Customized 50-59 years | 2 Participants |
| Age, Customized 60-69 years | 4 Participants |
| Age, Customized 70-79 years | 3 Participants |
| Age, Customized >80 years | 0 Participants |
| anticoagulant used Heparin | 1 Participants |
| anticoagulant used Low Molecular weight Heparin | 2 Participants |
| anticoagulant used None | 9 Participants |
| D-dimer (mcg/ml) | 3.25 mcg/ml |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| FiO2 | 55 Percent |
| O2 support mechanical ventilation | 10 Participants |
| O2 support nasal cannula/ mask | 2 Participants |
| Onset (time in days from diagnosis of SARS - CoV2 to onset of study therapy | 9 days |
| PaO2/FiO2 | 137 mmHg |
| Platelets (K/microliter) | 226 (K/microliter) |
| Pressors | 6 Participants |
| Prior Therapy Dexamethasone and remdesivir | 9 Participants |
| Prior Therapy Dexamethasone and remdesivir and tocilizumab | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 12 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 10 Participants |
| WHO Ordinal Score at Study Entry WHO score of 4 | 2 Participants |
| WHO Ordinal Score at Study Entry WHO score of 6 | 4 Participants |
| WHO Ordinal Score at Study Entry WHO score of 7 | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 12 |
| other Total, other adverse events | 9 / 12 |
| serious Total, serious adverse events | 6 / 12 |
Outcome results
Primary
Number of Major Hemorrhagic Complications Within 14 Days of Initiation of Treatment
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.
Time frame: 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Defibrotide | Number of Major Hemorrhagic Complications Within 14 Days of Initiation of Treatment | 0 Participants |
Secondary
Mean Change in the WHO COVID-19 Ordinal Scale During Therapy
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).
Time frame: up to 14 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Defibrotide | Mean Change in the WHO COVID-19 Ordinal Scale During Therapy | -1 score on a scale |
Secondary
Number of Ventilator Free Days Within 14 Days of Study Entry
Time frame: 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Defibrotide | Number of Ventilator Free Days Within 14 Days of Study Entry | 0 days |
Secondary
Overall Survival
Number of patients who are alive at Day 28 after starting treatment.
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Defibrotide | Overall Survival | 10 Participants |
Secondary
Overall Survival
Number of patients who are alive at Day 14 after starting treatment.
Time frame: 14 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Defibrotide | Overall Survival | 11 participants |
Secondary
The Time to Improvement in Oxygenation
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.
Time frame: up to 14 days
Population: 4 participants had improvement by day 14
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Defibrotide | The Time to Improvement in Oxygenation | 4 days |
Secondary
Ventilator-free Survival
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.
Time frame: 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Defibrotide | Ventilator-free Survival | 5 Participants |