Defibrotide Therapy for SARS-CoV2 (COVID-19) Acute Respir... | NCT04530604

NCT04530604

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
Jazz Pharmaceuticals	INDUSTRY

Description Module

Arms/Interventions Module

Label	Type	Description	Intervention Names
Defibrotide	Experimental		Drug: Defibrotide

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Defibrotide	Drug	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).

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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. Fatal Bleeding, and/or Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome, and/or 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. 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.	14 days

Secondary Outcomes

Measure	Description	Time Frame
Overall Survival	Number of patients who are alive at Day 28 after starting treatment.	28 days
Overall Survival	Number of patients who are alive at Day 14 after starting treatment.

Eligibility Module

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.

Name	Affiliation	Role
Gregory Yanik, MD	University of Michigan	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
University of Michigan		Ann Arbor	Michigan	48109	United States

PubMed Identifier	Type	Citation	Retractions
35413279	Derived	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.

Arm/Group Information

ID	Title	Description
FG000	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).

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	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).

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Customized			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

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.

Fatal Bleeding, and/or
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome, and/or
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.
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.

Posted

Count of Participants

Participants

14 days

ID	Title	Description
OG000	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).

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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).

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Pulmonary Bacterial Infection	Infections and infestations	CTCAE 5.0	Systematic Assessment	during treatment

ID	Term
D011024	Pneumonia, Viral
D011014	Pneumonia
D012141	Respiratory Tract Infections
D007239	Infections

ID	Term
D000086382	COVID-19
D012128	Respiratory Distress Syndrome