Back to resultsDefibrotide in the Human Endotoxemia Model --- an Exploratory Trial Investigating the Effects and the Mechanisms of Defibrotide (LPS_DF)
Primary Purpose
Healthy Volunteers, Endotoxemia
Status
Completed
Phase
Phase 4
Locations
Austria
Study Type
Interventional
Intervention
Defibrotide
Placebo (0.9% sodium chloride)
Lipopolysaccharide
Placebo (0.9% sodium chloride bolus)
Sponsored by
About this trial
This is an interventional basic science trial for Healthy Volunteers focused on measuring Coagulation, Inflammation, Defibrotide, Fibrinolysis
Eligibility Criteria
Inclusion Criteria:
- >18 years of age
- <90kg body weight
- Normal findings in medical history and physical examination unless the investigator considers the abnormality to be clinically irrelevant
- Normal laboratory values unless the investigator considers abnormalities to be clinically irrelevant
- Ability to understand the purpose and nature of the study, as well as the associated risks
Exclusion Criteria:
- Intake of any drugs that may interfere with the trial's endpoints or drugs (i.e. platelet inhibitors, anticoagulants, etc.)
- Positive results of HIV or hepatitis virology
- Acute illness with systemic inflammatory reactions
- Known allergies, hypersensitivities or intolerances to any of the used substances
- Acute or recent bleeding episodes, increased risk of bleeding at the discretion of the investigator
- Participation in an LPS trial within 6 weeks of the first study day
- Pregnancy or breastfeeding
Sites / Locations
- Department of Clinical Pharmacology, Medical University of Vienna
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Active Comparator
Placebo Comparator
Other
Other
Arm Label
Defibrotide/LPS
Placebo/LPS
Defibrotide/Placebo
Placebo/Placebo
Arm Description
2ng/kg lipopolysaccharide period I: 6.25mg/kg bodyweight defibrotide or placebo (0.9% sodium chloride) period II: vice versa 16 healthy volunteers will receive 2ng/kg bodyweight LPS plus Defibrotide or Placebo 4 healthy volunteers will receive 0.9% saline (NO LPS) plus Defibrotide or Placebo
2ng/kg lipopolysaccharide period I: 6.25mg/kg bodyweight defibrotide or placebo (0.9% sodium chloride) period II: vice versa 16 healthy volunteers will receive 2ng/kg bodyweight LPS plus Defibrotide or Placebo 4 healthy volunteers will receive 0.9% saline (NO LPS) plus Defibrotide or Placebo
Placebo (0.9% sodium chloride) period I: 6.25mg/kg bodyweight defibrotide or placebo (0.9% sodium chloride) period II: vice versa 16 healthy volunteers will receive 2ng/kg bodyweight LPS plus Defibrotide or Placebo 4 healthy volunteers will receive 0.9% saline (NO LPS) plus Defibrotide or Placebo
Placebo (0.9% sodium chloride) period I: 6.25mg/kg bodyweight defibrotide or placebo (0.9% sodium chloride) period II: vice versa 16 healthy volunteers will receive 2ng/kg bodyweight LPS plus Defibrotide or Placebo 4 healthy volunteers will receive 0.9% saline (NO LPS) plus Defibrotide or Placebo
Outcomes
Primary Outcome Measures
Prothrombin Fragments f1+2
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.
The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison
Secondary Outcome Measures
Thrombin-Antithrombin Complexes
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.
The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison
Plasmin-Antiplasmin Complexes
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.
The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison
Tumor Necrosis Factor (TNF)-Alpha
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject.
The respective arbitrary unit therefore is fold*h.
Tissue-type Plasminogen Activator
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject.
The respective arbitrary unit therefore is fold*h.
Interleukin-6
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.
E-Selectin
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject.
The respective arbitrary unit therefore is fold*h.
Plasminogen Activator Inhibitor 1
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject.
The respective arbitrary unit therefore is fold*h.
Von Willebrand Factor Antigen
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The quantification of von Willebrand Factor is based on reference values and results are in % of "normal".
The respective arbitrary unit therefore is %*h.
Clotting Time in Thromboelastometry
In this analysis, first of all a ratio of the measurement time point to the baseline was calculated. Thereafter deltas (baeline-ratio) were calculated. With the results an AUC was calculated.
The respective arbitrary unit therefore is fold*h.
Maximum Lysis in Thromboelastometry
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject.
The respective arbitrary unit therefore is fold*h.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02876601
Brief Title
Defibrotide in the Human Endotoxemia Model --- an Exploratory Trial Investigating the Effects and the Mechanisms of Defibrotide
Acronym
LPS_DF
Official Title
Defibrotide in the Human Endotoxemia Model -- an Exploratory Trial Investigating the Effects and the Mechanisms of Defibrotide
Study Type
Interventional
2. Study Status
Record Verification Date
December 2019
Overall Recruitment Status
Completed
Study Start Date
April 18, 2017 (Actual)
Primary Completion Date
February 12, 2018 (Actual)
Study Completion Date
February 12, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Bernd Jilma
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
Defibrotide is an anti-inflammatory and anti-coagulatory agent approved for treatment of veno-occlusive disease. Although it has been in clinical use for almost 30 years, the exact mechanism of action has never been fully elucidated. Thus, the effects of defibrotide will be investigated in the human endotoxemia model in order to gather further information on its actions.
Detailed Description
Defibrotide (DF) is a highly complex polydisperse mixture of single-stranded phosphodiester oligodeoxyribonucleotides derived from the controlled depolymerization of porcine intestinal mucosal DNA. The entire mode of action remains unknown. Its actions may be summarized to pro-fibrinolytic, anti-inflammatory and anti-coagulatory actions. To better define the mechanisms of Defibrotide the effects of the substance will be investigated in the well-established endotoxemia model. Sixteen healthy volunteers will be randomized to receive LPS±defibrotide/placebo and four subjects will be randomized to receive Placebo± defibrotide/placebo in a single center, randomized, double blind, placebo controlled, two-way crossover trial. Immediately after a 2h infusion of 6,25mg/kg bodyweight defibrotide or placebo a LPS bolus of 2ng/kg bodyweight will be infused. Analyses will be performed by blood sampling at pre-defined time-points.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Healthy Volunteers, Endotoxemia
Keywords
Coagulation, Inflammation, Defibrotide, Fibrinolysis
7. Study Design
Primary Purpose
Basic Science
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Model Description
Subjects will be randomized to receive LPS (n=16) or placebo (n=4) first. In each group they will undergo two study periods (crossover trial): a placebo period and a defibrotide period. The placebo group (n=4) will only be analyzed descriptively.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
20 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Defibrotide/LPS
Arm Type
Active Comparator
Arm Description
2ng/kg lipopolysaccharide period I: 6.25mg/kg bodyweight defibrotide or placebo (0.9% sodium chloride) period II: vice versa
16 healthy volunteers will receive 2ng/kg bodyweight LPS plus Defibrotide or Placebo 4 healthy volunteers will receive 0.9% saline (NO LPS) plus Defibrotide or Placebo
Arm Title
Placebo/LPS
Arm Type
Placebo Comparator
Arm Description
2ng/kg lipopolysaccharide period I: 6.25mg/kg bodyweight defibrotide or placebo (0.9% sodium chloride) period II: vice versa
16 healthy volunteers will receive 2ng/kg bodyweight LPS plus Defibrotide or Placebo 4 healthy volunteers will receive 0.9% saline (NO LPS) plus Defibrotide or Placebo
Arm Title
Defibrotide/Placebo
Arm Type
Other
Arm Description
Placebo (0.9% sodium chloride) period I: 6.25mg/kg bodyweight defibrotide or placebo (0.9% sodium chloride) period II: vice versa
16 healthy volunteers will receive 2ng/kg bodyweight LPS plus Defibrotide or Placebo 4 healthy volunteers will receive 0.9% saline (NO LPS) plus Defibrotide or Placebo
Arm Title
Placebo/Placebo
Arm Type
Other
Arm Description
Placebo (0.9% sodium chloride) period I: 6.25mg/kg bodyweight defibrotide or placebo (0.9% sodium chloride) period II: vice versa
16 healthy volunteers will receive 2ng/kg bodyweight LPS plus Defibrotide or Placebo 4 healthy volunteers will receive 0.9% saline (NO LPS) plus Defibrotide or Placebo
Intervention Type
Drug
Intervention Name(s)
Defibrotide
Intervention Description
6.25mg/kg bodyweight over 2h infusion
Intervention Type
Drug
Intervention Name(s)
Placebo (0.9% sodium chloride)
Intervention Description
(0.9% sodium chloride) infusion over 2h infusion
Intervention Type
Drug
Intervention Name(s)
Lipopolysaccharide
Intervention Description
bolus infusion of 2ng/kg bodyweight lps
Intervention Type
Drug
Intervention Name(s)
Placebo (0.9% sodium chloride bolus)
Intervention Description
(0.9% sodium chloride) bolus infusion
Primary Outcome Measure Information:
Title
Prothrombin Fragments f1+2
Description
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.
The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison
Time Frame
The parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h.
Secondary Outcome Measure Information:
Title
Thrombin-Antithrombin Complexes
Description
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.
The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison
Time Frame
This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Title
Plasmin-Antiplasmin Complexes
Description
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.
The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison
Time Frame
This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, and 6h and AUC was calculated based on these measurements.
Title
Tumor Necrosis Factor (TNF)-Alpha
Description
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject.
The respective arbitrary unit therefore is fold*h.
Time Frame
This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Title
Tissue-type Plasminogen Activator
Description
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject.
The respective arbitrary unit therefore is fold*h.
Time Frame
This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Title
Interleukin-6
Description
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.
Time Frame
This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Title
E-Selectin
Description
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject.
The respective arbitrary unit therefore is fold*h.
Time Frame
This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Title
Plasminogen Activator Inhibitor 1
Description
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject.
The respective arbitrary unit therefore is fold*h.
Time Frame
This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Title
Von Willebrand Factor Antigen
Description
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The quantification of von Willebrand Factor is based on reference values and results are in % of "normal".
The respective arbitrary unit therefore is %*h.
Time Frame
This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Title
Clotting Time in Thromboelastometry
Description
In this analysis, first of all a ratio of the measurement time point to the baseline was calculated. Thereafter deltas (baeline-ratio) were calculated. With the results an AUC was calculated.
The respective arbitrary unit therefore is fold*h.
Time Frame
This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Title
Maximum Lysis in Thromboelastometry
Description
Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject.
The respective arbitrary unit therefore is fold*h.
Time Frame
This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h and AUC was calculated based on these measurements.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
>18 years of age
<90kg body weight
Normal findings in medical history and physical examination unless the investigator considers the abnormality to be clinically irrelevant
Normal laboratory values unless the investigator considers abnormalities to be clinically irrelevant
Ability to understand the purpose and nature of the study, as well as the associated risks
Exclusion Criteria:
Intake of any drugs that may interfere with the trial's endpoints or drugs (i.e. platelet inhibitors, anticoagulants, etc.)
Positive results of HIV or hepatitis virology
Acute illness with systemic inflammatory reactions
Known allergies, hypersensitivities or intolerances to any of the used substances
Acute or recent bleeding episodes, increased risk of bleeding at the discretion of the investigator
Participation in an LPS trial within 6 weeks of the first study day
Pregnancy or breastfeeding
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bernd Jilma, MD
Organizational Affiliation
Medical University of Vienna
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Clinical Pharmacology, Medical University of Vienna
City
Vienna
ZIP/Postal Code
1090
Country
Austria
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing Plan Description
Data will be published in a peer-reviewed medical journal, individual data will not be presented or published, but may be made available by direct request to the PI (data may be made available in an anonymized fashion)
Learn more about this trial
Defibrotide in the Human Endotoxemia Model --- an Exploratory Trial Investigating the Effects and the Mechanisms of Defibrotide
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