Defibrotide in the Human Endotoxemia Model --‐ an Exploratory Trial Investigating the Effects and the Mechanisms of Defibrotide

Healthy Volunteers Clinical Trial

— LPS_DF  

Official title:

Defibrotide in the Human Endotoxemia Model -- an Exploratory Trial Investigating the Effects and the Mechanisms of Defibrotide

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02876601
• Other study ID #: LPS_DF Version 1.4
• Status: Completed
• Phase: Phase 4
• Start date: April 18, 2017
• Est. completion date: February 12, 2018

Study information

• Verified date: December 2019
• Source: Medical University of Vienna
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: February 12, 2018
• Est. primary completion date: February 12, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Endotoxemia
• Healthy Volunteers

Intervention

Drug:
• Defibrotide
6.25mg/kg bodyweight over 2h infusion
• Placebo (0.9% sodium chloride)
(0.9% sodium chloride) infusion over 2h infusion
• Lipopolysaccharide
bolus infusion of 2ng/kg bodyweight lps
• Placebo (0.9% sodium chloride bolus)
(0.9% sodium chloride) bolus infusion

Locations

Country	Name	City	State
Austria	Department of Clinical Pharmacology, Medical University of Vienna	Vienna

Sponsors (1)

Lead Sponsor	Collaborator
Bernd Jilma

Country where clinical trial is conducted

Austria, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	The parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h.
Secondary	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	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Secondary	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	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, and 6h and AUC was calculated based on these measurements.
Secondary	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.	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Secondary	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.	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Secondary	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.	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Secondary	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.	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Secondary	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.	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Secondary	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.	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Secondary	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.	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Secondary	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.	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h and AUC was calculated based on these measurements.