Clinical trial NCT02876601: Defibrotide in the Human Endotoxemia Model --- an Exploratory Trial Investigating the Effects and the Mechanisms of Defibrotide
Official title: Defibrotide in the Human Endotoxemia Model -- an Exploratory Trial Investigating the Effects and the Mechanisms of Defibrotide
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Healthy Volunteers
Endotoxemia
Keywords: Coagulation
Inflammation
Defibrotide
Fibrinolysis
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
First posted: 2016-08-24
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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.
Primary purpose: BASIC_SCIENCE

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.

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

Primary outcomes:
measure: Prothrombin Fragments f1+2
timeFrame: The parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h.
Secondary outcomes:
measure: Thrombin-Antithrombin Complexes
timeFrame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
measure: Plasmin-Antiplasmin Complexes
timeFrame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, and 6h and AUC was calculated based on these measurements.
measure: Tumor Necrosis Factor (TNF)-Alpha
timeFrame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
measure: Tissue-type Plasminogen Activator
timeFrame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
measure: Interleukin-6
timeFrame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
measure: E-Selectin
timeFrame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
measure: Plasminogen Activator Inhibitor 1
timeFrame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
measure: Von Willebrand Factor Antigen
timeFrame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
measure: Clotting Time in Thromboelastometry
timeFrame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
measure: Maximum Lysis in Thromboelastometry
timeFrame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h and AUC was calculated based on these measurements.
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Department of Clinical Pharmacology, Medical University of Vienna
Study officials:
affiliation: Medical University of Vienna
name: Bernd Jilma, MD
role: PRINCIPAL_INVESTIGATOR
References: