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

• ClinicalTrials.gov Identifier: NCT02876601
• Recruitment Status: Completed
• First Posted: August 24, 2016
• Results First Posted: December 19, 2019
• Last Update Posted: December 19, 2019
• Sponsor: Bernd Jilma
• Information provided by (Responsible Party): Bernd Jilma, Medical University of Vienna

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.

Condition or disease	Intervention/treatment	Phase
Healthy Volunteers; Endotoxemia	Drug: Defibrotide; Drug: Placebo (0.9% sodium chloride); Drug: Lipopolysaccharide; Drug: Placebo (0.9% sodium chloride bolus)	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• 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.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Defibrotide in the Human Endotoxemia Model -- an Exploratory Trial Investigating the Effects and the Mechanisms of Defibrotide
• Actual Study Start Date: April 18, 2017
• Actual Primary Completion Date: February 12, 2018
• Actual Study Completion Date: February 12, 2018

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Defibrotide/LPS; 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	Drug: Defibrotide; 6.25mg/kg bodyweight over 2h infusion; Drug: Lipopolysaccharide; bolus infusion of 2ng/kg bodyweight lps
Placebo Comparator: Placebo/LPS; 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	Drug: Placebo (0.9% sodium chloride); (0.9% sodium chloride) infusion over 2h infusion; Drug: Lipopolysaccharide; bolus infusion of 2ng/kg bodyweight lps
Defibrotide/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	Drug: Defibrotide; 6.25mg/kg bodyweight over 2h infusion; Drug: Placebo (0.9% sodium chloride bolus); (0.9% sodium chloride) bolus infusion
Placebo/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	Drug: Placebo (0.9% sodium chloride); (0.9% sodium chloride) infusion over 2h infusion; Drug: Placebo (0.9% sodium chloride bolus); (0.9% sodium chloride) bolus infusion

Outcome Measures

Primary Outcome Measures :

1. Prothrombin Fragments f1+2 [ Time Frame: The parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h. ]

   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 :

1. Thrombin-Antithrombin Complexes [ Time Frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements. ]

   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

2. Plasmin-Antiplasmin Complexes [ Time Frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, and 6h and AUC was calculated based on these measurements. ]

   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

3. Tumor Necrosis Factor (TNF)-Alpha [ Time Frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements. ]

   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.

4. Tissue-type Plasminogen Activator [ Time Frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements. ]

   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.

5. Interleukin-6 [ Time Frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements. ]
   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.
6. E-Selectin [ Time Frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements. ]

   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.

7. Plasminogen Activator Inhibitor 1 [ Time Frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements. ]

   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.

8. Von Willebrand Factor Antigen [ Time Frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements. ]

   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.

9. Clotting Time in Thromboelastometry [ Time Frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements. ]

   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.

10. Maximum Lysis in Thromboelastometry [ Time Frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h and AUC was calculated based on these measurements. ]

    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

Austria

Department of Clinical Pharmacology, Medical University of Vienna

Vienna, Austria, 1090

Sponsors and Collaborators

Bernd Jilma

Investigators

• Principal Investigator: Bernd Jilma, MD; Medical University of Vienna

  Study Documents (Full-Text)

Documents provided by Bernd Jilma, Medical University of Vienna:

Study Protocol and Statistical Analysis Plan  [PDF] July 24, 2017

More Information

• Responsible Party: Bernd Jilma, Ao.Univ.Prof.Dr.med, Medical University of Vienna
• ClinicalTrials.gov Identifier: NCT02876601
• Other Study ID Numbers: LPS_DF Version 1.4
• First Posted: August 24, 2016
• Results First Posted: December 19, 2019
• Last Update Posted: December 19, 2019
• Last Verified: December 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• 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)

• 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

Keywords provided by Bernd Jilma, Medical University of Vienna:

Coagulation; Inflammation; Defibrotide; Fibrinolysis

Additional relevant MeSH terms:

Endotoxemia; Bacteremia; Sepsis; Infections; Toxemia; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Defibrotide; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors