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

NCT02876601 | Completed Phase 4 Results

• 1 other identifier: LPS_DF Version 1.4
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy Volunteers; Endotoxemia

Keywords

Coagulation; Inflammation; Defibrotide; Fibrinolysis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (10)

• Thrombin-Antithrombin Complexes

  This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.

• Plasmin-Antiplasmin Complexes

  This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, and 6h and AUC was calculated based on these measurements.

• Tumor Necrosis Factor (TNF)-Alpha

  This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.

• Tissue-type Plasminogen Activator

  This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.

• Interleukin-6

  This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.

Study Arms (4)

Defibrotide/LPS

ACTIVE COMPARATOR

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; Drug: Lipopolysaccharide

Placebo/LPS

PLACEBO COMPARATOR

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); Drug: Lipopolysaccharide

Defibrotide/Placebo

OTHER

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; Drug: Placebo (0.9% sodium chloride bolus)

Placebo/Placebo

OTHER

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); Drug: Placebo (0.9% sodium chloride bolus)

Interventions

Defibrotide DRUG

6.25mg/kg bodyweight over 2h infusion

Defibrotide/LPS; Defibrotide/Placebo

Placebo (0.9% sodium chloride) DRUG

(0.9% sodium chloride) infusion over 2h infusion

Placebo/LPS; Placebo/Placebo

Lipopolysaccharide DRUG

bolus infusion of 2ng/kg bodyweight lps

Defibrotide/LPS; Placebo/LPS

Placebo (0.9% sodium chloride bolus) DRUG

(0.9% sodium chloride) bolus infusion

Defibrotide/Placebo; Placebo/Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \>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

You may not qualify if:

• 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

Sponsors & Collaborators

• Bernd Jilma: lead

Study Sites (1)

Department of Clinical Pharmacology, Medical University of Vienna

Vienna, 1090, Austria

Location

MeSH Terms

Conditions

Endotoxemia; Thrombosis; Inflammation

Interventions

defibrotide; Sodium Chloride; Lipopolysaccharides

Condition Hierarchy (Ancestors)

Bacteremia; Sepsis; Infections; Toxemia; Systemic Inflammatory Response Syndrome; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Glycoconjugates; Carbohydrates; Polysaccharides, Bacterial; Polysaccharides; Lipids; Antigens, Bacterial; Antigens; Biological Factors; Endotoxins; Bacterial Toxins; Toxins, Biological

Results Point of Contact

• Title: Univ.Prof. Dr. Bernd Jilma
• Organization: Medical University of Vienna

bernd.jilma@meduniwien.ac.at

+4314040029810

Study Officials

• Bernd Jilma, MD

  Medical University of Vienna

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Ao.Univ.Prof.Dr.med

Model Details: 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.

Study Record Dates

• First Submitted: June 27, 2016
• First Posted: August 24, 2016
• Study Start: April 18, 2017
• Primary Completion: February 12, 2018
• Study Completion: February 12, 2018
• Last Updated: December 19, 2019
• Results First Posted: December 19, 2019

Record last verified: 2019-12

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)