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

Bernd Jilma

Status and phase: Completed; Phase 4

Conditions: Healthy Volunteers; Endotoxemia

Treatments: Drug: Defibrotide; Drug: Lipopolysaccharide; Drug: Placebo (0.9% sodium chloride bolus); Drug: Placebo (0.9% sodium chloride)

Study type: Interventional

Funder types: Other

Identifiers

NCT02876601

LPS_DF Version 1.4

Details and patient eligibility

About

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.

Full 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.

Enrollment: 20 patients

Sex: All

Ages: 18+ years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

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20 participants in 4 patient groups, including a placebo group

Defibrotide/LPS

Active Comparator group

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

Treatment:

Drug: Lipopolysaccharide

Drug: Defibrotide

Placebo/LPS

Placebo Comparator group

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

Treatment:

Drug: Placebo (0.9% sodium chloride)

Drug: Lipopolysaccharide

Defibrotide/Placebo

Other group

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

Treatment:

Drug: Placebo (0.9% sodium chloride bolus)

Drug: Defibrotide

Placebo/Placebo

Other group

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

Treatment:

Drug: Placebo (0.9% sodium chloride bolus)

Drug: Placebo (0.9% sodium chloride)