Clinical trial NCT02875028: Vorapaxar in the Human Endotoxemia Model
Official title: Vorapaxar in the Human Endotoxemia Model A Randomized, Double-Blind, Crossover Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Healthy Volunteers
Keywords: Coagulations
Platelets
Inflammation
endotoxemia
vorapaxar
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
First posted: 2016-08-23
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Vorapaxar is a recently approved protease activated receptor - 1 (PAR-1) inhibitor. Platelet inhibition may also exert positive results on coagulation activation and may beneficially influence the inflammatory response. Since vorapaxar is the first available substance of a new class of platelet inhibitors its effects on the human coagulation system and the inflammatory response will be assessed in the well-established human endotoxemia model.

Detailed description: Vorapaxar is a novel platelet inhibitor inhibiting PAR-1. It is the first available substance of a new class of platelet inhibitors blocking the activation of platelets via thrombin or thrombin receptor activating peptides via PAR-1. As platelets contribute to the coagulation activation, i.e. by providing the surface for the assembly of the Tenase complex, and furthermore to the inflammatory response by releasing their stored granula containing promotors of both, inflammation and coagulation, we want to assess the effects of vorapaxar on these in the human endotoxemia model. Sixteen healthy volunteers will be included in this randomized, double-blind, placebo-controlled, single center, crossover trial with a washout period of 8 weeks. This wash out period was chosen based on the long elimination half-life of vorapaxar and to prevent any carry-over effects. After intake of 10mg vorapaxar (-24h) the degree of platelet inhibition will be assessed by whole bood aggregometry and, in case of insufficient platelet inhibition, subjects may receive another 10mg of vorapaxar. A bolus of 2ng/kg bodyweight lipopolysaccharide (LPS) will be infused and blood sampling will be performed at pre-defined time-points. After the washout-period the respective other treatment will be given to subjects.

Eligibility criteria: Inclusion Criteria:

* ≥18 years of age

  * ≥60 kg bodyweight
  * 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
  * Willingness to comply with the trial's safety demands (to refrain from excessive sporting activities two weeks after Vorapaxar intake, i.e. full contact sports, climbing, mountain biking etc.)
  * Ability to understand the purpose and nature of the study, as well as the associated risks No planned surgeries or other medical interventions in the planned study period

Exclusion Criteria:

* Intake of any drugs that may interfere with the trial's endpoints or drugs (i.e. platelet inhibitors, anticoagulants, CYP3A4 inhibitors, NSAIDs, selective serotonin reuptake inhibitors, selective noradrenaline and serotonin reuptake inhibitors)

  * 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
  * History of stroke, transient ischemic attacks or intracerebral hemorrhage
  * Known coagulation or platelet disorders
  * Participation in an LPS trial within 6 weeks of the first study day
  * Severe liver or kidney dysfunction
  * Pregnancy or breastfeeding

Primary outcomes:
measure: Changes in Prothrombin Fragments F1+2
timeFrame: Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h
Secondary outcomes:
measure: Protease Activated Receptor (PAR)-1 Expression on Platelets
timeFrame: Time points for evaluation were: baseline, 0h, 4h, 24h
measure: Thrombin-Antithrombin Complexes
timeFrame: Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h
measure: Plasmin-Antiplasmin Complexes
timeFrame: Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h
measure: E-Selectin
timeFrame: Time points for evaluation were baseline, 2h, 4h, 6h, 24h after LPS administration
measure: Von Willebrand Factor
timeFrame: Time points for evaluation were baseline, 2h, 4h, 6h, 24h after LPS administration
measure: P-Selectin
timeFrame: Time points for evaluation were baseline, 2h, 4h, 6h 24h after LPS administration
measure: Interleukin 6
timeFrame: Time points for evaluation were baseline, 2h, 4h, 6h 24h after LPS administration
measure: Tumor Necrosis Factor Alpha
timeFrame: Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h
measure: C-reactive Protein
timeFrame: Time points for evaluation were: baseline, and 24h after LPS administration
measure: Platelet Factor 4
timeFrame: Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h
measure: Thrombomodulin
timeFrame: Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h
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: