Vorapaxar in the Human Endotoxemia Model

Study Overview
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Brief Summary
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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
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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.

Official Title
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Vorapaxar in the Human Endotoxemia Model A Randomized, Double-Blind, Crossover Study

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Vorapaxar
* Drug: Placebo
* Other: LPS


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vorapaxar<br>subjects will be treated with 4x2,5mg vorapaxar in empty lactose-starch capsules | Drug: Vorapaxar<br>* 10mg-20mg vorapaxar to achieve >80% thrombin-receptor activated peptide-6 (TRAP) induced platelet inhibition<br>Other: LPS<br>* 2ng/kg Lipopolysaccharide as a bolus infusion<br>* Other names: Lipopolysaccharide;|
| Placebo Comparator: Placebo<br>subjects will be treated with 4 empty lactose-starch capsules | Drug: Placebo<br> <br> * Other names: capsules consisting of lactose-starch;Other: LPS<br>* 2ng/kg Lipopolysaccharide as a bolus infusion<br>* Other names: Lipopolysaccharide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Prothrombin Fragments F1+2 | prothrombin fragment F1+2 concentrations, individual maxima were compared between both study periods | Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Protease Activated Receptor (PAR)-1 Expression on Platelets | Protease Activated Receptor (PAR)-1 expression on platelets was measured by flow cytometric analysis. The change in protease activated receptor (PAR)-1 expression over time was assessed. The ratio of protease activated receptor (PAR)-1 expression from baseline to 4h was the main parameter of interest and is presented here. Since the presented data are ratios, the arbitrary unit is fold. Otherwise flow cytometric data is presented as hits during the analysis. | Time points for evaluation were: baseline, 0h, 4h, 24h | 
| Thrombin-Antithrombin Complexes | Thrombin-Antithrombin Complexes were quantified using commercially available ELISA assays. The individual maxima during the study periods were compared. | Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h | 
| Plasmin-Antiplasmin Complexes | Plasmin-Antiplasmin Complexes were quantified using commercially available ELISA assays. Individual maxima during both study periods were compared. | Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h | 
| E-Selectin | E-Selectin concentrations were quantified using commercially available ELISA assays, individual maxima were compared between both study periods | Time points for evaluation were baseline, 2h, 4h, 6h, 24h after LPS administration | 
| Von Willebrand Factor | von Willebrand factor concentrations were measured by commercially available ELISA assays, individual maxima were compared between both study periods. The result of this assay are % of normal (100%) for this specific assay. The unit therefore is %. | Time points for evaluation were baseline, 2h, 4h, 6h, 24h after LPS administration | 
| P-Selectin | P-Selectin is quantified using commercially available ELISA assays, individual maxima were compared between both study periods. | Time points for evaluation were baseline, 2h, 4h, 6h 24h after LPS administration | 
| Interleukin 6 | interleukin-6 concentrations were measured by commercially available ELISA assays, individual maxima were compared between both study periods | Time points for evaluation were baseline, 2h, 4h, 6h 24h after LPS administration | 
| Tumor Necrosis Factor Alpha | tumor necrosis factor alpha concentrations were measured using commercially available ELISA assays, individual maxima were compared between both study periods | Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h | 
| C-reactive Protein | C-reactive protein levels were measured in the certified central laboratory of the General Hospital, 24h values were compared with each other | Time points for evaluation were: baseline, and 24h after LPS administration | 
| Platelet Factor 4 | platelet factor 4 concentrations were quantified by ELISA, individual maxima were compared between both study periods | Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h | 
| Thrombomodulin | thrombomodulin concentrations were measured by commercially available ELISA assays, individual maxima were compared between both study periods | Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coagulations, Platelets, Inflammation, endotoxemia, vorapaxar