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Vorapaxar in the Human Endotoxemia Model

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ClinicalTrials.gov Identifier: NCT02875028
Recruitment Status : Completed
First Posted : August 23, 2016
Last Update Posted : March 28, 2017
Sponsor:
Information provided by (Responsible Party):
Bernd Jilma, Medical University of Vienna

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.

Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: Vorapaxar Drug: Placebo Other: LPS Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Vorapaxar in the Human Endotoxemia Model A Randomized, Double‐Blind, Crossover Study
Actual Study Start Date : June 2016
Actual Primary Completion Date : November 30, 2016
Actual Study Completion Date : November 30, 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Vorapaxar
subjects will be treated with 4x2,5mg vorapaxar in empty lactose-starch capsules
Drug: Vorapaxar
10mg-20mg vorapaxar to achieve >80% thrombin-receptor activated peptide-6 (TRAP) induced platelet inhibition

Other: LPS
2ng/kg Lipopolysaccharide as a bolus infusion
Other Name: Lipopolysaccharide

Placebo Comparator: Placebo
subjects will be treated with 4 empty lactose-starch capsules
Drug: Placebo
Other Name: capsules consisting of lactose-starch

Other: LPS
2ng/kg Lipopolysaccharide as a bolus infusion
Other Name: Lipopolysaccharide




Primary Outcome Measures :
  1. Changes in Prothrombin fragments F1+2 [ Time Frame: up to 48 hours ]
    prothrombin fragment F1+2 concentrations


Secondary Outcome Measures :
  1. PAR-1 expression on platelets [ Time Frame: up to 48 hours ]
    by flow cytometric analysis

  2. thromboelastometry [ Time Frame: up to 48 hours ]
    thromboelastometry by ROTEM analysis

  3. Coagulation specific biomarkers [ Time Frame: up to 48 hours ]
    by elisa: Thrombin-Antithrombin Complexes,

  4. Biomarkers of the fibrinolytic system [ Time Frame: up to 48 hours ]
    D-Dimer, Plasmin-Antiplasmin Complexes,

  5. Blood pressure [ Time Frame: up to 48 hours ]
    safety, mmHg

  6. Heart Rate [ Time Frame: up to 48 hours ]
    safety, Beats per minute

  7. Body Temperature [ Time Frame: up to 48 hours ]
    safety, degrees Celsius

  8. Oxygen Saturation [ Time Frame: up to 48 hours ]
    safety, Percent

  9. inflammatory biomarkers [ Time Frame: -24 hours - 0 hours - 1 hours- 1,5 hours - 2 hours - 4 hours - 6 hours - 8 hours - 24 hours ]
    C-reactive Protein, Fibrinogen,

  10. Biomarkers of endothelial activation [ Time Frame: up to 48 hours ]
    E-Selectin, glycocalyx thickness, von-Willebrand-factor

  11. differential blood counts [ Time Frame: up to 48 hours ]
    by flow cytometric analysis

  12. neutrophil subsets [ Time Frame: up to 48 hours ]
    by flow cytometric analysis

  13. monocyte subsets [ Time Frame: up to 48 hours ]
    by flow cytometric analysis



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02875028


Locations
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Austria
Department of Clinical Pharmacology, Medical University of Vienna
Vienna, Austria, 1090
Sponsors and Collaborators
Medical University of Vienna
Investigators
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Principal Investigator: Bernd Jilma, MD Medical University of Vienna

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Responsible Party: Bernd Jilma, Ao.Univ.Prof.Dr.med, Medical University of Vienna
ClinicalTrials.gov Identifier: NCT02875028     History of Changes
Other Study ID Numbers: LPS_Vorapaxar_1.1
First Posted: August 23, 2016    Key Record Dates
Last Update Posted: March 28, 2017
Last Verified: March 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: A manuscript will be published in a peer-reviewed journal, individual data will not be presented unless directly requested from the PI (anonymized data may be made publicly available)
Keywords provided by Bernd Jilma, Medical University of Vienna:
Coagulations
Platelets
Inflammation
endotoxemia
vorapaxar
Additional relevant MeSH terms:
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Endotoxemia
Bacteremia
Sepsis
Infection
Toxemia
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Vorapaxar
Platelet Aggregation Inhibitors