Vorapaxar in the Human Endotoxemia Model

• ClinicalTrials.gov Identifier: NCT02875028
• Recruitment Status: Completed
• First Posted: August 23, 2016
• Results First Posted: January 10, 2020
• Last Update Posted: January 10, 2020
• Sponsor: Medical University of Vienna
• Information provided by (Responsible Party): Bernd Jilma, Medical University of Vienna

Study Description

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Changes in Prothrombin Fragments F1+2 [ Time Frame: Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h ]
   prothrombin fragment F1+2 concentrations, individual maxima were compared between both study periods

Secondary Outcome Measures :

1. Protease Activated Receptor (PAR)-1 Expression on Platelets [ Time Frame: Time points for evaluation were: baseline, 0h, 4h, 24h ]

   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.

2. Thrombin-Antithrombin Complexes [ Time Frame: Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h ]

   Thrombin-Antithrombin Complexes were quantified using commercially available "ELISA" assays.

   The individual maxima during the study periods were compared.

3. Plasmin-Antiplasmin Complexes [ Time Frame: Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h ]
   Plasmin-Antiplasmin Complexes were quantified using commercially available "ELISA" assays. Individual maxima during both study periods were compared.
4. E-Selectin [ Time Frame: Time points for evaluation were baseline, 2h, 4h, 6h, 24h after LPS administration ]
   E-Selectin concentrations were quantified using commercially available "ELISA" assays, individual maxima were compared between both study periods
5. Von Willebrand Factor [ Time Frame: Time points for evaluation were baseline, 2h, 4h, 6h, 24h after LPS administration ]
   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 %.
6. P-Selectin [ Time Frame: Time points for evaluation were baseline, 2h, 4h, 6h 24h after LPS administration ]
   P-Selectin is quantified using commercially available "ELISA" assays, individual maxima were compared between both study periods.
7. Interleukin 6 [ Time Frame: Time points for evaluation were baseline, 2h, 4h, 6h 24h after LPS administration ]
   interleukin-6 concentrations were measured by commercially available "ELISA" assays, individual maxima were compared between both study periods
8. Tumor Necrosis Factor Alpha [ Time Frame: Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h ]
   tumor necrosis factor alpha concentrations were measured using commercially available "ELISA" assays, individual maxima were compared between both study periods
9. C-reactive Protein [ Time Frame: Time points for evaluation were: baseline, and 24h after LPS administration ]
   C-reactive protein levels were measured in the certified central laboratory of the General Hospital, 24h values were compared with each other
10. Platelet Factor 4 [ Time Frame: Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h ]
    platelet factor 4 concentrations were quantified by "ELISA", individual maxima were compared between both study periods
11. Thrombomodulin [ Time Frame: Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h ]
    thrombomodulin concentrations were measured by commercially available "ELISA" assays, individual maxima were compared between both study periods

Eligibility Criteria

• 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

Contacts and Locations

Locations

Austria

Department of Clinical Pharmacology, Medical University of Vienna

Vienna, Austria, 1090

Sponsors and Collaborators

Medical University of Vienna

Investigators

• Principal Investigator: Bernd Jilma, MD; Medical University of Vienna

More Information

• Responsible Party: Bernd Jilma, Ao.Univ.Prof.Dr.med, Medical University of Vienna
• ClinicalTrials.gov Identifier: NCT02875028
• Other Study ID Numbers: LPS_Vorapaxar_1.1
• First Posted: August 23, 2016
• Results First Posted: January 10, 2020
• Last Update Posted: January 10, 2020
• Last Verified: December 2019

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:

Endotoxemia; Bacteremia; Sepsis; Infection; Toxemia; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Vorapaxar; Platelet Aggregation Inhibitors