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Vorapaxar in the Human Endotoxemia Model

Primary Purpose

Healthy Volunteers

Status

Completed

Phase

Phase 4

Locations

Austria

Study Type

Interventional

Intervention

Vorapaxar

Placebo

LPS

About this trial

This is an interventional treatment trial for Healthy Volunteers focused on measuring Coagulations, Platelets, Inflammation, endotoxemia, vorapaxar

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Department of Clinical Pharmacology, Medical University of Vienna

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Vorapaxar

Placebo

Arm Description

subjects will be treated with 4x2,5mg vorapaxar in empty lactose-starch capsules

subjects will be treated with 4 empty lactose-starch capsules

Outcomes

Primary Outcome Measures

Changes in Prothrombin Fragments F1+2

prothrombin fragment F1+2 concentrations, individual maxima were compared between both study periods

Secondary Outcome Measures

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.

Thrombin-Antithrombin Complexes

Thrombin-Antithrombin Complexes were quantified using commercially available "ELISA" assays. The individual maxima during the study periods were compared.

Plasmin-Antiplasmin Complexes

Plasmin-Antiplasmin Complexes were quantified using commercially available "ELISA" assays. Individual maxima during both study periods were compared.

E-Selectin

E-Selectin concentrations were quantified using commercially available "ELISA" assays, individual maxima were compared between both study periods

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 %.

P-Selectin

P-Selectin is quantified using commercially available "ELISA" assays, individual maxima were compared between both study periods.

Interleukin 6

interleukin-6 concentrations were measured by commercially available "ELISA" assays, individual maxima were compared between both study periods

Tumor Necrosis Factor Alpha

tumor necrosis factor alpha concentrations were measured using commercially available "ELISA" assays, individual maxima were compared between both study periods

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

Platelet Factor 4

platelet factor 4 concentrations were quantified by "ELISA", individual maxima were compared between both study periods

Thrombomodulin

thrombomodulin concentrations were measured by commercially available "ELISA" assays, individual maxima were compared between both study periods

Full Information

NCT ID

NCT02875028

First Posted

June 27, 2016

Last Updated

December 20, 2019

Sponsor

Medical University of Vienna

1. Study Identification

Unique Protocol Identification Number

NCT02875028

Brief Title

Vorapaxar in the Human Endotoxemia Model

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2019

Overall Recruitment Status

Completed

Study Start Date

June 2016 (Actual)

Primary Completion Date

November 30, 2016 (Actual)

Study Completion Date

November 30, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Medical University of Vienna

4. Oversight

Data Monitoring Committee

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Healthy Volunteers

Keywords

Coagulations, Platelets, Inflammation, endotoxemia, vorapaxar

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

16 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Vorapaxar

Arm Type

Experimental

Arm Description

subjects will be treated with 4x2,5mg vorapaxar in empty lactose-starch capsules

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

subjects will be treated with 4 empty lactose-starch capsules

Intervention Type

Drug

Intervention Name(s)

Vorapaxar

Intervention Description

10mg-20mg vorapaxar to achieve >80% thrombin-receptor activated peptide-6 (TRAP) induced platelet inhibition

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

capsules consisting of lactose-starch

Intervention Type

Other

Intervention Name(s)

LPS

Other Intervention Name(s)

Lipopolysaccharide

Intervention Description

2ng/kg Lipopolysaccharide as a bolus infusion

Primary Outcome Measure Information:

Title

Changes in Prothrombin Fragments F1+2

Description

prothrombin fragment F1+2 concentrations, individual maxima were compared between both study periods

Time Frame

Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h

Secondary Outcome Measure Information:

Title

Protease Activated Receptor (PAR)-1 Expression on Platelets

Description

Time Frame

Time points for evaluation were: baseline, 0h, 4h, 24h

Title

Thrombin-Antithrombin Complexes

Description

Thrombin-Antithrombin Complexes were quantified using commercially available "ELISA" assays. The individual maxima during the study periods were compared.

Time Frame

Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h

Title

Plasmin-Antiplasmin Complexes

Description

Plasmin-Antiplasmin Complexes were quantified using commercially available "ELISA" assays. Individual maxima during both study periods were compared.

Time Frame

Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h

Title

E-Selectin

Description

E-Selectin concentrations were quantified using commercially available "ELISA" assays, individual maxima were compared between both study periods

Time Frame

Time points for evaluation were baseline, 2h, 4h, 6h, 24h after LPS administration

Title

Von Willebrand Factor

Description

Time Frame

Time points for evaluation were baseline, 2h, 4h, 6h, 24h after LPS administration

Title

P-Selectin

Description

P-Selectin is quantified using commercially available "ELISA" assays, individual maxima were compared between both study periods.

Time Frame

Time points for evaluation were baseline, 2h, 4h, 6h 24h after LPS administration

Title

Interleukin 6

Description

interleukin-6 concentrations were measured by commercially available "ELISA" assays, individual maxima were compared between both study periods

Time Frame

Time points for evaluation were baseline, 2h, 4h, 6h 24h after LPS administration

Title

Tumor Necrosis Factor Alpha

Description

tumor necrosis factor alpha concentrations were measured using commercially available "ELISA" assays, individual maxima were compared between both study periods

Time Frame

Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h

Title

C-reactive Protein

Description

C-reactive protein levels were measured in the certified central laboratory of the General Hospital, 24h values were compared with each other

Time Frame

Time points for evaluation were: baseline, and 24h after LPS administration

Title

Platelet Factor 4

Description

platelet factor 4 concentrations were quantified by "ELISA", individual maxima were compared between both study periods

Time Frame

Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h

Title

Thrombomodulin

Description

thrombomodulin concentrations were measured by commercially available "ELISA" assays, individual maxima were compared between both study periods

Time Frame

Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bernd Jilma, MD

Organizational Affiliation

Medical University of Vienna

Official's Role

Principal Investigator

Facility Information:

Facility Name

Department of Clinical Pharmacology, Medical University of Vienna

City

Vienna

ZIP/Postal Code

1090

Country

Austria

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing 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)

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Vorapaxar in the Human Endotoxemia Model

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