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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Vorapaxar | Experimental | subjects will be treated with 4x2,5mg vorapaxar in empty lactose-starch capsules |
|
| Placebo | Placebo Comparator | subjects will be treated with 4 empty lactose-starch capsules |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Vorapaxar | Drug | 10mg-20mg vorapaxar to achieve >80% thrombin-receptor activated peptide-6 (TRAP) induced platelet inhibition |
|
| 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 |
| 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. |
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Inclusion Criteria:
≥18 years of age
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)
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| Name | Affiliation | Role |
|---|---|---|
| Bernd Jilma, MD | Medical University of Vienna | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Clinical Pharmacology, Medical University of Vienna | Vienna | 1090 | Austria |
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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16 healthy volunteers participated in this crossover trial.
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| ID | Title | Description |
|---|---|---|
| FG000 | Vorapaxar, Then Placebo | Subjects randomized to this group received vorapaxar treatment first (10-20mg) plus 2ng/kg bodyweight lipopolysaccharide (LPS) bolus infusion and after a washout period of at least 8 weeks, the placebo treatment (0.9% sodium chloride infusion) plus 2ng/kg bodyweight LPS bolus infusion. |
| FG001 | Placebo First, Then Vorapaxar | Subjects randomized to this group received the placebo treatment (0.9% sodium chloride infusion) plus 2ng/kg bodyweight LPS bolus infusion first, and after a washout period of at least 8 weeks, vorapaxar treatment (10-20mg) plus a 2ng/kg bodyweight LPS bolus infusion. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (24 Hours) |
| |||||||||||||
| Washout Period |
| |||||||||||||
| Second Intervention (24 Hours) |
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| ID | Title | Description |
|---|---|---|
| BG000 | Vorapaxar | subjects will be treated with 4x2,5mg vorapaxar in empty lactose-starch capsules Vorapaxar: 10mg-20mg vorapaxar to achieve >80% thrombin-receptor activated peptide-6 (TRAP) induced platelet inhibition LPS: 2ng/kg Lipopolysaccharide as a bolus infusion |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Changes in Prothrombin Fragments F1+2 | prothrombin fragment F1+2 concentrations, individual maxima were compared between both study periods | This was a crossover trial, so all subjects were to complete both study periods (vorapaxar and placebo period). The results of those periods were compared with each other. One subject withdrew during the washout period and was excluded from analysis. | Posted | Median | Inter-Quartile Range | pmol/L | Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Vorapaxar | subjects will be treated with 4x2,5mg vorapaxar in empty lactose-starch capsules Vorapaxar: 10mg-20mg vorapaxar to achieve >80% thrombin-receptor activated peptide-6 (TRAP) induced platelet inhibition LPS: 2ng/kg Lipopolysaccharide as a bolus infusion |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| headache | Nervous system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Bernd Jilma | Medical University of Vienna | +4314040029910 | bernd.jilma@meduniwien.ac.at |
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| ID | Term |
|---|---|
| D007249 | Inflammation |
| D019446 | Endotoxemia |
| ID | Term |
|---|---|
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D016470 | Bacteremia |
| D018805 | Sepsis |
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| ID | Term |
|---|---|
| C530299 | vorapaxar |
| D008070 | Lipopolysaccharides |
| ID | Term |
|---|---|
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D011135 | Polysaccharides, Bacterial |
| D011134 | Polysaccharides |
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| Placebo | Drug |
|
|
| LPS | Other | 2ng/kg Lipopolysaccharide as a bolus infusion |
|
|
| 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 |
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subjects will be treated with 4 empty lactose-starch capsules Placebo LPS: 2ng/kg Lipopolysaccharide as a bolus infusion |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Inter-Quartile Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| weight | Median | Inter-Quartile Range | kg |
|
|
|
|
| Secondary | 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. | This was a crossover trial, so all subjects were to complete both study periods (vorapaxar and placebo period). The results of those periods were compared with each other. One subject withdrew during the washout period and was excluded from analysis. | Posted | Median | Inter-Quartile Range | fold | Time points for evaluation were: baseline, 0h, 4h, 24h |
|
|
|
| Secondary | Thrombin-Antithrombin Complexes | Thrombin-Antithrombin Complexes were quantified using commercially available "ELISA" assays. The individual maxima during the study periods were compared. | This was a crossover trial, so all subjects were to complete both study periods (vorapaxar and placebo period). The results of those periods were compared with each other. One subject withdrew during the washout period and was excluded from analysis. | Posted | Median | Inter-Quartile Range | µg/L | Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h |
|
|
|
| Secondary | Plasmin-Antiplasmin Complexes | Plasmin-Antiplasmin Complexes were quantified using commercially available "ELISA" assays. Individual maxima during both study periods were compared. | This was a crossover trial, so all subjects were to complete both study periods (vorapaxar and placebo period). The results of those periods were compared with each other. One subject withdrew during the washout period and was excluded from analysis. | Posted | Median | Inter-Quartile Range | µg/L | Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h |
|
|
|
| Secondary | E-Selectin | E-Selectin concentrations were quantified using commercially available "ELISA" assays, individual maxima were compared between both study periods | This was a crossover trial, so all subjects were to complete both study periods (vorapaxar and placebo period). The results of those periods were compared with each other. One subject withdrew during the washout period and was excluded from analysis. | Posted | Median | Inter-Quartile Range | ng/mL | Time points for evaluation were baseline, 2h, 4h, 6h, 24h after LPS administration |
|
|
|
| Secondary | 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 %. | This was a crossover trial, so all subjects were to complete both study periods (vorapaxar and placebo period). The results of those periods were compared with each other. One subject withdrew during the washout period and was excluded from analysis. | Posted | Median | Inter-Quartile Range | % of "normal" | Time points for evaluation were baseline, 2h, 4h, 6h, 24h after LPS administration |
|
|
|
| Secondary | P-Selectin | P-Selectin is quantified using commercially available "ELISA" assays, individual maxima were compared between both study periods. | This was a crossover trial, so all subjects were to complete both study periods (vorapaxar and placebo period). The results of those periods were compared with each other. One subject withdrew during the washout period and was excluded from analysis. | Posted | Median | Inter-Quartile Range | ng/ml | Time points for evaluation were baseline, 2h, 4h, 6h 24h after LPS administration |
|
|
|
| Secondary | Interleukin 6 | interleukin-6 concentrations were measured by commercially available "ELISA" assays, individual maxima were compared between both study periods | This was a crossover trial, so all subjects were to complete both study periods (vorapaxar and placebo period). The results of those periods were compared with each other. One subject withdrew during the washout period and was excluded from analysis. | Posted | Median | Inter-Quartile Range | pg/mL | Time points for evaluation were baseline, 2h, 4h, 6h 24h after LPS administration |
|
|
|
| Secondary | Tumor Necrosis Factor Alpha | tumor necrosis factor alpha concentrations were measured using commercially available "ELISA" assays, individual maxima were compared between both study periods | This was a crossover trial, so all subjects were to complete both study periods (vorapaxar and placebo period). The results of those periods were compared with each other. One subject withdrew during the washout period and was excluded from analysis. | Posted | Median | Inter-Quartile Range | pg/mL | Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h |
|
|
|
| Secondary | 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 | This was a crossover trial, so all subjects were to complete both study periods (vorapaxar and placebo period). The results of those periods were compared with each other. One subject withdrew during the washout period and was excluded from analysis. | Posted | Median | Inter-Quartile Range | mg/dL | Time points for evaluation were: baseline, and 24h after LPS administration |
|
|
|
| Secondary | Platelet Factor 4 | platelet factor 4 concentrations were quantified by "ELISA", individual maxima were compared between both study periods | This was a crossover trial, so all subjects were to complete both study periods (vorapaxar and placebo period). The results of those periods were compared with each other. One subject withdrew during the washout period and was excluded from analysis. | Posted | Median | Inter-Quartile Range | pg/mL | Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h |
|
|
|
| Secondary | Thrombomodulin | thrombomodulin concentrations were measured by commercially available "ELISA" assays, individual maxima were compared between both study periods | This was a crossover trial, so all subjects were to complete both study periods (vorapaxar and placebo period). The results of those periods were compared with each other. One subject withdrew during the washout period and was excluded from analysis. | Posted | Median | Inter-Quartile Range | ng/mL | Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h |
|
|
|
| 0 |
| 15 |
| 0 |
| 15 |
| 11 |
| 15 |
| EG001 | Placebo | subjects will be treated with 4 empty lactose-starch capsules Placebo LPS: 2ng/kg Lipopolysaccharide as a bolus infusion | 0 | 16 | 0 | 16 | 12 | 16 |
| Dizziness | General disorders | Systematic Assessment |
|
| Chills | General disorders | Systematic Assessment |
|
| Myalgia | General disorders | Systematic Assessment |
|
| malaise | General disorders | Systematic Assessment |
|
| exanthema | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
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| D007239 |
| Infections |
| D014115 | Toxemia |
| D018746 | Systemic Inflammatory Response Syndrome |
| D008055 |
| Lipids |
| D000942 | Antigens, Bacterial |
| D000941 | Antigens |
| D001685 | Biological Factors |
| D004731 | Endotoxins |
| D001427 | Bacterial Toxins |
| D014118 | Toxins, Biological |