Healthy Volunteers
Conditions
Keywords
Coagulations, Platelets, Inflammation, endotoxemia, vorapaxar
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.
Interventions
Sponsors
Medical University of Vienna
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Prothrombin Fragments F1+2 | 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
| Measure | Time frame | Description |
|---|---|---|
| E-Selectin | 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 |
| Protease Activated Receptor (PAR)-1 Expression on Platelets | 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. |
| Thrombin-Antithrombin Complexes | 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. |
| Von Willebrand Factor | 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 %. |
| P-Selectin | 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. |
| Plasmin-Antiplasmin Complexes | 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. |
| Tumor Necrosis Factor Alpha | 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 |
| C-reactive Protein | 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 |
| Platelet Factor 4 | 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 |
| Thrombomodulin | 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 |
| Interleukin 6 | 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 |
Countries
Austria
Participant flow
Recruitment details
16 healthy volunteers participated in this crossover trial.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 8 |
| Placebo subjects will be treated with 4 empty lactose-starch capsules
Placebo
LPS: 2ng/kg Lipopolysaccharide as a bolus infusion | 8 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout Period | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Vorapaxar |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 16 Participants | 8 Participants |
| Age, Continuous | 27 years | 31 years | 34 years |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Austria | 8 participants | 16 participants | 8 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 8 Participants | 15 Participants | 7 Participants |
| weight | 84 kg | 77 kg | 70 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 16 |
| other Total, other adverse events | 11 / 15 | 12 / 16 |
| serious Total, serious adverse events | 0 / 15 | 0 / 16 |
Outcome results
Primary
Changes in Prothrombin Fragments F1+2
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
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorapaxar | Changes in Prothrombin Fragments F1+2 | 1315 pmol/L |
| Placebo | Changes in Prothrombin Fragments F1+2 | 2530 pmol/L |
p-value: 0.029Wilcoxon (Mann-Whitney)
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
Time frame: Time points for evaluation were: baseline, and 24h after LPS administration
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorapaxar | C-reactive Protein | 1.53 mg/dL |
| Placebo | C-reactive Protein | 2.44 mg/dL |
Secondary
E-Selectin
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
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorapaxar | E-Selectin | 43.5 ng/mL |
| Placebo | E-Selectin | 76.5 ng/mL |
Secondary
Interleukin 6
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
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorapaxar | Interleukin 6 | 105 pg/mL |
| Placebo | Interleukin 6 | 180 pg/mL |
Secondary
Plasmin-Antiplasmin Complexes
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
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorapaxar | Plasmin-Antiplasmin Complexes | 745 µg/L |
| Placebo | Plasmin-Antiplasmin Complexes | 1437 µg/L |
Secondary
Platelet Factor 4
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
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorapaxar | Platelet Factor 4 | 53310 pg/mL |
| Placebo | Platelet Factor 4 | 59803 pg/mL |
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.
Time frame: Time points for evaluation were: baseline, 0h, 4h, 24h
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorapaxar | Protease Activated Receptor (PAR)-1 Expression on Platelets | 0.85 fold |
| Placebo | Protease Activated Receptor (PAR)-1 Expression on Platelets | 0.83 fold |
Secondary
P-Selectin
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
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorapaxar | P-Selectin | 30.8 ng/ml |
| Placebo | P-Selectin | 33.1 ng/ml |
Secondary
Thrombin-Antithrombin Complexes
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
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorapaxar | Thrombin-Antithrombin Complexes | 17.4 µg/L |
| Placebo | Thrombin-Antithrombin Complexes | 32.3 µg/L |
Secondary
Thrombomodulin
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
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorapaxar | Thrombomodulin | 5.05 ng/mL |
| Placebo | Thrombomodulin | 5.29 ng/mL |
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
Time frame: Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorapaxar | Tumor Necrosis Factor Alpha | 27 pg/mL |
| Placebo | Tumor Necrosis Factor Alpha | 75 pg/mL |
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 %.
Time frame: Time points for evaluation were baseline, 2h, 4h, 6h, 24h after LPS administration
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorapaxar | Von Willebrand Factor | 162 % of normal |
| Placebo | Von Willebrand Factor | 234 % of normal |