Trial Outcomes & Findings for Vorapaxar in the Human Endotoxemia Model (NCT NCT02875028)

NCT ID: NCT02875028

Last Updated: 2020-01-10

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 16 participants
• Primary outcome timeframe: Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h
• Results posted on: 2020-01-10

Participant Flow

16 healthy volunteers participated in this crossover trial.

Participant milestones

Measure	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.	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.
First Intervention (24 Hours) STARTED	8	8
First Intervention (24 Hours) COMPLETED	8	8
First Intervention (24 Hours) NOT COMPLETED	0	0
Washout Period STARTED	8	8
Washout Period COMPLETED	8	7
Washout Period NOT COMPLETED	0	1
Second Intervention (24 Hours) STARTED	8	7
Second Intervention (24 Hours) COMPLETED	8	7
Second Intervention (24 Hours) NOT COMPLETED	0	0

Reasons for withdrawal

Measure	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.	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.
Washout Period Withdrawal by Subject	0	1

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Measure	Vorapaxar n=8 Participants 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	Placebo n=8 Participants subjects will be treated with 4 empty lactose-starch capsules Placebo LPS: 2ng/kg Lipopolysaccharide as a bolus infusion	Total n=16 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=16 Participants
Age, Categorical Between 18 and 65 years	8 Participants n=8 Participants	8 Participants n=8 Participants	16 Participants n=16 Participants
Age, Categorical >=65 years	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=16 Participants
Age, Continuous	34 years n=8 Participants	27 years n=8 Participants	31 years n=16 Participants
Sex: Female, Male Female	1 Participants n=8 Participants	0 Participants n=8 Participants	1 Participants n=16 Participants
Sex: Female, Male Male	7 Participants n=8 Participants	8 Participants n=8 Participants	15 Participants n=16 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment Austria	8 participants n=8 Participants	8 participants n=8 Participants	16 participants n=16 Participants
weight	70 kg n=8 Participants	84 kg n=8 Participants	77 kg n=16 Participants

PRIMARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Vorapaxar n=15 Participants Intervention: 10(-20)mg vorapaxar and 2ng/kg bodyweight LPS bolus infusion	Placebo n=16 Participants Intervention: placebo tablet intake (lactose starch) and 2ng/kg bodyweight LPS bolus infusion
Changes in Prothrombin Fragments F1+2	1315 pmol/L Interval 835.0 to 1800.0	2530 pmol/L Interval 1175.0 to 3895.0

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Vorapaxar n=15 Participants Intervention: 10(-20)mg vorapaxar and 2ng/kg bodyweight LPS bolus infusion	Placebo n=15 Participants Intervention: placebo tablet intake (lactose starch) and 2ng/kg bodyweight LPS bolus infusion
Protease Activated Receptor (PAR)-1 Expression on Platelets	0.85 fold Interval 0.78 to 1.01	0.83 fold Interval 0.77 to 0.89

SECONDARY outcome

Timeframe: 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.

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

The individual maxima during the study periods were compared.

Outcome measures

Measure	Vorapaxar n=15 Participants Intervention: 10(-20)mg vorapaxar and 2ng/kg bodyweight LPS bolus infusion	Placebo n=15 Participants Intervention: placebo tablet intake (lactose starch) and 2ng/kg bodyweight LPS bolus infusion
Thrombin-Antithrombin Complexes	17.4 µg/L Interval 8.06 to 25.1	32.3 µg/L Interval 13.9 to 55.2

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Vorapaxar n=15 Participants Intervention: 10(-20)mg vorapaxar and 2ng/kg bodyweight LPS bolus infusion	Placebo n=15 Participants Intervention: placebo tablet intake (lactose starch) and 2ng/kg bodyweight LPS bolus infusion
Plasmin-Antiplasmin Complexes	745 µg/L Interval 625.0 to 1227.0	1437 µg/L Interval 764.0 to 1951.0

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Vorapaxar n=15 Participants Intervention: 10(-20)mg vorapaxar and 2ng/kg bodyweight LPS bolus infusion	Placebo n=15 Participants Intervention: placebo tablet intake (lactose starch) and 2ng/kg bodyweight LPS bolus infusion
E-Selectin	43.5 ng/mL Interval 39.85 to 89.0	76.5 ng/mL Interval 48.0 to 92.5

SECONDARY outcome

Timeframe: 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.

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 %.

Outcome measures

Measure	Vorapaxar n=15 Participants Intervention: 10(-20)mg vorapaxar and 2ng/kg bodyweight LPS bolus infusion	Placebo n=15 Participants Intervention: placebo tablet intake (lactose starch) and 2ng/kg bodyweight LPS bolus infusion
Von Willebrand Factor	162 % of "normal" Interval 122.0 to 193.0	234 % of "normal" Interval 151.0 to 279.0

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Vorapaxar n=15 Participants Intervention: 10(-20)mg vorapaxar and 2ng/kg bodyweight LPS bolus infusion	Placebo n=15 Participants Intervention: placebo tablet intake (lactose starch) and 2ng/kg bodyweight LPS bolus infusion
P-Selectin	30.8 ng/ml Interval 21.6 to 33.9	33.1 ng/ml Interval 22.4 to 37.9

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Vorapaxar n=15 Participants Intervention: 10(-20)mg vorapaxar and 2ng/kg bodyweight LPS bolus infusion	Placebo n=15 Participants Intervention: placebo tablet intake (lactose starch) and 2ng/kg bodyweight LPS bolus infusion
Interleukin 6	105 pg/mL Interval 74.0 to 193.0	180 pg/mL Interval 72.0 to 370.0

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Vorapaxar n=15 Participants Intervention: 10(-20)mg vorapaxar and 2ng/kg bodyweight LPS bolus infusion	Placebo n=15 Participants Intervention: placebo tablet intake (lactose starch) and 2ng/kg bodyweight LPS bolus infusion
Tumor Necrosis Factor Alpha	27 pg/mL Interval 13.0 to 70.0	75 pg/mL Interval 22.0 to 96.0

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Vorapaxar n=15 Participants Intervention: 10(-20)mg vorapaxar and 2ng/kg bodyweight LPS bolus infusion	Placebo n=15 Participants Intervention: placebo tablet intake (lactose starch) and 2ng/kg bodyweight LPS bolus infusion
C-reactive Protein	1.53 mg/dL Interval 1.15 to 2.19	2.44 mg/dL Interval 1.57 to 2.82

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Vorapaxar n=15 Participants Intervention: 10(-20)mg vorapaxar and 2ng/kg bodyweight LPS bolus infusion	Placebo n=15 Participants Intervention: placebo tablet intake (lactose starch) and 2ng/kg bodyweight LPS bolus infusion
Platelet Factor 4	53310 pg/mL Interval 36757.0 to 73273.0	59803 pg/mL Interval 39446.0 to 138624.0

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Vorapaxar n=15 Participants Intervention: 10(-20)mg vorapaxar and 2ng/kg bodyweight LPS bolus infusion	Placebo n=15 Participants Intervention: placebo tablet intake (lactose starch) and 2ng/kg bodyweight LPS bolus infusion
Thrombomodulin	5.05 ng/mL Interval 4.46 to 5.77	5.29 ng/mL Interval 4.58 to 5.49

Adverse Events

Vorapaxar

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Vorapaxar n=15 participants at risk 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	Placebo n=16 participants at risk subjects will be treated with 4 empty lactose-starch capsules Placebo LPS: 2ng/kg Lipopolysaccharide as a bolus infusion
Nervous system disorders headache	53.3% 8/15 • Number of events 8	31.2% 5/16 • Number of events 5
General disorders Dizziness	6.7% 1/15 • Number of events 1	0.00% 0/16
General disorders Chills	26.7% 4/15 • Number of events 4	43.8% 7/16 • Number of events 7
General disorders Myalgia	13.3% 2/15 • Number of events 2	31.2% 5/16 • Number of events 5
General disorders malaise	13.3% 2/15 • Number of events 2	0.00% 0/16
Skin and subcutaneous tissue disorders exanthema	0.00% 0/15	6.2% 1/16 • Number of events 1

Additional Information

Bernd Jilma

Medical University of Vienna

Phone: +4314040029910

Email: bernd.jilma@meduniwien.ac.at

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place