Clinical Trial Results:
Vorapaxar in the human endotoxemia model
Summary
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EudraCT number |
2016-000309-34 |
Trial protocol |
AT |
Global end of trial date |
30 Nov 2016
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Results information
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Results version number |
v1 |
This version publication date |
04 Jan 2019
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First version publication date |
04 Jan 2019
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Other versions |
v2 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
7654321
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Medical University of Vienna
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Sponsor organisation address |
Spitalgasse 23, Vienna, Austria, 1090
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Public contact |
Dept. of Clinical Pharmacology, Medical University of Vienna, 0043 14040029810, klin-pharmakologie@meduniwien.ac.at
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Scientific contact |
Dept. of Clinical Pharmacology, Medical University of Vienna, 0043 14040029810, klin-pharmakologie@meduniwien.ac.at
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 Nov 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Nov 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Nov 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To investigate whether vorapaxar reduces LPS induced coagulation activation assessed by prothrombin fragments F1+2
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Protection of trial subjects |
"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.)" was an inclusion criterion, which was applied to reduce the risk of bleeding.
Paracetamol was available to all subjects to alleviate flu-like symptoms associated with LPS-infusion.
The vorapaxar dose was titrated to a certain effect (based on whole blood aggregometry) to reduce the necessary dose.
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Background therapy |
not applicable- healthy volunteers. | ||
Evidence for comparator |
A placebo tablet was used as a comparator in this trial involving healthy volunteers. Since this was a model, no active treatment was necessary. | ||
Actual start date of recruitment |
01 Jun 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Austria: 16
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Worldwide total number of subjects |
16
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EEA total number of subjects |
16
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
16
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
16 healthy volunteers were included in this trial between July 25th 2016 and November 30th 2016. This was a single center study which was performed at the Medical University of Vienna, Austria. | |||||||||
Pre-assignment
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Screening details |
Sixteen healthy volunteers were screened, which were all successfully included in the trial according to the applicable in- and exclusion criteria. | |||||||||
Period 1
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Period 1 title |
Main Trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Carer | |||||||||
Blinding implementation details |
Placebos and Verum tablets were not distinguishable from each other by their physicochemical properties. An unblinded study nurse under supervision of an unblinded physician who had access to treatment allocation codes prepared study drugs. They were not otherwise involved in conducting the trial.
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Vorapaxar | |||||||||
Arm description |
Verum arm | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Vorapaxar
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Investigational medicinal product code |
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Other name |
Zontivity
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
10mg per os were administered on day 1. On day 2 platelet aggregation (TRAP-induced) was measured and according to the results (80% inhibition compared to baseline were the target) additional 10mg vorapaxar could be added to the initial dose. This was necessary in 2 subjects, in whom platelet inhibition did not achieve the defined criteria.
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Arm title
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Placebo | |||||||||
Arm description |
Subjects received a placebo tablet as a control during experimental endotoxemia | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Placebo tablet
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Healthy volunteers received placebo tablets on day 1. If platelet aggregation did not achieve the predefined target (80% inhibition in TRAP induced whole blood aggregometry), another dose was given to subjects on day 2. This was necessary in all 16 subjects.
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Baseline characteristics reporting groups
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Reporting group title |
Main Trial
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Reporting group description |
16 healthy volunteers were included in this trial. This was designed as a crossover trial meaning that each subject completed both study periods. One subject did not participate in the second study period due to unforeseen unavailability. Thus only 15 subjects were included in the final analysis. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
PP
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
15 Subjects completed the trial per protocol. 1 Subject did not participate in the second study period and was therefore excluded from analysis.
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Subject analysis set title |
FA
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All subjects that were included in the trial
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End points reporting groups
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Reporting group title |
Vorapaxar
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Reporting group description |
Verum arm | ||
Reporting group title |
Placebo
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Reporting group description |
Subjects received a placebo tablet as a control during experimental endotoxemia | ||
Subject analysis set title |
PP
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
15 Subjects completed the trial per protocol. 1 Subject did not participate in the second study period and was therefore excluded from analysis.
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Subject analysis set title |
FA
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects that were included in the trial
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End point title |
Primary Endpoint Prothrombin Fragments F1.2 | ||||||||||||
End point description |
individual maxima in each trial period (vorapaxar or placebo) were compared
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End point type |
Primary
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End point timeframe |
0-24h
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Statistical analysis title |
primary Analysis | ||||||||||||
Statistical analysis description |
Wilcoxon signed rank test
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Comparison groups |
Placebo v Vorapaxar
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.029 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
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End point title |
Thrombin Antithrombin Complexes | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
0-24h, each period
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Statistical analysis title |
TAT | ||||||||||||
Statistical analysis description |
Wilcoxon Signed rank test, individual maxima in both study periods
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Comparison groups |
Vorapaxar v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.005 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
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End point title |
Plasmin Antiplasmin complexes | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
0-24h, both periods
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Statistical analysis title |
PAP | ||||||||||||
Comparison groups |
Vorapaxar v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.012 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
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End point title |
von Willebrand Factor | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
0-24h, both study periods
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Statistical analysis title |
vWF | ||||||||||||
Comparison groups |
Vorapaxar v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.003 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
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End point title |
E-Selectin | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24h, both study periods
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Statistical analysis title |
E-Sel | ||||||||||||
Comparison groups |
Vorapaxar v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.031 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
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End point title |
Thrombomodulin | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
0-24h, both trial periods
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Statistical analysis title |
TM | ||||||||||||
Comparison groups |
Vorapaxar v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.69 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
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End point title |
soluble P-Selectin | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24h, both periods
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Statistical analysis title |
P-Sel | ||||||||||||
Comparison groups |
Vorapaxar v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.27 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
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End point title |
Platelet Factor 4 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24h, both periods
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Statistical analysis title |
PF4 | ||||||||||||
Comparison groups |
Vorapaxar v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.91 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
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End point title |
PAR-1 Receptor Expression | |||||||||
End point description |
Maximum decrease in receptors compared to baseline
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End point type |
Secondary
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End point timeframe |
24h, both periods
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Statistical analysis title |
PAR-1 | |||||||||
Comparison groups |
Vorapaxar v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | |||||||||
P-value |
= 0.19 | |||||||||
Method |
Wilcoxon (Mann-Whitney) | |||||||||
Confidence interval |
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End point title |
Tumor necrosis Factor alpha | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24h, both periods
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Statistical analysis title |
TNFa | ||||||||||||
Comparison groups |
Vorapaxar v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.005 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
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End point title |
Interleukin-6 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24h, both periods.
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Statistical analysis title |
IL6 | ||||||||||||
Comparison groups |
Vorapaxar v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.015 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
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End point title |
C-reactive Protein | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24h, both periods
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Statistical analysis title |
CRP | ||||||||||||
Comparison groups |
Vorapaxar v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.002 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Screening until follow up. The whole study period lasted approximately 3 months for each subject,
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
ICD | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
10
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Reporting groups
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Reporting group title |
Vorapaxar
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Reporting group description |
Verum group | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
short treatment with vorapaxar, very high variability in PF4 levels (sample handling?), timing of vorapaxar dosing (before LPS infusion) | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/29864779 |