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    Clinical Trial Results:
    Vorapaxar in the human endotoxemia model

    Summary
    EudraCT number
    		 2016-000309-34
    Trial protocol
    		 AT  
    Global end of trial date
    30 Nov 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    03 Sep 2019
    First version publication date
    04 Jan 2019
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    We have falsely described the statistical testing as testing for "equivalence", while it was done for "superiority". This will be corrected.

    Trial information

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    Trial identification
    Sponsor protocol code
    7654321
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University of Vienna
    Sponsor organisation address
    Spitalgasse 23, Vienna, Austria, 1090
    Public contact
    Dept. of Clinical Pharmacology, Medical University of Vienna, 0043 14040029810, klin-pharmakologie@meduniwien.ac.at
    Scientific contact
    Dept. of Clinical Pharmacology, Medical University of Vienna, 0043 14040029810, klin-pharmakologie@meduniwien.ac.at
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate whether vorapaxar reduces LPS induced coagulation activation assessed by prothrombin fragments F1+2
    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.
    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
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 16
    Worldwide total number of subjects
    16
    EEA total number of subjects
    16
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    16
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    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
    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
    Period 1 title
    Main Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    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.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Vorapaxar
    Arm description
    		 Verum arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vorapaxar
    Investigational medicinal product code
    Other name
    Zontivity
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    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.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received a placebo tablet as a control during experimental endotoxemia
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    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.

    Number of subjects in period 1
    		Vorapaxar Placebo
    Started
    15
    16
    Completed
    15
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Main Trial
    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.

    Reporting group values
    		 Main Trial Total
    Number of subjects
    		 16 16
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 16 16
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
        Age group
    		 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 31 (27 to 34) -
    Gender categorical
    Units: Subjects
        Female
    		 1 1
        Male
    		 15 15
    Weight
    Units: kg
        median (inter-quartile range (Q1-Q3))
    		 77 (67 to 88) -
    Subject analysis sets

    Subject analysis set title
    PP
    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.

    Subject analysis set title
    FA
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects that were included in the trial

    Subject analysis sets values
    		 PP FA
    Number of subjects
    15
    16
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    15
    15
        From 65-84 years
    0
    0
        85 years and over
    0
    0
        Age group
    0
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    30 (26 to 34)
    31 (27 to 34)
    Gender categorical
    Units: Subjects
        Female
    1
    1
        Male
    14
    15
    Weight
    Units: kg
        median (inter-quartile range (Q1-Q3))
    73 (67 to 87)
    77 (67 to 88)

    End points

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    End points reporting groups
    Reporting group title
    Vorapaxar
    Reporting group description
    		 Verum arm

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received a placebo tablet as a control during experimental endotoxemia

    Subject analysis set title
    PP
    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.

    Subject analysis set title
    FA
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects that were included in the trial

    Primary: Primary Endpoint Prothrombin Fragments F1.2

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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
    End point type
    Primary
    End point timeframe
    0-24h
    End point values
    		 Vorapaxar Placebo
    Number of subjects analysed
    15
    15
    Units: pmol/L
        median (inter-quartile range (Q1-Q3))
    1315 (835 to 1800)
    2530 (1175 to 3895)
    Statistical analysis title
    		 primary Analysis
    Statistical analysis description
    Wilcoxon signed rank test
    Comparison groups
    Placebo v Vorapaxar
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.029
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Thrombin Antithrombin Complexes

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    End point title
    		 Thrombin Antithrombin Complexes
    End point description
    End point type
    Secondary
    End point timeframe
    0-24h, each period
    End point values
    		 Vorapaxar Placebo
    Number of subjects analysed
    15
    15
    Units: µg/L
        median (inter-quartile range (Q1-Q3))
    17.4 (8.06 to 25.10)
    32.30 (3.9 to 55.2)
    Statistical analysis title
    		 TAT
    Statistical analysis description
    Wilcoxon Signed rank test, individual maxima in both study periods
    Comparison groups
    Vorapaxar v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Plasmin Antiplasmin complexes

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    End point title
    		 Plasmin Antiplasmin complexes
    End point description
    End point type
    Secondary
    End point timeframe
    0-24h, both periods
    End point values
    		 Vorapaxar Placebo
    Number of subjects analysed
    15
    15
    Units: µg/L
        median (inter-quartile range (Q1-Q3))
    745 (625 to 1227)
    1437 (764 to 1951)
    Statistical analysis title
    		 PAP
    Comparison groups
    Vorapaxar v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: von Willebrand Factor

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    End point title
    		 von Willebrand Factor
    End point description
    End point type
    Secondary
    End point timeframe
    0-24h, both study periods
    End point values
    		 Vorapaxar Placebo
    Number of subjects analysed
    15
    15
    Units: %
        median (inter-quartile range (Q1-Q3))
    162 (122 to 193)
    234 (151 to 279)
    Statistical analysis title
    		 vWF
    Comparison groups
    Vorapaxar v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: E-Selectin

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    End point title
    		 E-Selectin
    End point description
    End point type
    Secondary
    End point timeframe
    24h, both study periods
    End point values
    		 Vorapaxar Placebo
    Number of subjects analysed
    15
    15
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    43.5 (39.85 to 89)
    76.5 (48 to 92.5)
    Statistical analysis title
    		 E-Sel
    Comparison groups
    Vorapaxar v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.031
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Thrombomodulin

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    End point title
    		 Thrombomodulin
    End point description
    End point type
    Secondary
    End point timeframe
    0-24h, both trial periods
    End point values
    		 Vorapaxar Placebo
    Number of subjects analysed
    15
    15
    Units: ng/mL
        median (inter-quartile range (Q1-Q3))
    5.05 (4.46 to 5.77)
    5.29 (4.58 to 5.49)
    Statistical analysis title
    		 TM
    Comparison groups
    Vorapaxar v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.69
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: soluble P-Selectin

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    End point title
    		 soluble P-Selectin
    End point description
    End point type
    Secondary
    End point timeframe
    24h, both periods
    End point values
    		 Vorapaxar Placebo
    Number of subjects analysed
    15
    15
    Units: ng/mL
        median (inter-quartile range (Q1-Q3))
    30.8 (21.6 to 33.9)
    33.1 (22.4 to 37.9)
    Statistical analysis title
    		 P-Sel
    Comparison groups
    Vorapaxar v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.27
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Platelet Factor 4

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    End point title
    		 Platelet Factor 4
    End point description
    End point type
    Secondary
    End point timeframe
    24h, both periods
    End point values
    		 Vorapaxar Placebo
    Number of subjects analysed
    15
    15
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    53310 (36757 to 73273)
    59803 (39446 to 138624)
    Statistical analysis title
    		 PF4
    Comparison groups
    Vorapaxar v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.91
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: PAR-1 Receptor Expression

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    End point title
    		 PAR-1 Receptor Expression
    End point description
    Maximum decrease in receptors compared to baseline
    End point type
    Secondary
    End point timeframe
    24h, both periods
    End point values
    		 Vorapaxar Placebo
    Number of subjects analysed
    15
    15
    Units: Receptors on platelets
    121
    118
    Statistical analysis title
    		 PAR-1
    Comparison groups
    Vorapaxar v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Tumor necrosis Factor alpha

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    End point title
    		 Tumor necrosis Factor alpha
    End point description
    End point type
    Secondary
    End point timeframe
    24h, both periods
    End point values
    		 Vorapaxar Placebo
    Number of subjects analysed
    15
    15
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    27 (13 to 70)
    75 (22 to 96)
    Statistical analysis title
    		 TNFa
    Comparison groups
    Vorapaxar v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Interleukin-6

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    End point title
    		 Interleukin-6
    End point description
    End point type
    Secondary
    End point timeframe
    24h, both periods.
    End point values
    		 Vorapaxar Placebo
    Number of subjects analysed
    15
    15
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    82.03 (49.48 to 220.39)
    227.7 (103.20 to 320.20)
    Statistical analysis title
    		 IL6
    Comparison groups
    Vorapaxar v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: C-reactive Protein

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    End point title
    		 C-reactive Protein
    End point description
    End point type
    Secondary
    End point timeframe
    24h, both periods
    End point values
    		 Vorapaxar Placebo
    Number of subjects analysed
    15
    15
    Units: mg/dL
        median (inter-quartile range (Q1-Q3))
    1.53 (1.15 to 2.19)
    2.44 (1.57 to 2.82)
    Statistical analysis title
    		 CRP
    Comparison groups
    Vorapaxar v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening until follow up. The whole study period lasted approximately 3 months for each subject,
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ICD
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Vorapaxar
    Reporting group description
    		 Verum group

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Vorapaxar Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Vorapaxar Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 15 (73.33%)
    12 / 16 (75.00%)
    Nervous system disorders
    Headache
    Additional description: commonly associated with endotoxemia
         subjects affected / exposed
    8 / 15 (53.33%)
    5 / 16 (31.25%)
         occurrences all number
    8
    5
    Dizziness
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chills
    Additional description: Chills are a regularly associated with endotoxemia
         subjects affected / exposed
    4 / 15 (26.67%)
    7 / 16 (43.75%)
         occurrences all number
    4
    7
    Myalgia
    Additional description: myalgia is commonly associated with endotoxemia
         subjects affected / exposed
    2 / 15 (13.33%)
    5 / 16 (31.25%)
         occurrences all number
    2
    5
    malaise
    Additional description: Commonly associated with endoxemia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    Skin and subcutaneous tissue disorders
    Exanthema
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    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
    http://www.ncbi.nlm.nih.gov/pubmed/29864779
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