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    Clinical Trial Results:
    A Comparative Bioavailability Study of a Tablet versus an Investigational Oral Suspension of Vorapaxar

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2014-004350-34
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    12 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Feb 2016
    First version publication date
    18 Feb 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    P08074
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Study Number: MK-5348-040
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000778-PIP02-12
    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
    12 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to evaluate the comparative bioavailability between Vorapaxar (MK-5348) 0.2085 mg/mL 10 mL Oral Solution and Vorapaxar (MK-5348) 2.08 mg Tablets (Zontivity™) after a single dose in healthy participants under fasting conditions.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Oct 2014
    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
    Canada: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    0
    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)
    24
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was an open-label, single-dose, randomized, two-period, two-treatment, two-sequence, crossover study.

    Pre-assignment
    Screening details
    		 Healthy, non-smoking, male and female participants, from 18 to 55 years of age with body mass index (BMI) ≥19.0 and ≤30.0 kg/m^2 and weight ≥60 kg. Other inclusion and exclusion criteria applied.

    Period 1
    Period 1 title
    Period 1 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All Enrolled
    Arm description
    		 Participants received single oral dose of Vorapaxar 0.2085 mg/mL 10 mL Oral Solution and Vorapaxar 2.08 mg Tablets (Zontivity™) in a crossover fashion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vorapaxar 0.2085 mg/mL 10 mL Oral Solution
    Investigational medicinal product code
    Other name
    MK-5348
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Single oral dose of Vorapaxar 0.2085 mg/mL 10 mL Oral Solution

    Investigational medicinal product name
    Vorapaxar 0.2085 mg tablet
    Investigational medicinal product code
    Other name
    MK-5348; Zontivity
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single oral dose of Vorapaxar 0.2085 mg tablet

    Number of subjects in period 1
    		All Enrolled
    Started
    24
    Completed
    24

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    All Enrolled
    Reporting group description
    		 Participants received single oral dose of Vorapaxar 0.2085 mg/mL 10 mL Oral Solution and Vorapaxar 2.08 mg Tablets (Zontivity™) in a crossover fashion.

    Reporting group values
    		 All Enrolled Total
    Number of subjects
    		 24 24
    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)
    		 24 24
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44 ± 8 -
    Gender Categorical
    Units: Subjects
        Female
    		 14 14
        Male
    		 10 10

    End points

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    End points reporting groups
    Reporting group title
    All Enrolled
    Reporting group description
    		 Participants received single oral dose of Vorapaxar 0.2085 mg/mL 10 mL Oral Solution and Vorapaxar 2.08 mg Tablets (Zontivity™) in a crossover fashion.

    Subject analysis set title
    Vorapaxar-Oral Solution
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who received single oral dose of vorapaxar oral solution regardless of sequence.

    Subject analysis set title
    Vorapaxar-Tablet
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who received single oral dose of vorapaxar tablet regardless of sequence.

    Primary: Area Under the Concentration-time Curve From Time 0 to the LastMeasurable Sample (AUC0-last)

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    End point title
    		 Area Under the Concentration-time Curve From Time 0 to the LastMeasurable Sample (AUC0-last)
    End point description
    Blood samples taken at pre-dose (0-hour) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 24, 48, and 72 hours after drug administration to determine the AUC0-last. Results were natural log-transformed and analyzed with a linear mixed effects model with fixed effects terms for treatment and period.
    End point type
    Primary
    End point timeframe
    Pre‐dose (0‐hour) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 24, 48, and 72 hours after drug administration
    End point values
    		 Vorapaxar-Oral Solution Vorapaxar-Tablet
    Number of subjects analysed
    24
    24
    Units: nM•hr
        geometric mean (confidence interval 95%)
    634 (571 to 704)
    629 (570 to 695)
    Statistical analysis title
    		 Bioequivalence
    Statistical analysis description
    Geometric mean ratio (GMR) determined by dividing the GM for Oral solution by GM for tablet. The two forms were considered bioequivalent if the 90% confidence interval for the GMR was within 80.00-125.00%
    Comparison groups
    Vorapaxar-Oral Solution v Vorapaxar-Tablet
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 GMR
    Point estimate
    100.72
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 97.86
         upper limit
    		 103.66

    Primary: Maximum measured analyte concentration over the sampling period (Cmax)

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    End point title
    		 Maximum measured analyte concentration over the sampling period (Cmax)
    End point description
    Blood samples taken at pre-dose (0-hour) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 24, 48, and 72 hours after drug administration to determine the Cmax. Results were natural log-transformed and analyzed with a linear mixed effects model with fixed effects terms for treatment and period.
    End point type
    Primary
    End point timeframe
    Pre‐dose (0‐hour) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 24, 48, and 72 hours after drug administration
    End point values
    		 Vorapaxar-Oral Solution Vorapaxar-Tablet
    Number of subjects analysed
    24
    24
    Units: nM
        geometric mean (confidence interval 95%)
    54.1 (50 to 58.4)
    48.7 (44.4 to 53.5)
    Statistical analysis title
    		 Geometric mean ratio (GMR)
    Statistical analysis description
    GMR determined by dividing the GM for Oral solution by GM for tablet. The two forms were considered bioequivalent if the 90% confidence interval for the GMR was within 80.00-125.00%.
    Comparison groups
    Vorapaxar-Oral Solution v Vorapaxar-Tablet
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric mean ratio (GMR)
    Point estimate
    110.94
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 101.52
         upper limit
    		 121.24

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to 14 days after last dose of study drug for each period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Vorapaxar-Oral Solution
    Reporting group description
    		 All participants who received single oral dose of vorapaxar oral solution regardless of sequence

    Reporting group title
    Vorapaxar-Tablet
    Reporting group description
    		 All participants who received single oral dose of vorapaxar tablet regardless of sequence

    Serious adverse events
    		 Vorapaxar-Oral Solution Vorapaxar-Tablet
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 24 (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: 5%
    Non-serious adverse events
    		 Vorapaxar-Oral Solution Vorapaxar-Tablet
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 24 (4.17%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 24 (4.17%)
         occurrences all number
    2
    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.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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