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    Clinical Trial Results:
    A Single Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of ER Niacin/Laropiprant in Adolescents with Heterozygous Familial Hypercholesterolemia

    Summary
    EudraCT number
    		 2012-001443-49
    Trial protocol
    		 GB   Outside EU/EEA  
    Global end of trial date
    13 Dec 2012

    Results information
    Results version number
    		 v2(current)
    This version publication date
    24 Apr 2016
    First version publication date
    13 Jun 2015
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    0524A-158
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01583647
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, 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-000063-PIP01-07
    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
    13 Dec 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Dec 2012
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the pharmacokinetics of laropiprant following administration of a single dose of 1 (Panel A) and 2 (Panel B) combination tablets of MK-0524A (1000mg ER niacin/20mg laropiprant) between adolescents with heterozygous familial hypercholesterolemia and healthy adults (historical data from MK-0524A P057 and P059).
    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
    23 Jul 2012
    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
    Norway: 2
    Country: Number of subjects enrolled
    New Zealand: 5
    Country: Number of subjects enrolled
    South Africa: 3
    Worldwide total number of subjects
    10
    EEA total number of subjects
    2
    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)
    10
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 MK-0524A-158 was terminated after the Phase 3 study HPS2-THRIVE (MK-0524A -042;NCT00461630) didn’t meet its primary endpoint of reduction of major vascular events; there was also a significant increase in some types of non-fatal serious adverse events. MK-0524A-158 was terminated after 10 participants completed Panel A. Panel B was not conducted.

    Pre-assignment
    Screening details
    		 The study enrolled participants 10 to 16 years of age, with a genotype-confirmed or clinical diagnosis of heterozygous hypercholesterolemia. Other inclusion and exclusion criteria applied.

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

    Arms
    Arm title
    		 MK-0524A 1 g/20 mg (Panel A)
    Arm description
    		 Single oral dose of 1 tablet of MK-0524A. Each tablet contained Extended Release (ER) Niacin 1g and laropiprant 20 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-0524A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single oral dose of 1 or 2 tablets of MK-0524A (1g ER niacin/20mg laropripant)

    Number of subjects in period 1
    		MK-0524A 1 g/20 mg (Panel A)
    Started
    10
    Completed
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MK-0524A 1 g/20 mg (Panel A)
    Reporting group description
    		 Single oral dose of 1 tablet of MK-0524A. Each tablet contained Extended Release (ER) Niacin 1g and laropiprant 20 mg

    Reporting group values
    		 MK-0524A 1 g/20 mg (Panel A) Total
    Number of subjects
    		 10 10
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.4 ± 0.8 -
    Gender categorical
    Units: Subjects
        Female
    		 5 5
        Male
    		 5 5

    End points

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    End points reporting groups
    Reporting group title
    MK-0524A 1 g/20 mg (Panel A)
    Reporting group description
    		 Single oral dose of 1 tablet of MK-0524A. Each tablet contained Extended Release (ER) Niacin 1g and laropiprant 20 mg

    Primary: Plasma Area Under the Concentration Curve from 0 to infinity (AUC0-∞) of Laropiprant

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    End point title
    		 Plasma Area Under the Concentration Curve from 0 to infinity (AUC0-∞) of Laropiprant [1]
    End point description
    The study was terminated during Panel A and the decision was made to not analyze the blood and urine pharmacokinetic samples collected during Panel A; Panel B was not conducted.
    End point type
    Primary
    End point timeframe
    Predose Day 1 up to 24 hours postdose
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Blood and urine pharmacokinetic samples were not analyzed. No statistical analyses could be performed.
    End point values
    		 MK-0524A 1 g/20 mg (Panel A)
    Number of subjects analysed
    0 [2]
    Units: h r * n g /mL
        geometric mean (confidence interval 95%)
    ( to )
    Notes
    [2] - Blood and urine samples from Panel A were not analyzed.
    No statistical analyses for this end point

    Primary: Plasma Maximum Concentration (Cmax) of Laropiprant

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    End point title
    		 Plasma Maximum Concentration (Cmax) of Laropiprant [3]
    End point description
    The study was terminated during Panel A and the decision was made to not analyze the blood and urine pharmacokinetic samples collected during Panel A; Panel B was not conducted.
    End point type
    Primary
    End point timeframe
    Predose on Day 1 up to 48 hours postdose
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Blood and urine pharmacokinetic samples were not analyzed. No statistical analyses could be performed.
    End point values
    		 MK-0524A 1 g/20 mg (Panel A)
    Number of subjects analysed
    0 [4]
    Units: ng /mL
        geometric mean (confidence interval 95%)
    ( to )
    Notes
    [4] - Blood and urine pharmacokinetic samples collected during Panel A were not analyzed
    No statistical analyses for this end point

    Primary: Total urinary excretion of niacin and niacin metabolites

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    End point title
    		 Total urinary excretion of niacin and niacin metabolites [5]
    End point description
    The study was terminated during Panel A and the decision was made to not analyze the blood and urine pharmacokinetic samples collected during Panel A; Panel B was not conducted.
    End point type
    Primary
    End point timeframe
    Predose on Day 1 up to 72 hours postdose
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Blood and urine pharmacokinetic samples were not analyzed. No statistical analyses could be performed.
    End point values
    		 MK-0524A 1 g/20 mg (Panel A)
    Number of subjects analysed
    0 [6]
    Units: μmol
        geometric mean (confidence interval 95%)
    ( to )
    Notes
    [6] - Blood and urine pharmacokinetic samples collected during Panel A were not analyzed
    No statistical analyses for this end point

    Primary: Plasma Cmax of nicotinuric acid (NUA)

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    End point title
    		 Plasma Cmax of nicotinuric acid (NUA) [7]
    End point description
    The study was terminated during Panel A and the decision was made to not analyze the blood and urine pharmacokinetic samples collected during Panel A; Panel B was not conducted.
    End point type
    Primary
    End point timeframe
    Predose on Day 1 up to 48 hours postdose
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Blood and urine pharmacokinetic samples were not analyzed. No statistical analyses could be performed.
    End point values
    		 MK-0524A 1 g/20 mg (Panel A)
    Number of subjects analysed
    0 [8]
    Units: ng /mL
        geometric mean (confidence interval 95%)
    ( to )
    Notes
    [8] - Blood and urine pharmacokinetic samples collected during Panel A were not analyzed
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to 14 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    1 tablet of MK-0524A 1 g/20 mg
    Reporting group description
    		 Participants who received at least 1 dose of study drug.

    Serious adverse events
    		 1 tablet of MK-0524A 1 g/20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 1 tablet of MK-0524A 1 g/20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 10 (70.00%)
    Injury, poisoning and procedural complications
    Bruising of arm
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Sprain
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Facial flushing
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Renal and urinary disorders
    Diuresis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Low back pain
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    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? Yes
    Date
    Interruption
    Restart date
    13 Dec 2012
    MK-0524A-158 was terminated after the Phase 3 study HPS2-THRIVE (MK-0524A-042;NCT00461630) didn’t meet its primary endpoint of reduction of major vascular events; there was also a significant increase in some types of non-fatal serious adverse events in the Phase 3 HPS2-THRIVE study.
    -

    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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