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    Clinical Trial Results:
    A double-blind, placebo-controlled, randomized study to evaluate the efficacy and safety of TAK-475 or placebo when co-administered with current lipid-lowering therapy in subjects with homozygous familial hypercholesterolemia

    Summary
    EudraCT number
    2005-003626-26
    Trial protocol
    GB  
    Global end of trial date
    04 May 2008

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Mar 2016
    First version publication date
    01 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    01-05-TL-475-016
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00263081
    WHO universal trial number (UTN)
    U1111-1122-7919
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    One Takeda Parkway, Deerfield, IL , United States, 60015
    Public contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, trialdisclosures@takeda.com
    Scientific contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, trialdisclosures@takeda.com
    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?
    Yes
    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
    15 Oct 2007
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Dec 2006
    Global end of trial reached?
    Yes
    Global end of trial date
    04 May 2008
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the effect of TAK-475 QD compared to placebo on low-density lipoprotein cholesterol (LDL-C) in subjects with HoFH when co-administered with current lipid-lowering therapy for 12 weeks. This study was prematurely terminated since overall profile of the compound does not offer significant clinical advantage to patients over currently available lipid lowering agents.
    Protection of trial subjects
    All participants signed an informed consent form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Nov 2005
    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
    United States: 8
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    South Africa: 3
    Country: Number of subjects enrolled
    United Kingdom: 1
    Worldwide total number of subjects
    44
    EEA total number of subjects
    20
    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)
    7
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    30
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study at 12 investigative sites in the United States, Canada, France, Poland, Netherlands, the United Kingdom, South Africa, and Israel from 22 November 2005 to 4 May 2008.

    Pre-assignment
    Screening details
    Participants with a diagnosis of homozygous familial hypercholesterolemia were enrolled equally in 1 of 23 treatment groups, once a day placebo, 50 mg or 100 mg or lapaquistat acetate (depending on participant screening body weight of <50 or >=50kg) followed by 50 mg or/ 100 mg lapaquistat acetate open label.

    Period 1
    Period 1 title
    Double-Blind (DB) Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    lapaquistat acetate
    Arm description
    Lapaquistat acetate, 50 or 100 mg based on body weight, orally, once daily, for 12 weeks, co-administered with the participant's current lipid lowering therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    lapaquistat acetate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    lapaquistat acetate tablet

    Arm title
    Placebo
    Arm description
    Placebo matching lapaquistat acetate, tablets, orally, once daily, for 12 weeks, co-administered with the participant's current lipid lowering therapy
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo matching lapaquistat acetate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching lapaquistat acetate

    Number of subjects in period 1
    lapaquistat acetate Placebo
    Started
    23
    21
    Completed
    23
    21
    Period 2
    Period 2 title
    Open-Label (OL) Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    lapaquistat acetate
    Arm description
    Lapaquistat acetate 50 or 100 mg based on body weight, tablets, orally, once daily, co-administered with the participant's current lipid lowering therapy during the open label treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    lapaquistat acetate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    lapaquistat acetate tablet

    Number of subjects in period 2 [1]
    lapaquistat acetate
    Started
    40
    Completed
    0
    Not completed
    40
         Voluntary Withdrawal
             7
         Other
             2
         Major Protocol Deviation
             2
         Study Termination
             26
         Adverse event, non-fatal
             2
         Lost to follow-up
             1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 4 participants enrolled in the Double-blind Treatment Period of the study did not enter the Open Label Treatment Period of the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    lapaquistat acetate
    Reporting group description
    Lapaquistat acetate, 50 or 100 mg based on body weight, orally, once daily, for 12 weeks, co-administered with the participant's current lipid lowering therapy.

    Reporting group title
    Placebo
    Reporting group description
    Placebo matching lapaquistat acetate, tablets, orally, once daily, for 12 weeks, co-administered with the participant's current lipid lowering therapy

    Reporting group values
    lapaquistat acetate Placebo Total
    Number of subjects
    23 21 44
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    4 3 7
        Adolescents (12-17 years)
    5 1 6
        Adults (18-64 years)
    13 17 30
        From 65-84 years
    1 0 1
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    24 ± 15.1 28 ± 13.63 -
    Gender categorical
    Units: Subjects
        Female
    11 8 19
        Male
    12 13 25
    Race
    Units: Subjects
        American Indian/Alaskan Native
    1 2 3
        Asian
    0 1 1
        Black/African American
    2 0 2
        White
    20 18 38
    Smoking Classification
    Units: Subjects
        Subject never smoked
    19 16 35
        Subject is a current smoker
    2 5 7
        Subject is a former smoker
    2 0 2
    Family History of Premature Coronary Heart Disease
    Units: Subjects
        Yes
    13 12 25
        No
    9 8 17
        Unknown
    1 1 2
    Genotypic Diagnosis of Homozygous Familial Hypercholesterolemia (HoFH) Confirmed at Baseline
    Units: Subjects
        Yes
    21 19 40
        No
    2 2 4
    Low-Density Lipoprotein Apheresis
    Units: Subjects
        Yes
    17 13 30
        No
    6 8 14
    Baseline Weight
    Units: Subjects
        <50 kg
    6 5 11
        ≥50 kg
    17 16 33
    Height
    Units: cm
        arithmetic mean (standard deviation)
    161.9 ± 14.08 162.5 ± 15.08 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    61.71 ± 20.1 65.3 ± 25.38 -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    22.94 ± 5.44 23.81 ± 5.9 -

    End points

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    End points reporting groups
    Reporting group title
    lapaquistat acetate
    Reporting group description
    Lapaquistat acetate, 50 or 100 mg based on body weight, orally, once daily, for 12 weeks, co-administered with the participant's current lipid lowering therapy.

    Reporting group title
    Placebo
    Reporting group description
    Placebo matching lapaquistat acetate, tablets, orally, once daily, for 12 weeks, co-administered with the participant's current lipid lowering therapy
    Reporting group title
    lapaquistat acetate
    Reporting group description
    Lapaquistat acetate 50 or 100 mg based on body weight, tablets, orally, once daily, co-administered with the participant's current lipid lowering therapy during the open label treatment period.

    Primary: Percent Change from Baseline in Direct Low Density Lipoprotein Cholesterol

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    End point title
    Percent Change from Baseline in Direct Low Density Lipoprotein Cholesterol
    End point description
    Fasting blood samples were collected and sent to a central laboratory for analysis of Direct Low Density Lipoprotein Cholesterol in millimoles/liter (mmol/L). The percent change was calculated as the value at Week 12 - Value at Baseline/Value at Baseline * 100. A negative percent change indicated improvement.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12 or Final Visit
    End point values
    lapaquistat acetate Placebo
    Number of subjects analysed
    23
    21
    Units: Percent change
        least squares mean (standard error)
    -10.66 ± 3.769
    -3.59 ± 3.945
    Statistical analysis title
    Primary Endpoint Analysis
    Comparison groups
    lapaquistat acetate v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.203 [1]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -7.065
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.102
         upper limit
    3.971
    Notes
    [1] - Analysis of covariance (ANCOVA) model with terms for treatment effect and baseline value (as covariate).

    Secondary: Percent Change from Baseline in Calculated Low Density Lipoprotein Cholesterol

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    End point title
    Percent Change from Baseline in Calculated Low Density Lipoprotein Cholesterol
    End point description
    Fasting blood samples were collected and sent to a central laboratory for analysis of calculated Low Density Lipoprotein Cholesterol in millimoles/liter (mmol/L). The percent change was calculated as the value at Week 12 - Value at Baseline/Value at Baseline * 100. A negative percent change indicated improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12 or Final Visit
    End point values
    lapaquistat acetate Placebo
    Number of subjects analysed
    23
    21
    Units: Percent change
        least squares mean (standard error)
    -11.27 ± 3.672
    -4.6 ± 3.843
    Statistical analysis title
    Secondary Endpoint Analysis
    Comparison groups
    lapaquistat acetate v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.217 [2]
    Method
    ANCOVA
    Parameter type
    Median difference (final values)
    Point estimate
    -6.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.419
         upper limit
    4.079
    Notes
    [2] - Analysis of covariance (ANCOVA) model with terms for treatment effect and baseline value (as covariate).

    Secondary: Percent Change from Baseline in non- High Density Lipoprotein Cholesterol

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    End point title
    Percent Change from Baseline in non- High Density Lipoprotein Cholesterol
    End point description
    Fasting blood samples were collected and sent to a central laboratory for analysis of non-High Density Lipoprotein Cholesterol in millimoles/liter (mmol/L). The percent change was calculated as the value at Week 12 - Value at Baseline/Value at Baseline * 100. A negative percent change indicated improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12 or Final Visit
    End point values
    lapaquistat acetate Placebo
    Number of subjects analysed
    23
    21
    Units: Percent change
        least squares mean (standard error)
    -11.11 ± 3.62
    -3.9 ± 3.789
    Statistical analysis title
    Secondary Endpoint Analysis
    Comparison groups
    lapaquistat acetate v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.177 [3]
    Method
    ANCOVA
    Parameter type
    Median difference (final values)
    Point estimate
    -7.209
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.809
         upper limit
    3.39
    Notes
    [3] - Analysis of covariance (ANCOVA) model with terms for treatment effect and baseline value (as covariate).

    Secondary: Percent Change from Baseline in Triglycerides

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    End point title
    Percent Change from Baseline in Triglycerides
    End point description
    Fasting blood samples were collected and sent to a central laboratory for analysis of Triglycerides in millimoles/liter (mmol/). The percent change was calculated as the value at Week 12/Value at Baseline * 100. A negative percent change indicated improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12 or Final Visit
    End point values
    lapaquistat acetate Placebo
    Number of subjects analysed
    23
    21
    Units: Percent change
        least squares mean (standard error)
    -5.203 ± 6.5399
    9.242 ± 6.8454
    Statistical analysis title
    Secondary Endpoint Analysis
    Comparison groups
    lapaquistat acetate v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.135 [4]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -14.446
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -33.6
         upper limit
    4.709
    Notes
    [4] - Analysis of covariance (ANCOVA) model with terms for treatment effect and baseline value (as covariate).

    Secondary: Percent Change from Baseline in Total Cholesterol

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    End point title
    Percent Change from Baseline in Total Cholesterol
    End point description
    Fasting blood samples were collected and sent to a central laboratory for analysis of Total Cholesterol in millimoles/liter (mmol/L). The percent change was calculated as the value at Week 12 - Value at Baseline/Value at Baseline * 100. A negative percent change indicated improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12 or Final Visit
    End point values
    lapaquistat acetate Placebo
    Number of subjects analysed
    23
    21
    Units: Percent change
        least squares mean (standard error)
    -10.01 ± 3.348
    -3.39 ± 3.504
    Statistical analysis title
    Secondary Endpoint Analysis
    Comparison groups
    lapaquistat acetate v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.18 [5]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -6.615
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.418
         upper limit
    3.187
    Notes
    [5] - Analysis of covariance (ANCOVA) model with terms for treatment effect and baseline value (as covariate).

    Secondary: Percent Change from Baseline in High Density Lipoprotein Cholesterol

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    End point title
    Percent Change from Baseline in High Density Lipoprotein Cholesterol
    End point description
    Fasting blood samples were collected and sent to a central laboratory for analysis of High Density Lipoprotein Cholesterol in millimoles/liter (mmol/L). The percent change was calculated as the value at Week 12 - Value at Baseline/Value at Baseline * 100. A negative percent change indicated improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12 or Final Visit
    End point values
    lapaquistat acetate Placebo
    Number of subjects analysed
    23
    21
    Units: Percent change
        least squares mean (standard error)
    -4.97 ± 2.712
    2.28 ± 2.838
    Statistical analysis title
    Secondary Endpoint Analysis
    Comparison groups
    lapaquistat acetate v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.072 [6]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -7.248
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.178
         upper limit
    0.681
    Notes
    [6] - Analysis of covariance (ANCOVA) model with terms for treatment effect and baseline value (as covariate).

    Secondary: Percent Change from Baseline in Very Low Density Lipoprotein Cholesterol

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    End point title
    Percent Change from Baseline in Very Low Density Lipoprotein Cholesterol
    End point description
    Fasting blood samples were collected and sent to a central laboratory for analysis of Very Low Density Lipoprotein Cholesterol in millimoles/liter (mmol/L). The percent change was calculated as the value at Week 12 - Value at Baseline/Value at Baseline * 100. A negative percent change indicated improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12 or Final Visit
    End point values
    lapaquistat acetate Placebo
    Number of subjects analysed
    23
    21
    Units: Percent change
        least squares mean (standard error)
    -4.88 ± 6.826
    9.61 ± 7.145
    Statistical analysis title
    Secondary Endpoint Analysis
    Comparison groups
    lapaquistat acetate v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.151 [7]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -14.495
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -34.488
         upper limit
    5.497
    Notes
    [7] - Analysis of covariance (ANCOVA) model with terms for treatment effect and baseline value (as covariate).

    Secondary: Percent Change from Baseline in Apolipoprotein A1

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    End point title
    Percent Change from Baseline in Apolipoprotein A1
    End point description
    Fasting blood samples were collected and sent to a central laboratory for analysis of Apolipoprotein A1 in milligrams/deciliter (mg/dL). The percent change was calculated as the value at Week 12/Value at Baseline * 100. A negative percent change indicated improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12 or Final Visit
    End point values
    lapaquistat acetate Placebo
    Number of subjects analysed
    23
    21
    Units: mg/dL
        least squares mean (standard error)
    -2.68 ± 3.048
    0.04 ± 3.191
    Statistical analysis title
    Secondary Endpoint Analysis
    Comparison groups
    lapaquistat acetate v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.541 [8]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.65
         upper limit
    6.2
    Notes
    [8] - Analysis of covariance (ANCOVA) model with terms for treatment effect and baseline value (as covariate).

    Secondary: Percent Change from Baseline in Apolipoprotein B

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    End point title
    Percent Change from Baseline in Apolipoprotein B
    End point description
    Fasting blood samples were collected and sent to a central laboratory for analysis of Apolipoprotein B in milligrams/deciliter (mg/dL). The percent change was calculated as the value at Week 12 - Value at Baseline/Value at Baseline * 100. A negative percent change indicated improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12 or Final Visit
    End point values
    lapaquistat acetate Placebo
    Number of subjects analysed
    23
    21
    Units: Percent change
        least squares mean (standard error)
    -8.59 ± 3.379
    -3.97 ± 3.536
    Statistical analysis title
    Secondary Endpoint Analysis
    Comparison groups
    lapaquistat acetate v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.35 [9]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -4.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.51
         upper limit
    5.26
    Notes
    [9] - Analysis of covariance (ANCOVA) model with terms for treatment effect and baseline value (as covariate).

    Secondary: Change from Baseline in the Ratio of Low Density Lipoprotein Cholesterol (LDL-C)/High Density Lipoprotein Cholesterol (HDL-C)

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    End point title
    Change from Baseline in the Ratio of Low Density Lipoprotein Cholesterol (LDL-C)/High Density Lipoprotein Cholesterol (HDL-C)
    End point description
    Fasting blood samples were collected and sent to a central laboratory for analysis of LDL-C and HDL-C. The ratio of LDL-C/HDL-C was calculated.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12 or Final Visit
    End point values
    lapaquistat acetate Placebo
    Number of subjects analysed
    23
    21
    Units: mmol/L
        least squares mean (standard error)
    -0.13 ± 0.53
    -0.65 ± 0.555
    Statistical analysis title
    Secondary Endpoint Analysis
    Comparison groups
    lapaquistat acetate v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.504 [10]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.518
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.033
         upper limit
    2.068
    Notes
    [10] - Analysis of covariance (ANCOVA) model with terms for treatment effect and baseline value (as covariate).

    Secondary: Change from Baseline in the Ratio of Total Cholesterol (TC)/High Density Lipoprotein Cholesterol (HDL-C)

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    End point title
    Change from Baseline in the Ratio of Total Cholesterol (TC)/High Density Lipoprotein Cholesterol (HDL-C)
    End point description
    Fasting blood samples were collected and sent to a central laboratory for analysis of Total Cholesterol and HDL-C.. The ratio of Total Cholesterol/HDL-C was calculated.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12 or Final Visit
    End point values
    lapaquistat acetate Placebo
    Number of subjects analysed
    23
    21
    Units: mmol/L
        least squares mean (standard error)
    -0.19 ± 0.528
    -0.72 ± 0.553
    Statistical analysis title
    Secondary Endpoint Analysis
    Comparison groups
    lapaquistat acetate v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.491 [11]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.532
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.014
         upper limit
    2.077
    Notes
    [11] - Analysis of covariance (ANCOVA) model with terms for treatment effect and baseline value (as covariate).

    Secondary: Change from Baseline in the Ratio of Apolipoprotein B/Apolipoprotein A1

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    End point title
    Change from Baseline in the Ratio of Apolipoprotein B/Apolipoprotein A1
    End point description
    Fasting blood samples were collected and sent to a central laboratory for analysis of Apolipoprotein A1 and Apolipoprotein B. The ratio of Apolipoprotein B/Apolipoprotein A1 was calculated.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12 or Final Visit
    End point values
    lapaquistat acetate Placebo
    Number of subjects analysed
    23
    21
    Units: mg/dL
        least squares mean (standard error)
    -0.09 ± 0.109
    -0.09 ± 0.114
    Statistical analysis title
    Secondary Endpoint Analysis
    Comparison groups
    lapaquistat acetate v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.975 [12]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.005
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.324
         upper limit
    0.314
    Notes
    [12] - Analysis of covariance (ANCOVA) model with terms for treatment effect and baseline value (as covariate).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 30 days after the last dose of study drug (up to 73 weeks).
    Adverse event reporting additional description
    Due to the design of the study, the most common (≥ 5%) non-serious adverse events were determined separately for each period of the study, the Double Blind period and the Open Label period. A result of 0 in a column means that the event did not meet the ≥ 5% threshold for that study period but did meet the threshold for the other study period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    lapaquistat acetate
    Reporting group description
    Lapaquistat acetate, 50 or 100 mg based on body weight, orally, once daily, for 12 weeks, co-administered with the participant's current lipid lowering therapy.

    Reporting group title
    Placebo
    Reporting group description
    Placebo matching lapaquistat acetate, tablets, orally, once daily, for 12 weeks, co-administered with the participant's current lipid lowering therapy

    Reporting group title
    Lapaquistat acetate 50 mg _OL
    Reporting group description
    Lapaquistat acetate, 50 mg based on body weight, orally, once daily, co-administered with the participant's current lipid lowering therapy in the open-label (OL) treatment period.

    Reporting group title
    Lapaquistat acetate 100 mg _OL
    Reporting group description
    Lapaquistat acetate, 100 mg based on body weight, orally, once daily, co-administered with the participant's current lipid lowering therapy in the open-label (OL) treatment period.

    Serious adverse events
    lapaquistat acetate Placebo Lapaquistat acetate 50 mg _OL Lapaquistat acetate 100 mg _OL
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 21 (4.76%)
    1 / 10 (10.00%)
    3 / 30 (10.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Leiomyoma
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery stenosis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    lapaquistat acetate Placebo Lapaquistat acetate 50 mg _OL Lapaquistat acetate 100 mg _OL
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 23 (30.43%)
    10 / 21 (47.62%)
    8 / 10 (80.00%)
    23 / 30 (76.67%)
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Xanthoma
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Malaise
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Injury, poisoning and procedural complications
    Muscle strain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Red blood cells urine
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    4 / 30 (13.33%)
         occurrences all number
    0
    0
    0
    5
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 21 (9.52%)
    0 / 10 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Cardiac disorders
    Aortic valve incompetence
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Pharyngolaryngeal pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Wheezing
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 21 (9.52%)
    1 / 10 (10.00%)
    2 / 30 (6.67%)
         occurrences all number
    3
    2
    1
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 23 (4.35%)
    4 / 21 (19.05%)
    1 / 10 (10.00%)
    1 / 30 (3.33%)
         occurrences all number
    1
    5
    1
    1
    Constipation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    1
    2
    Diarrhoea
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Dyspepsia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Toothache
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    0
    0
    3
    Vomiting
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 21 (9.52%)
    2 / 10 (20.00%)
    1 / 30 (3.33%)
         occurrences all number
    5
    2
    4
    1
    Nausea
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    5
    0
    0
    5
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    2 / 10 (20.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    5 / 30 (16.67%)
         occurrences all number
    0
    0
    0
    6
    Muscle spasms
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Musculoskeletal pain
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    2
    0
    0
    2
    Neck pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    2 / 30 (6.67%)
         occurrences all number
    4
    0
    1
    4
    Tendonitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    1
    2
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Iron deficiency
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 21 (9.52%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Erythema infectiosum
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    3 / 10 (30.00%)
    4 / 30 (13.33%)
         occurrences all number
    0
    0
    3
    5
    Pharyngitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    4 / 10 (40.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    0
    4
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Aug 2006
    Amendment 2: For Poland Only: Changed age minimum from 8 to 12 years.
    13 Dec 2007
    Amendment 3: Dose reductions of lapaquistat acetate. Participants taking 100 mg reduced to 50 mg. Participants taking 50 mg (Less than 50 kg) were no longer allowed to participate in the study because a lower dose was not available.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    02 Dec 2007
    Interruption in dosing with lapaquistat acetate until Protocol Amendment 3 was approved and the revised ICF was signed.
    -

    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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