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    Clinical Trial Results:
    Efficacy, Safety, and Tolerability of Ezetimibe in Coadministration With Simvastatin in the Therapy of Adolescents With Heterozygous Familial Hypercholesterolemia

    Summary
    EudraCT number
    2004-002627-40
    Trial protocol
    FI   AT   DE   IT   ES   Outside EU/EEA  
    Global end of trial date
    25 Jun 2007

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Mar 2016
    First version publication date
    20 May 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    P02579
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00129402
    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 Dislosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Dislosure, 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-000007-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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Jun 2007
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jun 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jun 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study is to test the hypothesis that in adolescent participants with heterozygous familial hypercholesterolemia (HeFH) the reduction in Low-Density-Lipoprotein Cholesterol (LDL-C) from baseline to 6 weeks measured as percent change in the pooled groups assigned to receive randomized treatment with ezetimibe (EZ) plus simvastatin 10 mg, 20 mg, or 40 mg will be greater compared with the reduction of LDL-C in the pooled groups assigned to receive randomized treatment with simvastatin 10 mg, 20 mg, or 40 mg as monotherapy.
    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
    02 Aug 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
    Norway: 8
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Canada: 53
    Country: Number of subjects enrolled
    Chile: 4
    Country: Number of subjects enrolled
    Colombia: 14
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Netherlands: 55
    Country: Number of subjects enrolled
    South Africa: 38
    Country: Number of subjects enrolled
    United States: 36
    Worldwide total number of subjects
    248
    EEA total number of subjects
    93
    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)
    23
    Adolescents (12-17 years)
    225
    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
    -

    Pre-assignment
    Screening details
    The study enrolled adolescents (age >=10 to <=17 years) of either sex and of any race, Tanner Stage II or higher, body weight at least 40 kg and above 10th percentile . Girls were to be postmenarchal, defined as at least 1 year after first menstrual period and having had at least 3 menstrual periods. Other inclusion and exclusion criteria applied.

    Period 1
    Period 1 title
    Period 1 - Week 1 to Week 6
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ezetimibe 10 mg + Simvastatin 10 mg
    Arm description
    Participants received ezetimibe 10 mg plus simvastatin 10 mg orally once daily for 6 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Ezetimibe
    Investigational medicinal product code
    Other name
    SCH 058235, MK-0653
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one 10-mg tablet orally once daily.

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one 10-, 20-, or 40-mg tablet, orally once daily.

    Arm title
    Ezetimibe 10 mg + Simvastatin 20 mg
    Arm description
    Participants received ezetimibe 10 mg plus simvastatin 20 mg orally once daily for 6 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Ezetimibe
    Investigational medicinal product code
    Other name
    SCH 058235, MK-0653
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one 10-mg tablet orally once daily.

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one 10-, 20-, or 40-mg tablet, orally once daily.

    Arm title
    Ezetimibe 10 mg + Simvastatin 40 mg
    Arm description
    Participants received ezetimibe 10 mg plus simvastatin 40 mg orally once daily for 6 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Ezetimibe
    Investigational medicinal product code
    Other name
    SCH 058235, MK-0653
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one 10-mg tablet orally once daily.

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one 10-, 20-, or 40-mg tablet, orally once daily.

    Arm title
    Simvastatin 10 mg
    Arm description
    Participants received simvastatin monotherapy 10 mg plus placebo for EZ 10 mg orally, once daily for 6 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one 10-, 20-, or 40-mg tablet, orally once daily.

    Investigational medicinal product name
    Placebo to Match Ezetimibe
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one placebo tablet orally, once daily.

    Arm title
    Simvastatin 20 mg
    Arm description
    Participants received simvastatin 20 mg plus placebo for EZ 10 mg orally, once daily for 6 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one 10-, 20-, or 40-mg tablet, orally once daily.

    Investigational medicinal product name
    Placebo to Match Ezetimibe
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one placebo tablet orally, once daily.

    Arm title
    Simvastatin 40 mg
    Arm description
    Participants received simvastatin monotherapy 40 mg plus placebo for EZ 10 mg orally, once daily for 6 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one 10-, 20-, or 40-mg tablet, orally once daily.

    Investigational medicinal product name
    Placebo to Match Ezetimibe
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one placebo tablet orally, once daily.

    Number of subjects in period 1
    Ezetimibe 10 mg + Simvastatin 10 mg Ezetimibe 10 mg + Simvastatin 20 mg Ezetimibe 10 mg + Simvastatin 40 mg Simvastatin 10 mg Simvastatin 20 mg Simvastatin 40 mg
    Started
    43
    40
    43
    40
    40
    42
    Completed
    43
    39
    41
    39
    39
    40
    Not completed
    0
    1
    2
    1
    1
    2
         Protocol deviation
             -
             -
             -
             1
             -
             -
         Adverse event, non-fatal
             -
             1
             1
             -
             -
             1
         Consent withdrawn by subject
             -
             -
             1
             -
             1
             -
         Lost to follow-up
             -
             -
             -
             -
             -
             1
    Period 2
    Period 2 title
    Period 2 - Week 7 to Week 33
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ezetimibe 10 mg + Simvastatin 40 mg
    Arm description
    Participants who received 10-mg ezetimibe coadministered with either 10-, 20-, or 40-mg simvastatin in Period 1 and received 10 mg ezetimibe coadministered with 40-mg simvastatin once daily for 27 weeks in Period 2.
    Arm type
    Experimental

    Investigational medicinal product name
    Ezetimibe
    Investigational medicinal product code
    Other name
    SCH 058235, MK-0653
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one 10-mg tablet orally once daily.

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one 10-, 20-, or 40-mg tablet, orally once daily.

    Arm title
    Simvastatin 40 mg
    Arm description
    Participants who received either 10-, 20-, or 40-mg simvastatin montherapy in Period 1 and received 40-mg simvastatin and placebo to match ezetimibe once daily for 27 weeks in Period 2.
    Arm type
    Active comparator

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one 10-, 20-, or 40-mg tablet, orally once daily.

    Investigational medicinal product name
    Placebo to Match Ezetimibe
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one placebo tablet orally, once daily.

    Number of subjects in period 2 [1]
    Ezetimibe 10 mg + Simvastatin 40 mg Simvastatin 40 mg
    Started
    122
    118
    Completed
    114
    113
    Not completed
    8
    5
         Protocol deviation
             1
             1
         Laboratory Adverse Event
             -
             1
         Laboratoy Adverse Event
             3
             -
         Adverse event, non-fatal
             2
             -
         Consent withdrawn by subject
             1
             3
         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: One participant who completed Period 1 did not enter Period 2. Participant did enter and complete Period 3.
    Period 3
    Period 3 title
    Period 3 - Long-Term Experience
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Ezetimibe + simvastatin - Long Term Experience
    Arm description
    All participants, regardless of assigned treatment groups in Periods 1 and 2 initially received open-label simvastatin 10 or 20 mg (based upon physician judgment for the treatment of the individual participant) and ezetimibe 10 mg for 20 weeks. The continued simvastatin dose may have been adjusted based on response and titrated up to 20 mg or 40 mg as necessary, based upon response and in accordance with National Cholesterol Education Program guidelines. Similarly, the dose of simvastatin 20 or 40 mg may be titrated downward as necessary.
    Arm type
    Experimental

    Investigational medicinal product name
    Ezetimibe
    Investigational medicinal product code
    Other name
    SCH 058235, MK-0653
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one 10-mg tablet orally once daily.

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one 10-, 20-, or 40-mg tablet, orally once daily.

    Number of subjects in period 3 [2]
    Ezetimibe + simvastatin - Long Term Experience
    Started
    226
    Completed
    222
    Not completed
    5
         Protocol deviation
             1
         Consent withdrawn by subject
             3
         Participant moved
             1
    Joined
    1
         Completer from Period 1
             1
    Notes
    [2] - 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: One participant who completed Period 1 did not enter Period 2. Participant did enter and complete Period 3.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ezetimibe 10 mg + Simvastatin 10 mg
    Reporting group description
    Participants received ezetimibe 10 mg plus simvastatin 10 mg orally once daily for 6 weeks.

    Reporting group title
    Ezetimibe 10 mg + Simvastatin 20 mg
    Reporting group description
    Participants received ezetimibe 10 mg plus simvastatin 20 mg orally once daily for 6 weeks.

    Reporting group title
    Ezetimibe 10 mg + Simvastatin 40 mg
    Reporting group description
    Participants received ezetimibe 10 mg plus simvastatin 40 mg orally once daily for 6 weeks.

    Reporting group title
    Simvastatin 10 mg
    Reporting group description
    Participants received simvastatin monotherapy 10 mg plus placebo for EZ 10 mg orally, once daily for 6 weeks.

    Reporting group title
    Simvastatin 20 mg
    Reporting group description
    Participants received simvastatin 20 mg plus placebo for EZ 10 mg orally, once daily for 6 weeks.

    Reporting group title
    Simvastatin 40 mg
    Reporting group description
    Participants received simvastatin monotherapy 40 mg plus placebo for EZ 10 mg orally, once daily for 6 weeks.

    Reporting group values
    Ezetimibe 10 mg + Simvastatin 10 mg Ezetimibe 10 mg + Simvastatin 20 mg Ezetimibe 10 mg + Simvastatin 40 mg Simvastatin 10 mg Simvastatin 20 mg Simvastatin 40 mg Total
    Number of subjects
    43 40 43 40 40 42 248
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    14.1 ± 1.8 14 ± 2 14 ± 2 14.5 ± 1.8 14.1 ± 2.1 14.4 ± 1.5 -
    Gender categorical
    Units: Subjects
        Female
    18 17 18 17 18 18 106
        Male
    25 23 25 23 22 24 142

    End points

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    End points reporting groups
    Reporting group title
    Ezetimibe 10 mg + Simvastatin 10 mg
    Reporting group description
    Participants received ezetimibe 10 mg plus simvastatin 10 mg orally once daily for 6 weeks.

    Reporting group title
    Ezetimibe 10 mg + Simvastatin 20 mg
    Reporting group description
    Participants received ezetimibe 10 mg plus simvastatin 20 mg orally once daily for 6 weeks.

    Reporting group title
    Ezetimibe 10 mg + Simvastatin 40 mg
    Reporting group description
    Participants received ezetimibe 10 mg plus simvastatin 40 mg orally once daily for 6 weeks.

    Reporting group title
    Simvastatin 10 mg
    Reporting group description
    Participants received simvastatin monotherapy 10 mg plus placebo for EZ 10 mg orally, once daily for 6 weeks.

    Reporting group title
    Simvastatin 20 mg
    Reporting group description
    Participants received simvastatin 20 mg plus placebo for EZ 10 mg orally, once daily for 6 weeks.

    Reporting group title
    Simvastatin 40 mg
    Reporting group description
    Participants received simvastatin monotherapy 40 mg plus placebo for EZ 10 mg orally, once daily for 6 weeks.
    Reporting group title
    Ezetimibe 10 mg + Simvastatin 40 mg
    Reporting group description
    Participants who received 10-mg ezetimibe coadministered with either 10-, 20-, or 40-mg simvastatin in Period 1 and received 10 mg ezetimibe coadministered with 40-mg simvastatin once daily for 27 weeks in Period 2.

    Reporting group title
    Simvastatin 40 mg
    Reporting group description
    Participants who received either 10-, 20-, or 40-mg simvastatin montherapy in Period 1 and received 40-mg simvastatin and placebo to match ezetimibe once daily for 27 weeks in Period 2.
    Reporting group title
    Ezetimibe + simvastatin - Long Term Experience
    Reporting group description
    All participants, regardless of assigned treatment groups in Periods 1 and 2 initially received open-label simvastatin 10 or 20 mg (based upon physician judgment for the treatment of the individual participant) and ezetimibe 10 mg for 20 weeks. The continued simvastatin dose may have been adjusted based on response and titrated up to 20 mg or 40 mg as necessary, based upon response and in accordance with National Cholesterol Education Program guidelines. Similarly, the dose of simvastatin 20 or 40 mg may be titrated downward as necessary.

    Subject analysis set title
    Ezetimibe + Simvastatin - Pooled
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All participants who received randomized treatment assignment, had at least one baseline assessment, and had had evaluable data for endpoint. Data for participants randomly assigned to receive ezetimibe 10 mg coadministered with simvastatin 10, 20, or 40 mg were pooled.

    Subject analysis set title
    Simvastatin Monotherapy - Pooled
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All participants who received randomized treatment assignment, had at least one baseline assessment, and had evaluable data for endpoint. Data for participants randomly assigned to simvastatin 10, 20, or 40 mg monotherapy were pooled.

    Primary: Percentage Change from Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Week 6

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    End point title
    Percentage Change from Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Week 6
    End point description
    LDL-C levels calculated at baseline and after 6 weeks of treatment. LDL-C determined by the Friedewald equation (LDL-C = Total Cholesterol − [Triglyceride/5] − High-density Lipoprotein Cholesterol). Least-square means and standard errors calulated using an analysis of variance (ANOVA) model that extracted effects due to treatment (ezetimibe 10 mg, placebo), dose (simvastatin 10 mg, 20 mg, and 40 mg), treatment by dose interaction, and sex effects.
    End point type
    Primary
    End point timeframe
    Baseline and Week 6
    End point values
    Ezetimibe + Simvastatin - Pooled Simvastatin Monotherapy - Pooled
    Number of subjects analysed
    126
    120
    Units: Percentage Change
        least squares mean (standard error)
    -49.45 ± 1.19
    -34.43 ± 1.22
    Statistical analysis title
    Difference in Percentage Change from Baseline
    Statistical analysis description
    Statisical comparison performed using an ANOVA model that extracts effects due to treatment (EZ 10 mg, placebo), dose (simva 10 mg, 20 mg, and 40 mg), treatment by dose interaction, and sex effects.
    Comparison groups
    Ezetimibe + Simvastatin - Pooled v Simvastatin Monotherapy - Pooled
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.01
    Method
    ANOVA
    Parameter type
    Difference in Least-squares Means
    Point estimate
    -15.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.36
         upper limit
    -11.7

    Secondary: Percentage Change from Baseline in Total Cholesterol (TC)

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    End point title
    Percentage Change from Baseline in Total Cholesterol (TC)
    End point description
    Serum TC levels measured using at baseline and after 6 weeks of study drug administration. Least-square means and standard errors calulated using an analysis of variance (ANOVA) model that extracted effects due to treatment (ezetimibe 10 mg, placebo), dose (simvastatin 10 mg, 20 mg, and 40 mg), treatment by dose interaction, and sex effects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6
    End point values
    Ezetimibe + Simvastatin - Pooled Simvastatin Monotherapy - Pooled
    Number of subjects analysed
    126
    120
    Units: Percentage Change
        least squares mean (standard error)
    -38.23 ± 0.96
    -26.28 ± 0.99
    Statistical analysis title
    Difference in Percentage Change from Baseline
    Statistical analysis description
    Statistical comparison performed using an ANOVA model that extracts effects due to treatment (ezetimibe 10 mg, placebo), dose (simvastatin 10 mg, 20 mg, and 40 mg), treatment by dose interaction, and sex effects.
    Comparison groups
    Simvastatin Monotherapy - Pooled v Ezetimibe + Simvastatin - Pooled
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.01
    Method
    ANCOVA
    Parameter type
    Difference in Least-square means
    Point estimate
    -11.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.65
         upper limit
    -9.26

    Secondary: Percentage Change from Baseline in Non High-density Lipoprotein Cholesterol (non HDL-C)

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    End point title
    Percentage Change from Baseline in Non High-density Lipoprotein Cholesterol (non HDL-C)
    End point description
    Serum Non-HDL-C calculated at baseline and after 6 weeks of study drug administration. Least-square means and standard errors calulated using an analysis of variance (ANOVA) model that extracted effects due to treatment (ezetimibe 10 mg, placebo), dose (simvastatin 10 mg, 20 mg, and 40 mg), treatment by dose interaction, and sex effects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6
    End point values
    Ezetimibe + Simvastatin - Pooled Simvastatin Monotherapy - Pooled
    Number of subjects analysed
    126
    120
    Units: Percentage Change
        least squares mean (standard error)
    -46.84 ± 1.13
    -32.68 ± 1.16
    Statistical analysis title
    Difference in Percentage Change from Baseline
    Statistical analysis description
    Statistical comparison performed using an ANOVA model that extracts effects due to treatment (ezetimibe 10 mg, placebo), dose (simvastatin 10 mg, 20 mg, and 40 mg), treatment by dose interaction, and sex effects.
    Comparison groups
    Ezetimibe + Simvastatin - Pooled v Simvastatin Monotherapy - Pooled
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.01
    Method
    ANOVA
    Parameter type
    Difference in Least-squares means
    Point estimate
    -14.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.32
         upper limit
    -11

    Secondary: Percentage Change from Baseline in Trigycerides (TG)

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    End point title
    Percentage Change from Baseline in Trigycerides (TG)
    End point description
    Serum TG levels measured at baseline and after 6 weeks of study drug administration.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6
    End point values
    Ezetimibe + Simvastatin - Pooled Simvastatin Monotherapy - Pooled
    Number of subjects analysed
    126
    120
    Units: Percentage Change
        median (standard deviation)
    -16.56 ± 30.26
    -12.28 ± 31.49
    Statistical analysis title
    Difference in Percentage Change from Baseline
    Statistical analysis description
    Analyzed using ANOVA on the ranks extracting effects due to treatment (ezetimibe, placebo) and sex.
    Comparison groups
    Ezetimibe + Simvastatin - Pooled v Simvastatin Monotherapy - Pooled
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.48
    Method
    non-parametric model
    Parameter type
    Hodges-Lehmann Method
    Point estimate
    -2.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.09
         upper limit
    4.12

    Secondary: Percentage Change from Baseline in Apolipoprotein B (Apo B)

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    End point title
    Percentage Change from Baseline in Apolipoprotein B (Apo B)
    End point description
    Serum Apo B measured at baseline and after 6 weeks of study drug administration. Least-square means and standard errors calulated using an analysis of variance (ANOVA) model that extracted effects due to treatment (ezetimibe 10 mg, placebo), dose (simvastatin 10 mg, 20 mg, and 40 mg), treatment by dose interaction, and sex effects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6
    End point values
    Ezetimibe + Simvastatin - Pooled Simvastatin Monotherapy - Pooled
    Number of subjects analysed
    122
    118
    Units: Percentage Change
        least squares mean (standard error)
    -38.92 ± 1.1
    -26.69 ± 1.11
    Statistical analysis title
    Difference in Percentage Change from Baseline
    Statistical analysis description
    Statistical comparison performed using an ANOVA model that extracts effects due to treatment (ezetimibe 10 mg, placebo), dose (simvastatin 10 mg, 20 mg, and 40 mg), treatment by dose interaction, and sex effects.
    Comparison groups
    Ezetimibe + Simvastatin - Pooled v Simvastatin Monotherapy - Pooled
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.01
    Method
    ANOVA
    Parameter type
    Difference in Least-squares Means
    Point estimate
    -12.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.29
         upper limit
    -9.18

    Secondary: Percentage Change from Baseline in HDL-C

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    End point title
    Percentage Change from Baseline in HDL-C
    End point description
    Serum HDL-C levels measured at baseline and after 6 weeks of study drug administration. Least-square means and standard errors calulated using an analysis of variance (ANOVA) model that extracted effects due to treatment (ezetimibe 10 mg, placebo), dose (simvastatin 10 mg, 20 mg, and 40 mg), treatment by dose interaction, and sex effects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6
    End point values
    Ezetimibe + Simvastatin - Pooled Simvastatin Monotherapy - Pooled
    Number of subjects analysed
    126
    120
    Units: Percentage Change
        least squares mean (standard error)
    6.58 ± 1.16
    6.47 ± 1.19
    Statistical analysis title
    Difference in Percentage Change from Baseline
    Statistical analysis description
    Statistical comparison performed using an ANOVA model that extracts effects due to treatment (ezetimibe 10 mg, placebo), dose (simvastatin 10 mg, 20 mg, and 40 mg), treatment by dose interaction, and sex effects.
    Comparison groups
    Ezetimibe + Simvastatin - Pooled v Simvastatin Monotherapy - Pooled
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.95
    Method
    ANOVA
    Parameter type
    Difference in Least-squares means
    Point estimate
    0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.14
         upper limit
    3.35

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to 53 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    9.1
    Reporting groups
    Reporting group title
    Ezetimibe + Simvastatin
    Reporting group description
    Participants who received ezetimibe coadminsitered with simvastatin in Period 1 and Period 2.

    Reporting group title
    Ezetimibe + Simvastatin - Long Term Experience
    Reporting group description
    Participants who received Ezetimibe + Simvastatin in Period 3 (Weeks 33 to 53)

    Reporting group title
    Simvastatin Monotherapy
    Reporting group description
    Participants who received simivastatin monotherapy in Period 1 and Period 2.

    Serious adverse events
    Ezetimibe + Simvastatin Ezetimibe + Simvastatin - Long Term Experience Simvastatin Monotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 126 (3.17%)
    3 / 227 (1.32%)
    1 / 122 (0.82%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 227 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 227 (0.44%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 227 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 227 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Tendonitis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 227 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Subcutaneous Abscess
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 227 (0.44%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis Bacterial
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 227 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pilonidal Cyst
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 227 (0.44%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 227 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Ezetimibe + Simvastatin Ezetimibe + Simvastatin - Long Term Experience Simvastatin Monotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 126 (46.03%)
    42 / 227 (18.50%)
    59 / 122 (48.36%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 126 (3.17%)
    5 / 227 (2.20%)
    8 / 122 (6.56%)
         occurrences all number
    4
    6
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 126 (12.70%)
    6 / 227 (2.64%)
    16 / 122 (13.11%)
         occurrences all number
    25
    6
    22
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 126 (7.14%)
    2 / 227 (0.88%)
    3 / 122 (2.46%)
         occurrences all number
    9
    2
    3
    Nausea
         subjects affected / exposed
    8 / 126 (6.35%)
    2 / 227 (0.88%)
    4 / 122 (3.28%)
         occurrences all number
    12
    2
    4
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    4 / 126 (3.17%)
    3 / 227 (1.32%)
    9 / 122 (7.38%)
         occurrences all number
    4
    3
    9
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    7 / 126 (5.56%)
    0 / 227 (0.00%)
    1 / 122 (0.82%)
         occurrences all number
    10
    0
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    8 / 126 (6.35%)
    12 / 227 (5.29%)
    12 / 122 (9.84%)
         occurrences all number
    9
    12
    14
    Nasopharyngitis
         subjects affected / exposed
    27 / 126 (21.43%)
    16 / 227 (7.05%)
    27 / 122 (22.13%)
         occurrences all number
    30
    16
    31

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jan 2007
    Added fusidic acid to the list of prohibited medications and referred investigators to consult the local labeling for ezetimibe or simvastatin for a complete list of prohibited concomitant therapies for each therapy.

    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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