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    Clinical Trial Results:
    A 12-week, Double-blind, Randomized Study to Compare the Efficacy and Safety of Fixed Combinations of Fenofibrate/Simvastatin 145/20 mg and Fenofibrate/Simvastatin 145/40 mg Tablets vs. Matching Monotherapies in Dyslipidemic Subjects at High Risk of Cardiovascular Disease

    Summary
    EudraCT number
    2011-005924-16
    Trial protocol
    CZ   PL  
    Global end of trial date
    28 Oct 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Aug 2019
    First version publication date
    15 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M13-377
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01674712
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Abbott Laboratories Ireland Ltd
    Sponsor organisation address
    4051 Kingswood Drive, Citywest Business Campus, Dublin, Ireland, 24
    Public contact
    Hind Ounis, Abbott Healthcare Products B.V., Hind.Ounis@abbott.com
    Scientific contact
    Dmitri Kazei, Abbott Healthcare Products B.V., Dmitri.Kazei@abbott.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?
    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
    28 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to compare the efficacy of the two fixed-combinations (FCs) (fenofibrate/simvastatin 145/20 milligrams [mg] tablet and fenofibrate/simvastatin 145/40 mg tablet) in reducing triglyceride (TG) and increasing high density lipoprotein cholesterol (HDL-C) versus simvastatin 20 mg or 40 mg, and in reducing low density lipoprotein cholesterol (LDL-C) versus fenofibrate 145 mg in subjects with mixed dyslipidemia (type IIb) at high or very high risk of cardiovascular (CV) disease after 12 weeks of treatment.
    Protection of trial subjects
    The study was conducted in compliance with Good Clinical Practice ethical and scientific quality standards and the applicable national regulations to assure that the rights, safety, and well being of the participating study subjects were protected consistent with the ethical principles that have their origin in the Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Jun 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
    Argentina: 105
    Country: Number of subjects enrolled
    Czech Republic: 111
    Country: Number of subjects enrolled
    Germany: 164
    Country: Number of subjects enrolled
    Mexico: 39
    Country: Number of subjects enrolled
    Poland: 44
    Country: Number of subjects enrolled
    Romania: 27
    Country: Number of subjects enrolled
    Russian Federation: 85
    Worldwide total number of subjects
    575
    EEA total number of subjects
    346
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    389
    From 65 to 84 years
    186
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects with documented mixed dyslipidemia (based on fasting lipids) and assessed to be at high or very high CV risk were recruited to this randomized, double-blind, active-controlled parallel-arm study from June 2012, conducted at 70 centres in 7 countries. The last subject completed in October 2013. Parts A and B were conducted in parallel.

    Pre-assignment
    Screening details
    576 subjects met all the inclusion and none of the exclusion criteria, 1 subject withdrew consent and 575 were allocated to treatment. Estimation of CV risk was based on European Society of Cardiology/European Atherosclerosis Society guidelines for the management of dyslipidemias using the Systemic Coronary Risk Estimation chart.

    Period 1
    Period 1 title
    Overall Study (overall 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
    Fenofibrate/Simvastatin 145/20 mg
    Arm description
    In Part A subjects were randomized to receive FC fenofibrate/simvastatin 145/20 mg tablets once daily for 12 +/- 1 weeks. Subjects also received placebo simvastatin 20 mg capsules and placebo fenofibrate 145 mg tablets.
    Arm type
    Experimental

    Investigational medicinal product name
    Fenofibrate/Simvastatin 145/20 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one FC tablet containing 145 mg fenofibrate and 20 mg simvastatin daily for 12 +/- 1 weeks.

    Investigational medicinal product name
    Simvastatin 20 mg placebo capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one simvastatin 20 mg placebo capsule daily for 12 +/- 1 weeks. The placebo capsules were identical in terms of shape, size and colour as the simvastatin 20 mg capsules containing the active substance.

    Investigational medicinal product name
    Fenofibrate 145 mg placebo tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one fenofibrate 145 mg placebo tablet daily for 12 +/- 1 weeks. The placebo tablets were identical in terms of shape, size, colour and inscriptions as the fenofibrate 145 mg tablets containing the active substance.

    Arm title
    Simvastatin 20 mg
    Arm description
    In Part A subjects were randomized to receive simvastatin 20 mg tablets once daily for 12 +/- 1 weeks. Subjects also received placebo FC fenofibrate/simvastatin 145/20 mg tablets and placebo fenofibrate 145 mg tablets.
    Arm type
    Active comparator

    Investigational medicinal product name
    Simvastatin 20 mg capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one 20 mg simvastatin capsule daily for 12 +/- 1 weeks.

    Investigational medicinal product name
    Fenofibrate/Simvastatin 145/20 mg placebo tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one fenofibrate/simvastatin 145/20 mg placebo tablet daily for 12 +/- 1 weeks. The placebo tablets were identical in terms of shape, size and colour as the fenofibrate/simvastatin 145/20 mg tablets containing the active substances.

    Investigational medicinal product name
    Fenofibrate 145 mg placebo tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one fenofibrate 145 mg placebo tablet daily for 12 +/- 1 weeks. The placebo tablets were identical in terms of shape, size, colour and inscriptions as the fenofibrate 145 mg tablets containing the active substance.

    Arm title
    Fenofibrate/Simvastatin 145/40 mg
    Arm description
    In Part B subjects were randomized to receive FC fenofibrate/simvastatin 145/40 mg tablets once daily for 12 +/- 1 weeks. Subjects also received placebo simvastatin 40 mg capsules and placebo fenofibrate 145 mg tablets.
    Arm type
    Experimental

    Investigational medicinal product name
    Fenofibrate/Simvastatin 145/40 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one FC tablet containing 145 mg fenofibrate and 40 mg simvastatin daily for 12 +/- 1 weeks.

    Investigational medicinal product name
    Simvastatin 40 mg placebo capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one simvastatin 40 mg placebo capsule daily for 12 +/- 1 weeks. The placebo capsules were identical in terms of shape, size and colour as the simvastatin 40 mg capsules containing the active substance.

    Investigational medicinal product name
    Fenofibrate 145 mg placebo tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one fenofibrate 145 mg placebo tablet daily for 12 +/- 1 weeks. The placebo tablets were identical in terms of shape, size, colour and inscriptions as the fenofibrate 145 mg tablets containing the active substance.

    Arm title
    Simvastatin 40 mg
    Arm description
    In Part B subjects were randomized to receive simvastatin 40 mg capsules once daily for 12 +/- 1 weeks. Subjects also received placebo FC fenofibrate/simvastatin 145/40 mg tablets and placebo fenofibrate 145 mg tablets.
    Arm type
    Active comparator

    Investigational medicinal product name
    Simvastatin 40 mg capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one 40 mg simvastatin capsule daily for 12 +/- 1 weeks.

    Investigational medicinal product name
    Fenofibrate/Simvastatin 145/40 mg placebo tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one fenofibrate/simvastatin 145/40 mg placebo tablet daily for 12 +/- 1 weeks. The placebo tablets were identical in terms of shape, size and colour as the fenofibrate/simvastatin 145/40 mg tablets containing the active substances.

    Investigational medicinal product name
    Fenofibrate 145 mg placebo tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one fenofibrate 145 mg placebo tablet daily for 12 +/- 1 weeks. The placebo tablets were identical in terms of shape, size, colour and inscriptions as the fenofibrate 145 mg tablets containing the active substance.

    Arm title
    Fenofibrate 145 mg
    Arm description
    In Part A and in Part B subjects were randomized to receive fenofibrate 145 mg tablets once daily for 12 +/- 1 weeks. In Part A, subjects also received placebo FC fenofibrate/simvastatin 145/20 mg tablets and placebo simvastatin 20 mg capsules. In Part B, subjects also received placebo FC fenofibrate/simvastatin 145/40 mg tablets and placebo simvastatin 40 mg capsules.
    Arm type
    Active comparator

    Investigational medicinal product name
    Fenofibrate 145 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one 145 mg fenofibrate tablet daily for 12 +/- 1 weeks.

    Investigational medicinal product name
    Fenofibrate/Simvastatin 145/20 mg placebo tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects (in Part A) received one fenofibrate/simvastatin 145/20 mg placebo tablet daily for 12 +/- 1 weeks. The placebo tablets were identical in terms of shape, size and colour as the fenofibrate/simvastatin 145/20 mg tablets containing the active substances.

    Investigational medicinal product name
    Simvastatin 20 mg placebo capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects (in Part A) received one simvastatin 20 mg placebo capsule daily for 12 +/- 1 weeks. The placebo capsules were identical in terms of shape, size and colour as the simvastatin 20 mg capsules containing the active substance.

    Investigational medicinal product name
    Fenofibrate/Simvastatin 145/40 mg placebo tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects (in Part B) received one fenofibrate/simvastatin 145/40 mg placebo tablet daily for 12 +/- 1 weeks. The placebo tablets were identical in terms of shape, size and colour as the fenofibrate/simvastatin 145/40 mg tablets containing the active substances.

    Investigational medicinal product name
    Simvastatin 40 mg placebo capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects (in Part B) received one simvastatin 40 mg placebo capsule daily for 12 +/- 1 weeks. The placebo capsules were identical in terms of shape, size and colour as the simvastatin 40 mg capsules containing the active substance.

    Number of subjects in period 1
    Fenofibrate/Simvastatin 145/20 mg Simvastatin 20 mg Fenofibrate/Simvastatin 145/40 mg Simvastatin 40 mg Fenofibrate 145 mg
    Started
    114
    117
    115
    116
    113
    Completed
    104
    108
    106
    108
    102
    Not completed
    10
    9
    9
    8
    11
         Protocol deviation
    2
    -
    -
    -
    -
         Lack of efficacy
    -
    -
    1
    -
    1
         Adverse event, non-fatal
    5
    6
    3
    4
    6
         Consent withdrawn by subject
    2
    2
    5
    4
    3
         Administrative
    -
    1
    -
    -
    1
         Lost to follow-up
    1
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fenofibrate/Simvastatin 145/20 mg
    Reporting group description
    In Part A subjects were randomized to receive FC fenofibrate/simvastatin 145/20 mg tablets once daily for 12 +/- 1 weeks. Subjects also received placebo simvastatin 20 mg capsules and placebo fenofibrate 145 mg tablets.

    Reporting group title
    Simvastatin 20 mg
    Reporting group description
    In Part A subjects were randomized to receive simvastatin 20 mg tablets once daily for 12 +/- 1 weeks. Subjects also received placebo FC fenofibrate/simvastatin 145/20 mg tablets and placebo fenofibrate 145 mg tablets.

    Reporting group title
    Fenofibrate/Simvastatin 145/40 mg
    Reporting group description
    In Part B subjects were randomized to receive FC fenofibrate/simvastatin 145/40 mg tablets once daily for 12 +/- 1 weeks. Subjects also received placebo simvastatin 40 mg capsules and placebo fenofibrate 145 mg tablets.

    Reporting group title
    Simvastatin 40 mg
    Reporting group description
    In Part B subjects were randomized to receive simvastatin 40 mg capsules once daily for 12 +/- 1 weeks. Subjects also received placebo FC fenofibrate/simvastatin 145/40 mg tablets and placebo fenofibrate 145 mg tablets.

    Reporting group title
    Fenofibrate 145 mg
    Reporting group description
    In Part A and in Part B subjects were randomized to receive fenofibrate 145 mg tablets once daily for 12 +/- 1 weeks. In Part A, subjects also received placebo FC fenofibrate/simvastatin 145/20 mg tablets and placebo simvastatin 20 mg capsules. In Part B, subjects also received placebo FC fenofibrate/simvastatin 145/40 mg tablets and placebo simvastatin 40 mg capsules.

    Reporting group values
    Fenofibrate/Simvastatin 145/20 mg Simvastatin 20 mg Fenofibrate/Simvastatin 145/40 mg Simvastatin 40 mg Fenofibrate 145 mg Total
    Number of subjects
    114 117 115 116 113 575
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0
        Adults (18-64 years)
    78 74 81 82 74 389
        From 65-84 years
    36 43 34 34 39 186
        85 years and over
    0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    41 42 43 40 38 204
        Male
    73 75 72 76 75 371

    End points

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    End points reporting groups
    Reporting group title
    Fenofibrate/Simvastatin 145/20 mg
    Reporting group description
    In Part A subjects were randomized to receive FC fenofibrate/simvastatin 145/20 mg tablets once daily for 12 +/- 1 weeks. Subjects also received placebo simvastatin 20 mg capsules and placebo fenofibrate 145 mg tablets.

    Reporting group title
    Simvastatin 20 mg
    Reporting group description
    In Part A subjects were randomized to receive simvastatin 20 mg tablets once daily for 12 +/- 1 weeks. Subjects also received placebo FC fenofibrate/simvastatin 145/20 mg tablets and placebo fenofibrate 145 mg tablets.

    Reporting group title
    Fenofibrate/Simvastatin 145/40 mg
    Reporting group description
    In Part B subjects were randomized to receive FC fenofibrate/simvastatin 145/40 mg tablets once daily for 12 +/- 1 weeks. Subjects also received placebo simvastatin 40 mg capsules and placebo fenofibrate 145 mg tablets.

    Reporting group title
    Simvastatin 40 mg
    Reporting group description
    In Part B subjects were randomized to receive simvastatin 40 mg capsules once daily for 12 +/- 1 weeks. Subjects also received placebo FC fenofibrate/simvastatin 145/40 mg tablets and placebo fenofibrate 145 mg tablets.

    Reporting group title
    Fenofibrate 145 mg
    Reporting group description
    In Part A and in Part B subjects were randomized to receive fenofibrate 145 mg tablets once daily for 12 +/- 1 weeks. In Part A, subjects also received placebo FC fenofibrate/simvastatin 145/20 mg tablets and placebo simvastatin 20 mg capsules. In Part B, subjects also received placebo FC fenofibrate/simvastatin 145/40 mg tablets and placebo simvastatin 40 mg capsules.

    Subject analysis set title
    Feno/Simv 145/20 mg + Feno/Simv 145/40 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects who were randomized to receive FC treatment of either fenofibrate/simvastatin 145/20 mg tablets or fenofibrate/simvastatin 145/40 mg tablets once daily for 12 +/- 1 weeks.

    Subject analysis set title
    Simvastatin 20 mg + Simvastatin 40 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects who were randomized to receive monotherapy of either simvastatin 20 mg tablets or simvastatin 40 mg tablets once daily for 12 +/- 1 weeks.

    Primary: Percentage Change from Baseline in Serum TG, LDL-C and HDL-C Levels at 12 Weeks

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    End point title
    Percentage Change from Baseline in Serum TG, LDL-C and HDL-C Levels at 12 Weeks [1]
    End point description
    The baseline value was defined as the mean of the lipid measured in the blood samples collected at the inclusion visit (Visit 1) and at the randomization visit (Visit 2). The endpoint value was defined as the last non-missing value assigned to treatment for the subject. The mean percentage changes from baseline in TG, LDL-C and HDL-C levels after 12 weeks of treatment are presented for the Full Analysis (FA) subject sample which consisted of all subjects who were allocated to treatment, received at least one dose of investigational study drug and had data for at least one post-baseline assessment of any efficacy measurement (TG, HDL-C or LDL-C) before or at Visit 4.
    End point type
    Primary
    End point timeframe
    Baseline (Visits 1 and 2) and after 12 weeks of treatment (Visit 4).
    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: Summary descriptive statistics for percentage change from baseline at 12 weeks in the lipid parameters are presented in this endpoint without comparative statistical analyses.
    End point values
    Fenofibrate/Simvastatin 145/20 mg Simvastatin 20 mg Fenofibrate/Simvastatin 145/40 mg Simvastatin 40 mg Fenofibrate 145 mg
    Number of subjects analysed
    96
    102
    97
    101
    93
    Units: Percentage change
    arithmetic mean (standard deviation)
        TG
    -30.562 ± 25.794
    10.703 ± 48.791
    -27.326 ± 35.878
    -2.892 ± 34.286
    -21.630 ± 34.176
        LDL-C
    1.866 ± 25.400
    -1.973 ± 24.786
    -6.074 ± 26.223
    -8.157 ± 25.826
    30.235 ± 35.573
        HDL-C
    9.019 ± 16.816
    0.278 ± 12.101
    8.826 ± 16.497
    2.209 ± 12.480
    7.648 ± 15.710
    No statistical analyses for this end point

    Primary: Percentage Least Squares (LS) Mean Change from Baseline in Serum TG Level at 12 Weeks

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    End point title
    Percentage Least Squares (LS) Mean Change from Baseline in Serum TG Level at 12 Weeks [2]
    End point description
    The baseline value was defined as the mean of the lipid measured in the blood samples collected at the inclusion visit (Visit 1) and at the randomization visit (Visit 2). The endpoint value was defined as the last non-missing value assigned to treatment for the subject. The LS mean percentage change from baseline in TG levels after 12 weeks of treatment are presented for the FA subject sample which consisted of all subjects who were allocated to treatment, received at least one dose of investigational study drug and had data for at least one post-baseline assessment of any efficacy measurement (TG, HDL-C or LDL-C) before or at Visit 4. The LS mean of the percentage change from baseline at 12 weeks was determined using a mixed model repeated measures (MMRM) analysis with treatment group, visit, gender, country and treatment by visit interaction as fixed factors, and the lipid parameter at baseline as covariate.
    End point type
    Primary
    End point timeframe
    Baseline (Visit 2) and after 12 weeks of treatment (Visit 4).
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary analysis tested superiority for the following treatment comparisons for percentage change in TG from baseline at 12 weeks: - FC fenofibrate/simvastatin 145/20 mg vs Simvastatin 20 mg - FC fenofibrate/simvastatin 145/40 mg vs Simvastatin 40 mg - Feno/Simv 145/20 mg + Feno/Simv 145/40 mg vs Simvastatin 20 mg + Simvastatin 40 mg. Therefore the reporting arm Fenofibrate 145 mg was not included in this endpoint.
    End point values
    Fenofibrate/Simvastatin 145/20 mg Simvastatin 20 mg Fenofibrate/Simvastatin 145/40 mg Simvastatin 40 mg Feno/Simv 145/20 mg + Feno/Simv 145/40 mg Simvastatin 20 mg + Simvastatin 40 mg
    Number of subjects analysed
    96
    102
    97
    101
    193
    203
    Units: Percentage change
        least squares mean (standard error)
    -32.484 ± 3.400
    7.766 ± 3.288
    -29.265 ± 3.363
    -5.155 ± 3.303
    -30.874 ± 2.442
    1.305 ± 2.379
    Statistical analysis title
    All FC Feno/Simv vs all Simvastatin Monotherapy
    Statistical analysis description
    Comparison of FC fenofibrate/simvastatin (fenofibrate/simvastatin 145/20 mg and 145/40 mg) versus simvastatin monotherapy (simvastatin 20 mg and 40 mg). Analysis was based on a MMRM analysis with treatment group, visit, gender, country and treatment by visit interaction as factors and lipid parameter at baseline as covariate.
    Comparison groups
    Feno/Simv 145/20 mg + Feno/Simv 145/40 mg v Simvastatin 20 mg + Simvastatin 40 mg
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -32.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -38.61
         upper limit
    -25.75
    Statistical analysis title
    Feno/Simv 145/20 mg vs Simvastatin 20 mg
    Statistical analysis description
    Comparison of FC fenofibrate/simvastatin 145/20 mg versus simvastatin 20 mg monotherapy. Analysis was based on a MMRM analysis with treatment group, visit, gender, country and treatment by visit interaction as factors and lipid parameter at baseline as covariate.
    Comparison groups
    Fenofibrate/Simvastatin 145/20 mg v Simvastatin 20 mg
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -40.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -49.339
         upper limit
    -31.161
    Statistical analysis title
    Feno/Simv 145/40 mg vs Simvastatin 40 mg
    Statistical analysis description
    Comparison of FC fenofibrate/simvastatin 145/40 mg versus simvastatin 40 mg monotherapy. Analysis was based on a MMRM analysis with treatment group, visit, gender, country and treatment by visit interaction as factors and lipid parameter at baseline as covariate.
    Comparison groups
    Fenofibrate/Simvastatin 145/40 mg v Simvastatin 40 mg
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -24.109
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -33.194
         upper limit
    -15.025

    Primary: Percentage LS Mean Change from Baseline in Serum LDL-C Level at 12 Weeks

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    End point title
    Percentage LS Mean Change from Baseline in Serum LDL-C Level at 12 Weeks [3]
    End point description
    The baseline value was defined as the mean of the lipid measured in the blood samples collected at the inclusion visit (Visit 1) and at the randomization visit (Visit 2). The endpoint value was defined as the last non-missing value assigned to treatment for the subject. The LS mean percentage change from baseline in LDL-C levels after 12 weeks of treatment are presented for the FA subject sample which consisted of all subjects who were allocated to treatment, received at least one dose of investigational study drug and had data for at least one post-baseline assessment of any efficacy measurement (TG, HDL-C or LDL-C) before or at Visit 4. The LS mean of the percentage change from baseline at 12 weeks was determined using an MMRM analysis with treatment group, visit, gender, country and treatment by visit interaction as fixed factors, and the lipid parameter at baseline as covariate.
    End point type
    Primary
    End point timeframe
    Baseline (Visits 1 and 2) and after 12 weeks of treatment (Visit 4).
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary analysis tested superiority for the following treatment comparisons for percentage change in LDL-C from baseline at 12 weeks: - FC fenofibrate/simvastatin 145/20 mg vs Fenofibrate 145 mg - FC fenofibrate/simvastatin 145/40 mg vs Fenofibrate 145 mg - Feno/Simv 145/20 mg + Feno/Simv 145/40 mg vs Simvastatin 20 mg + Simvastatin 40 mg. Therefore the reporting arms Simvastatin 20 mg and Simvastatin 40 mg were not included in this endpoint.
    End point values
    Fenofibrate/Simvastatin 145/20 mg Fenofibrate/Simvastatin 145/40 mg Fenofibrate 145 mg Feno/Simv 145/20 mg + Feno/Simv 145/40 mg
    Number of subjects analysed
    96
    97
    93
    193
    Units: Percentage change
        least squares mean (standard error)
    -0.352 ± 2.577
    -8.561 ± 2.550
    30.200 ± 2.616
    -4.457 ± 1.852
    Statistical analysis title
    All FC Feno/Simv vs Fenofibrate Monotherapy
    Statistical analysis description
    Comparison of FC fenofibrate/simvastatin (fenofibrate/simvastatin 145/20 mg and 145/40 mg) versus fenofibrate 145 mg monotherapy. Analysis was based on a MMRM analysis with treatment group, visit, gender, country and treatment by visit interaction as factors and lipid parameter at baseline as covariate.
    Comparison groups
    Fenofibrate 145 mg v Feno/Simv 145/20 mg + Feno/Simv 145/40 mg
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -34.657
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -40.775
         upper limit
    -28.539
    Statistical analysis title
    Feno/Simv 145/20 mg vs Fenofibrate Monotherapy
    Statistical analysis description
    Comparison of FC fenofibrate/simvastatin 145/20 mg versus fenofibrate 145 mg monotherapy. Analysis was based on a MMRM analysis with treatment group, visit, gender, country and treatment by visit interaction as factors and lipid parameter at baseline as covariate.
    Comparison groups
    Fenofibrate/Simvastatin 145/20 mg v Fenofibrate 145 mg
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -30.552
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -37.595
         upper limit
    -23.509
    Statistical analysis title
    Feno/Simv 145/40 mg vs Fenofibrate Monotherapy
    Statistical analysis description
    Comparison of FC fenofibrate/simvastatin 145/40 mg versus fenofibrate 145 mg monotherapy. Analysis was based on a MMRM analysis with treatment group, visit, gender, country and treatment by visit interaction as factors and lipid parameter at baseline as covariate.
    Comparison groups
    Fenofibrate/Simvastatin 145/40 mg v Fenofibrate 145 mg
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -38.761
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -45.797
         upper limit
    -31.725

    Primary: Percentage LS Mean Change from Baseline in Serum HDL-C Level at 12 Weeks

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    End point title
    Percentage LS Mean Change from Baseline in Serum HDL-C Level at 12 Weeks [4]
    End point description
    The baseline value was defined as the mean of the lipid measured in the blood samples collected at the inclusion visit (Visit 1) and at the randomization visit (Visit 2). The endpoint value was defined as the last non-missing value assigned to treatment for the subject. The LS mean percentage change from baseline in HDL-C levels after 12 weeks of treatment are presented for the FA subject sample which consisted of all subjects who were allocated to treatment, received at least one dose of investigational study drug and had data for at least one post-baseline assessment of any efficacy measurement (TG, HDL-C or LDL-C) before or at Visit 4. The LS mean of the percentage change from baseline at 12 weeks was determined using an MMRM analysis with treatment group, visit, gender, country and treatment by visit interaction as fixed factors, and the lipid parameter at baseline as covariate.
    End point type
    Primary
    End point timeframe
    Baseline (Visits 1 and 2) and after 12 weeks of treatment (Visit 4).
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary analysis tested superiority for the following treatment comparisons for percentage change in HDL-C from baseline at 12 weeks: - FC fenofibrate/simvastatin 145/20 mg vs Simvastatin 20 mg - FC fenofibrate/simvastatin 145/40 mg vs Simvastatin 40 mg - Feno/Simv 145/20 mg + Feno/Simv 145/40 mg vs Simvastatin 20 mg + Simvastatin 40 mg. Therefore the reporting arm Fenofibrate 145 mg was not included in this endpoint.
    End point values
    Fenofibrate/Simvastatin 145/20 mg Simvastatin 20 mg Fenofibrate/Simvastatin 145/40 mg Simvastatin 40 mg Feno/Simv 145/20 mg + Feno/Simv 145/40 mg Simvastatin 20 mg + Simvastatin 40 mg
    Number of subjects analysed
    96
    102
    97
    101
    193
    203
    Units: Percentage change
        least squares mean (standard error)
    9.660 ± 1.457
    1.288 ± 1.406
    10.045 ± 1.441
    3.445 ± 1.417
    9.852 ± 1.046
    2.367 ± 1.019
    Statistical analysis title
    All FC Feno/Simv vs all Simvastatin Monotherapy
    Statistical analysis description
    Comparison of FC fenofibrate/simvastatin (fenofibrate/simvastatin 145/20 mg and 145/40 mg) versus simvastatin monotherapy (simvastatin 20 mg and 40 mg). Analysis was based on a MMRM analysis with treatment group, visit, gender, country and treatment by visit interaction as factors and lipid parameter at baseline as covariate.
    Comparison groups
    Feno/Simv 145/20 mg + Feno/Simv 145/40 mg v Simvastatin 20 mg + Simvastatin 40 mg
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    7.486
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.731
         upper limit
    10.24
    Statistical analysis title
    Feno/simv 145/20 mg vs simvastatin 20 mg
    Statistical analysis description
    Comparison of FC fenofibrate/simvastatin 145/20 mg versus simvastatin 20 mg monotherapy. Analysis was based on a MMRM analysis with treatment group, visit, gender, country and treatment by visit interaction as factors and lipid parameter at baseline as covariate.
    Comparison groups
    Fenofibrate/Simvastatin 145/20 mg v Simvastatin 20 mg
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    8.372
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.479
         upper limit
    12.265
    Statistical analysis title
    Feno/simv 145/40 mg vs Simvastatin 40 mg
    Statistical analysis description
    Comparison of FC fenofibrate/simvastatin 145/40 mg versus simvastatin 40 mg monotherapy. Analysis was based on a MMRM analysis with treatment group, visit, gender, country and treatment by visit interaction as factors and lipid parameter at baseline as covariate.
    Comparison groups
    Fenofibrate/Simvastatin 145/40 mg v Simvastatin 40 mg
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    6.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.707
         upper limit
    10.492

    Secondary: Percentage Change from Baseline in Serum Non-HDL-C, Total Cholesterol (TC), Apolipoprotein A-I (ApoAI), Apolipoprotein B (ApoB) and High-sensitivity C-reactive Protein (hsCRP) at 12 Weeks

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    End point title
    Percentage Change from Baseline in Serum Non-HDL-C, Total Cholesterol (TC), Apolipoprotein A-I (ApoAI), Apolipoprotein B (ApoB) and High-sensitivity C-reactive Protein (hsCRP) at 12 Weeks
    End point description
    The baseline value was defined as the last non-missing value collected before first study drug administration at the randomization visit (Visit 2). The endpoint value was defined as the last non-missing value assigned to treatment for the subject. The mean percentage changes from baseline in non-HDL-C, TC, ApoAI, ApoB and hsCRP levels after 12 weeks of treatment are presented for the FA subject sample which consisted of all subjects who were allocated to treatment, received at least one dose of investigational study drug and had data for at least one post-baseline assessment of any efficacy measurement (TG, HDL-C or LDL-C) before or at Visit 4. n = number of subjects with data analysed for each parameter.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) and after 12 weeks of treatment (Visit 4).
    End point values
    Fenofibrate/Simvastatin 145/20 mg Simvastatin 20 mg Fenofibrate/Simvastatin 145/40 mg Simvastatin 40 mg Fenofibrate 145 mg
    Number of subjects analysed
    109
    114
    110
    112
    111
    Units: Percentage change
    arithmetic mean (standard deviation)
        Non-HDL-C (n=96, 102, 97, 101, 93)
    -7.938 ± 21.031
    0.382 ± 24.739
    -13.722 ± 25.892
    -8.655 ± 21.656
    16.003 ± 28.801
        TC (n=96, 102, 97, 101, 93)
    -3.921 ± 15.917
    0.014 ± 18.268
    -8.347 ± 19.304
    -6.515 ± 16.574
    13.540 ± 20.133
        ApoAI (n=94, 101, 95, 100, 93)
    3.592 ± 15.153
    2.829 ± 13.664
    5.449 ± 12.209
    2.678 ± 9.990
    6.122 ± 14.105
        ApoB (n=94, 101, 95, 100, 93)
    -7.268 ± 22.506
    -1.069 ± 23.109
    -9.427 ± 24.170
    -4.526 ± 24.785
    15.026 ± 28.617
        hsCRP (n=94, 101, 95, 101, 93)
    36.777 ± 217.732
    88.114 ± 270.344
    -9.039 ± 64.811
    33.687 ± 170.088
    60.909 ± 195.658
    No statistical analyses for this end point

    Secondary: Percentage of Lipid Level Responders for TG, LDL-C and Non-HDL-C at 12 Weeks

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    End point title
    Percentage of Lipid Level Responders for TG, LDL-C and Non-HDL-C at 12 Weeks [5]
    End point description
    The percentage of subjects who met the target levels of lipids for TG, LDL-C and non-HDL-C after 12 weeks of treatment is presented (defined as lipid level responders). The target lipid levels were as follows: TG: < 150 milligrams per deciliter (mg/dL) in very high and high CV risk subjects. LDL-C: < 70 mg/dL or a >= 50% reduction from baseline in very high CV risk subjects and < 100 mg/dL in high CV risk subjects. Non-HDL-C: < 100 mg/dL in very high CV risk subjects and < 130 mg/dL in high CV risk subjects. Percentages are based on the number of subjects with data available in the FA subject sample which consisted of all subjects who were allocated to treatment, received at least one dose of investigational study drug and had data for at least one post-baseline assessment of any efficacy measurement (TG, HDL-C or LDL-C) before or at Visit 4.
    End point type
    Secondary
    End point timeframe
    After 12 weeks of treatment (Visit 4).
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The secondary endpoint assessed the effect of treatment with fenofibrate or simvastatin monotherapy and combined fenofibrate and simvastatin treatment on target lipid levels in the following reporting groups only: - Fenofibrate 145 mg - Feno/Simv 145/20 mg + Feno/Simv 145/40 mg - Simvastatin 20 mg + Simvastatin 40 mg
    End point values
    Fenofibrate 145 mg Feno/Simv 145/20 mg + Feno/Simv 145/40 mg Simvastatin 20 mg + Simvastatin 40 mg
    Number of subjects analysed
    93
    192
    202
    Units: Percentage of responders
    number (not applicable)
        TG Responders
    33.3
    47.9
    20.8
        LDL-C Responders
    4.5
    16.4
    19.0
        Non-HDL-C Responders
    9.0
    28.8
    25.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events were collected from randomization (Visit 2) until 30 days after the treatment was completed (Visit 4).
    Adverse event reporting additional description
    The Safety subject sample consisted of all subjects who were allocated to treatment and received at least one dose of investigational study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Fenofibrate/Simvastatin 145/20 mg
    Reporting group description
    In Part A subjects were randomized to receive FC fenofibrate/simvastatin 145/20 mg tablets once daily for 12 +/- 1 weeks. Subjects also received placebo simvastatin 20 mg capsules and placebo fenofibrate 145 mg tablets.

    Reporting group title
    Simvastatin 20 mg
    Reporting group description
    In Part A subjects were randomized to receive simvastatin 20 mg capsules once daily for 12 +/- 1 weeks. Subjects also received placebo FC fenofibrate/simvastatin 145/20 mg tablets and placebo fenofibrate 145 mg tablets.

    Reporting group title
    Fenofibrate/Simvastatin 145/40 mg
    Reporting group description
    In Part B subjects were randomized to receive FC fenofibrate/simvastatin 145/40 mg tablets once daily for 12 +/- 1 weeks. Subjects also received placebo simvastatin 40 mg capsules and placebo fenofibrate 145 mg tablets.

    Reporting group title
    Simvastatin 40 mg
    Reporting group description
    In Part B subjects were randomized to receive simvastatin 40 mg capsules once daily for 12 +/- 1 weeks. Subjects also received placebo FC fenofibrate/simvastatin 145/40 mg tablets and placebo fenofibrate 145 mg tablets.

    Reporting group title
    Fenofibrate 145 mg
    Reporting group description
    In Part A and in Part B subjects were randomized to receive fenofibrate 145 mg tablets once daily for 12 +/- 1 weeks. In Part A, subjects also received placebo FC fenofibrate/simvastatin 145/20 mg tablets and placebo simvastatin 20 mg capsules. In Part B, subjects also received placebo FC fenofibrate/simvastatin 145/40 mg tablets and placebo simvastatin 40 mg capsules.

    Serious adverse events
    Fenofibrate/Simvastatin 145/20 mg Simvastatin 20 mg Fenofibrate/Simvastatin 145/40 mg Simvastatin 40 mg Fenofibrate 145 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 111 (2.70%)
    3 / 117 (2.56%)
    3 / 113 (2.65%)
    1 / 115 (0.87%)
    3 / 112 (2.68%)
         number of deaths (all causes)
    0
    1
    1
    0
    0
         number of deaths resulting from adverse events
    0
    1
    1
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 117 (0.00%)
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 117 (0.00%)
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Surgical and medical procedures
    Diabetes mellitus management
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 117 (0.00%)
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 117 (0.85%)
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 117 (0.00%)
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 117 (0.00%)
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 117 (0.00%)
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 117 (0.85%)
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vestibular disorder
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 117 (0.00%)
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Umbilical hernia, obstructive
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 117 (0.00%)
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 117 (0.00%)
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 117 (0.00%)
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 117 (0.00%)
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 117 (0.00%)
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 117 (0.00%)
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 117 (0.85%)
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Fenofibrate/Simvastatin 145/20 mg Simvastatin 20 mg Fenofibrate/Simvastatin 145/40 mg Simvastatin 40 mg Fenofibrate 145 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 111 (6.31%)
    7 / 117 (5.98%)
    4 / 113 (3.54%)
    9 / 115 (7.83%)
    12 / 112 (10.71%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    4 / 111 (3.60%)
    0 / 117 (0.00%)
    1 / 113 (0.88%)
    1 / 115 (0.87%)
    1 / 112 (0.89%)
         occurrences all number
    4
    0
    1
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 117 (2.56%)
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    1 / 112 (0.89%)
         occurrences all number
    0
    3
    0
    2
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 117 (1.71%)
    2 / 113 (1.77%)
    0 / 115 (0.00%)
    5 / 112 (4.46%)
         occurrences all number
    1
    2
    2
    0
    5
    Dyspepsia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 117 (0.00%)
    0 / 113 (0.00%)
    4 / 115 (3.48%)
    1 / 112 (0.89%)
         occurrences all number
    1
    0
    0
    4
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 117 (0.00%)
    1 / 113 (0.88%)
    3 / 115 (2.61%)
    3 / 112 (2.68%)
         occurrences all number
    1
    0
    1
    3
    3
    Gastroenteritis
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 117 (1.71%)
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    4 / 112 (3.57%)
         occurrences all number
    1
    3
    0
    0
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 May 2012
    - Withdrawal criteria were clarified to include reasons for study treatment discontinuation: Aspartate aminotransferase and alanine aminotransferase levels after a repeated measurement increase to more than three times the upper limit of normal, diffuse myalgia, myositis, muscle cramps and/or a significant increase in creatine kinase (to more than five times the upper limit of normal) after a repeated measurement indicating myotoxicity. - Amendments were made in relation to justification of the sample size and global study power. The sample size was not changed but the global study power was increased from 90% to 93.2%. The mean difference in percentage change from baseline to 12 weeks treatment the trial was set up to detect HDL-C was updated to 6.5% from 7%.
    16 Jul 2012
    - Clarification that the laboratory results for lipid parameters (TG, LDL-C, HDL-C and non-HDL-C) measured at Visits 3 and 4 during the blinded study period would not be provided to the investigators or trial physician, clinical study manager or trial monitors. The investigator was also instructed not to request laboratory tests for these lipid parameters to be done locally for their patients participating in the study. - The rescreening process between Visits 1 and 2 was clarified. Rescreening was not permitted if the safety laboratory results obtained at Visit 1 did not meet the inclusion/randomization criteria, and the subject was considered a screen failure. Rescreening of a subject after at least one week was allowed if one or both lipid criteria values obtained from Visit 1 did not meet the inclusion/randomization criteria. The condition for retesting was the lipid criteria value was outside +/-5% of the range for inclusion, all lipids measured were repeated. Sponsor authorization for retesting was also no longer required. - Recommendations on the contraceptive methods to be used by women of childbearing potential were added to the protocol.
    11 Dec 2012
    - Following the split of Abbott into two companies effective as of 1 January 2013, the name of the Sponsor changed from Fournier Laboratories Ireland Limited to Abbott Laboratories Ireland Limited.

    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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