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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia Not Adequately Controlled with Their Lipid-Modifying Therapy

    Summary
    EudraCT number
    2012-001222-95
    Trial protocol
    GB   NL   CZ  
    Global end of trial date
    09 Jan 2015

    Results information
    Results version number
    v2(current)
    This version publication date
    03 Dec 2019
    First version publication date
    07 Aug 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Minor corrections

    Trial information

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    Trial identification
    Sponsor protocol code
    R727-CL-1112
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01709500
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Study Name: ODYSSEY FH II
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Rd., Tarrytown, United States, 10591
    Public contact
    Clinical Trial Management, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trial Management, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.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
    Interim
    Date of interim/final analysis
    10 Jun 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Subjects entered into the 78 weeks double blind treatment period. The main objective of double blind treatment period was to demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on therapy to stable, maximally tolerated daily statin therapy with or without other Lipid Modifying Therapy (LMT) in comparison with placebo after 24 weeks of treatment in subjects with Heterozygous familial hypercholesterolemia (heFH). All subjects who successfully completed the 78-week double-blind treatment period had the opportunity to participate in an open-label extension study, receiving alirocumab at entry into the open-label extension regardless of the study treatment they had received during the double-blind treatment period.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    All subjects were on a maximally tolerated stable daily dose of statin (atorvastatin, rosuvastatin, or simvastatin) with or without other LMT throughout the duration of the study.
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Nov 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    Czech Republic: 75
    Country: Number of subjects enrolled
    Netherlands: 100
    Country: Number of subjects enrolled
    Norway: 49
    Worldwide total number of subjects
    249
    EEA total number of subjects
    249
    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)
    198
    From 65 to 84 years
    50
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 26 sites in 4 countries. Overall, 322 subjects were screened between 28 Nov 2012 and 26 April 2013, 73 of whom were screen failures.

    Pre-assignment
    Screening details
    Randomization was stratified according to prior history of myocardial infarction or ischemic stroke, and intensity of statin treatment. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 2:1 (alirocumab:placebo) ratio after confirmation of selection criteria.

    Period 1
    Period 1 title
    Up to primary completion (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Alirocumab 75 mg/up to 150 mg
    Arm description
    Alirocumab 75 mg every two weeks (Q2W) added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-­titrated to 150 mg Q2W from Week 12 when LDL-­C levels ≥70 mg/dL at Week 8.
    Arm type
    Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    REGN727/SAR236553
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Alirocumab administered as a subcutaneous (SC) injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.

    Arm title
    Placebo
    Arm description
    Placebo matched to alirocumab for 78-week treatment duration.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to alirocumab administered as a SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.

    Number of subjects in period 1
    Alirocumab 75 mg/up to 150 mg Placebo
    Started
    167
    82
    Treated
    167
    81
    Completed
    0
    0
    Not completed
    167
    82
         Randomized but not treated
    -
    1
         Adverse event
    5
    1
         Poor compliance to protocol
    2
    1
         Unspecified
    3
    1
         Related to IMP administration
    1
    -
         Treatment ongoing
    156
    78

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alirocumab 75 mg/up to 150 mg
    Reporting group description
    Alirocumab 75 mg every two weeks (Q2W) added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-­titrated to 150 mg Q2W from Week 12 when LDL-­C levels ≥70 mg/dL at Week 8.

    Reporting group title
    Placebo
    Reporting group description
    Placebo matched to alirocumab for 78-week treatment duration.

    Reporting group values
    Alirocumab 75 mg/up to 150 mg Placebo Total
    Number of subjects
    167 82 249
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.2 ± 12.93 53.2 ± 12.55 -
    Gender categorical
    Units: Subjects
        Female
    81 37 118
        Male
    86 45 131
    Calculated LDL-C in mmol/L
    Calculated LDL-C values were obtained using Friedewald formula.
    Units: mmol/L
        arithmetic mean (standard deviation)
    3.485 ± 1.065 3.471 ± 1.071 -
    Calculated LDL-C in mg/dL
    Units: mg/dL
        arithmetic mean (standard deviation)
    134.6 ± 41.1 134 ± 41.4 -

    End points

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    End points reporting groups
    Reporting group title
    Alirocumab 75 mg/up to 150 mg
    Reporting group description
    Alirocumab 75 mg every two weeks (Q2W) added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-­titrated to 150 mg Q2W from Week 12 when LDL-­C levels ≥70 mg/dL at Week 8.

    Reporting group title
    Placebo
    Reporting group description
    Placebo matched to alirocumab for 78-week treatment duration.

    Primary: Percent Change From Baseline in Calculated LDL­-C at Week 24 ­- Intent-­to-­Treat (ITT) Analysis

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    End point title
    Percent Change From Baseline in Calculated LDL­-C at Week 24 ­- Intent-­to-­Treat (ITT) Analysis
    End point description
    Adjusted Least-squares (LS) means and standard errors at Week 24 were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were used in the model (ITT analysis). ITT population: all randomized subjects with one baseline and at least one post-baseline calculated LDL-C value on- or off-treatment.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        least squares mean (standard error)
    -48.7 ± 1.9
    2.8 ± 2.8
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Alirocumab group was compared to the placebo group using an appropriate contrast statement.
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -51.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -58.1
         upper limit
    -44.8
    Notes
    [1] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Calculated LDL­-C at Week 24 - ­On­-Treatment Analysis

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    End point title
    Percent Change From Baseline in Calculated LDL­-C at Week 24 - ­On­-Treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis). Modified ITT (mITT) population: all randomized and treated subjects with one baseline and at least one post-baseline calculated LDL-C value on-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        least squares mean (standard error)
    -49.4 ± 1.9
    2.7 ± 2.7
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 5% level.
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -52.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -58.7
         upper limit
    -45.6
    Notes
    [2] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Calculated LDL-­C at Week 12 - ITT Analysis

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    End point title
    Percent Change From Baseline in Calculated LDL-­C at Week 12 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment (ITT analysis). ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        least squares mean (standard error)
    -43.8 ± 1.8
    4.6 ± 2.6
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -48.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -54.7
         upper limit
    -42.2
    Notes
    [3] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Calculated LDL-­C at Week 12 -­ On-­Treatment Analysis

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    End point title
    Percent Change From Baseline in Calculated LDL-­C at Week 12 -­ On-­Treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis). mITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        least squares mean (standard error)
    -44.2 ± 1.8
    4.6 ± 2.6
    Statistical analysis title
    Alirocumab 75 mg /up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -48.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -55
         upper limit
    -42.5
    Notes
    [4] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 -­ ITT Analysis

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    End point title
    Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 -­ ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline Apo B value on- or off-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    163
    81
    Units: percent change
        least squares mean (standard error)
    -42.8 ± 1.4
    -3.5 ± 2
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [5]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -39.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -44.1
         upper limit
    -34.5
    Notes
    [5] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Apo B at Week 24 - ­On­-Treatment Analysis

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    End point title
    Percent Change From Baseline in Apo B at Week 24 - ­On­-Treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection). Subjects analyzed: subjects of the mITT population with one baseline and at least one post-baseline Apo B value on-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    162
    80
    Units: percent change
        least squares mean (standard error)
    -43.2 ± 1.4
    -3.5 ± 2
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [6]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -39.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -44.5
         upper limit
    -35.1
    Notes
    [6] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Non-­High­-Density Lipoprotein Cholesterol (non-­HDL­-C) at Week 24 -­ ITT Analysis

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    End point title
    Percent Change From Baseline in Non-­High­-Density Lipoprotein Cholesterol (non-­HDL­-C) at Week 24 -­ ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline non-HDL-C value on- or off-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        least squares mean (standard error)
    -42.6 ± 1.8
    3.1 ± 2.5
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [7]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -45.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -51.8
         upper limit
    -39.7
    Notes
    [7] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Non-­HDL-­C at Week 24 -­ On-­Treatment Analysis

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    End point title
    Percent Change From Baseline in Non-­HDL-­C at Week 24 -­ On-­Treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection). Subjects analyzed: subjects of the mITT population with one baseline and at least one post-baseline non-HDL-C value on-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        least squares mean (standard error)
    -43.2 ± 1.7
    3.1 ± 2.5
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [8]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -46.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -52.3
         upper limit
    -40.4
    Notes
    [8] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Total Cholesterol (Total­-C) at Week 24 ­- ITT Analysis

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    End point title
    Percent Change From Baseline in Total Cholesterol (Total­-C) at Week 24 ­- ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline Total-C value on- or off-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        least squares mean (standard error)
    -30.6 ± 1.4
    2.1 ± 1.9
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [9]
    Method
    Mixed models analysis
    Parameter type
    LS Mean difference
    Point estimate
    -32.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -37.4
         upper limit
    -28.1
    Notes
    [9] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Apo B at Week 12 -­ ITT Analysis

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    End point title
    Percent Change From Baseline in Apo B at Week 12 -­ ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Apo B ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    163
    81
    Units: percent change
        least squares mean (standard error)
    -35.4 ± 1.4
    -0.9 ± 2
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [10]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -34.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -39.2
         upper limit
    -29.8
    Notes
    [10] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Non-­HDL­-C at Week 12 -­ ITT Analysis

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    End point title
    Percent Change From Baseline in Non-­HDL­-C at Week 12 -­ ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Non-HDL-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        least squares mean (standard error)
    -37.9 ± 1.7
    4.1 ± 2.4
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [11]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -47.8
         upper limit
    -36.2
    Notes
    [11] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Total­-C at Week 12 -­ ITT Analysis

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    End point title
    Percent Change From Baseline in Total­-C at Week 12 -­ ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Total-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        least squares mean (standard error)
    -26.6 ± 1.3
    3.4 ± 1.9
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [12]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -29.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -34.5
         upper limit
    -25.4
    Notes
    [12] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Calculated LDL-C at Week 52 -­ ITT Analysis

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    End point title
    Percent Change From Baseline in Calculated LDL-C at Week 52 -­ ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 52 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        least squares mean (standard error)
    -50.3 ± 2.3
    8.4 ± 3.3
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [13]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -58.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -66.8
         upper limit
    -50.8
    Notes
    [13] - Threshold for significance ≤ 0.05.

    Secondary: Percentage of Very High CV Risk Subjects Reaching Calculated LDL­-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL­-C <100 mg/dL (2.59 mmol/L) at Week 24 -­ ITT Analysis

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    End point title
    Percentage of Very High CV Risk Subjects Reaching Calculated LDL­-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL­-C <100 mg/dL (2.59 mmol/L) at Week 24 -­ ITT Analysis
    End point description
    Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were included in the imputation model (ITT analysis). ITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percentage of subjects
        number (not applicable)
    81.4
    11.3
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [14]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    52.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.9
         upper limit
    130
    Notes
    [14] - Threshold for significance ≤ 0.05

    Secondary: Percentage of Very High CV Risk Subjects Reaching Calculated LDL­-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL-­C <100 mg/dL (2.59 mmol/L) at Week 24 -­ On­-Treatment Analysis

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    End point title
    Percentage of Very High CV Risk Subjects Reaching Calculated LDL­-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL-­C <100 mg/dL (2.59 mmol/L) at Week 24 -­ On­-Treatment Analysis
    End point description
    Adjusted percentages at Week 24 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis). mITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percentage of subjects
        number (not applicable)
    82.1
    11.6
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [15]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    53.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    21.4
         upper limit
    132.6
    Notes
    [15] - Threshold for significance ≤ 0.05.

    Secondary: Percentage of Subjects Reaching Calculated LDL­-C <70 mg/dL (1.81 mmol/L) at Week 24 -­ ITT Analysis

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    End point title
    Percentage of Subjects Reaching Calculated LDL­-C <70 mg/dL (1.81 mmol/L) at Week 24 -­ ITT Analysis
    End point description
    Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were included in the imputation model (ITT analysis). ITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percentage of subjects
        number (not applicable)
    68.2
    1.2
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [16]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    239.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    31.6
         upper limit
    1820.3
    Notes
    [16] - Threshold for significance ≤ 0.05.

    Secondary: Percentage of Subjects Reaching Calculated LDL-­C <70 mg/dL (1.81 mmol/L) at Week 24 -­ On-Treatment Analysis

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    End point title
    Percentage of Subjects Reaching Calculated LDL-­C <70 mg/dL (1.81 mmol/L) at Week 24 -­ On-Treatment Analysis
    End point description
    Adjusted percentages at Week 24 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis). mITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percentage of subjects
        number (not applicable)
    68.8
    1.3
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [17]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    240.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    31.4
         upper limit
    1841.7
    Notes
    [17] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Lipoprotein (a) at Week 24 -­ ITT Analysis

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    End point title
    Percent Change From Baseline in Lipoprotein (a) at Week 24 -­ ITT Analysis
    End point description
    Adjusted means and standard errors at Week 24 from from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        arithmetic mean (standard error)
    -30.3 ± 1.8
    -10 ± 2.5
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a robust regression model.
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [18]
    Method
    Regression, Robust
    Parameter type
    Adjusted Mean Difference
    Point estimate
    -20.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -26.4
         upper limit
    -14.2
    Notes
    [18] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in HDL-­C at Week 24 -­ ITT Analysis

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    End point title
    Percent Change From Baseline in HDL-­C at Week 24 -­ ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline HDL-C value on- or off-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        least squares mean (standard error)
    6 ± 1.2
    -0.8 ± 1.6
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0009 [19]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    6.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.8
         upper limit
    10.7
    Notes
    [19] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Fasting Triglycerides at Week 24 -­ ITT Analysis

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    End point title
    Percent Change From Baseline in Fasting Triglycerides at Week 24 -­ ITT Analysis
    End point description
    Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        arithmetic mean (standard error)
    -10.4 ± 2
    0.5 ± 2.8
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a robust regression model.
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0012 [20]
    Method
    Regression, Robust
    Parameter type
    Adjusted Mean Difference
    Point estimate
    -10.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.5
         upper limit
    -4.3
    Notes
    [20] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Apo A-­1 at Week 24 -­ ITT Analysis

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    End point title
    Percent Change From Baseline in Apo A-­1 at Week 24 -­ ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. ITT population: all randomized and treated subjects with one baseline and at least one post-baseline Apo A-1 value on- or off-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    163
    81
    Units: percent change
        least squares mean (standard error)
    2.8 ± 0.9
    -1.6 ± 1.3
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0062 [21]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    4.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.3
         upper limit
    7.5
    Notes
    [21] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Lipoprotein (a) at Week 12 -­ ITT Analysis

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    End point title
    Percent Change From Baseline in Lipoprotein (a) at Week 12 -­ ITT Analysis
    End point description
    Adjusted means and standard errors at Week 12 from from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Lipoprotein (a) ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        arithmetic mean (standard error)
    -24.7 ± 1.7
    -5.6 ± 2.5
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a robust regression model.
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [22]
    Method
    Regression, Robust
    Parameter type
    Adjusted Mean Difference
    Point estimate
    -19.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -25
         upper limit
    -13.1
    Notes
    [22] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in HDL­-C at Week 12 -­ ITT Analysis

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    End point title
    Percent Change From Baseline in HDL­-C at Week 12 -­ ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. HDL-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        least squares mean (standard error)
    6 ± 1
    -0.8 ± 1.6
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0147 [23]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    4.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    7.8
    Notes
    [23] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Fasting Triglycerides at Week 12 -­ ITT Analysis

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    End point title
    Percent Change From Baseline in Fasting Triglycerides at Week 12 -­ ITT Analysis
    End point description
    Adjusted means and standard errors at Week 12 from from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Fasting Triglycerides ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    166
    81
    Units: percent change
        arithmetic mean (standard error)
    -8.1 ± 2.2
    0.6 ± 3.1
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a robust regression model.
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.024 [24]
    Method
    Regression, Robust
    Parameter type
    Adjusted Mean Difference
    Point estimate
    -8.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.1
         upper limit
    -1.1
    Notes
    [24] - Threshold for significance ≤ 0.05.

    Secondary: Percent Change From Baseline in Apo A­-1 at Week 12 -­ ITT Analysis

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    End point title
    Percent Change From Baseline in Apo A­-1 at Week 12 -­ ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Apo A-1 ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Alirocumab 75 mg/up to 150 mg Placebo
    Number of subjects analysed
    163
    81
    Units: percent change
        least squares mean (standard error)
    0.4 ± 0.9
    -1.9 ± 1.3
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Placebo
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1475 [25]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    2.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    5.5
    Notes
    [25] - Threshold for significance ≤ 0.05.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline up to Week 52
    Adverse event reporting additional description
    Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo matched to alirocumab for 78 week treatment duration.

    Reporting group title
    Alirocumab 75 mg/up to 150 mg
    Reporting group description
    Alirocumab 75 mg Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-­C levels ≥70 mg/dL at Week 8.

    Serious adverse events
    Placebo Alirocumab 75 mg/up to 150 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 81 (8.64%)
    10 / 167 (5.99%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiogenic shock
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-Cardiac chest pain
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis a
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Alirocumab 75 mg/up to 150 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 81 (43.21%)
    65 / 167 (38.92%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 81 (8.64%)
    14 / 167 (8.38%)
         occurrences all number
    8
    16
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    6 / 81 (7.41%)
    18 / 167 (10.78%)
         occurrences all number
    14
    68
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 81 (1.23%)
    9 / 167 (5.39%)
         occurrences all number
    1
    12
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    5 / 81 (6.17%)
    10 / 167 (5.99%)
         occurrences all number
    5
    15
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 81 (19.75%)
    18 / 167 (10.78%)
         occurrences all number
    24
    25
    Influenza
         subjects affected / exposed
    6 / 81 (7.41%)
    24 / 167 (14.37%)
         occurrences all number
    8
    25

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Feb 2013
    The purpose of this amendment was to: - Change an exclusion criterion from HbA1c >8.5% to HbA1c >9%. - Clarify that repeat testing was allowed for eligibility with respect to Thyroid-stimulating hormone (TSH) laboratory results. - Clarify fulfillment of applicable local regulatory requirements through the Informed consent form (ICF) or a local protocol addendum in women of childbearing potential and add a definition for the duration of required contraception use after discontinuation of the study drug. - Add contingency language to ensure the continuity of study drug treatment without interruption (in the event the manufacturer faced any performance or supply issues of the auto-injector). - Widen some visit windows to allow more scheduling flexibility, and make the visit window for the end of double-blind treatment visit (visit 12, week 78) narrower. - Clarify that reporting of Adverse event of special interests (AESIs) that require accelerated reporting was to be done within 24 hours of the site’s learning of the event. - Add neurologic and ophthalmologic events that require additional examinations/procedures and/or referral to a specialist as reportable AESIs that require accelerated reporting. - Define neurologic and ophthalmologic events that did not require additional examinations/procedures and/or referral to a specialist as AESIs that did not require accelerated reporting. - Remove hospitalization for unanticipated coronary revascularization from the list of Clinical events committee (CEC) adjudication categories, and add that all coronary revascularizations was to be submitted to the CEC. - Make miscellaneous administrative corrections and clarifications.
    09 Apr 2014
    The purpose of this amendment was to: - Modify the primary efficacy analysis population to the ITT population for the primary and secondary efficacy endpoints, which included assessments both on study treatment and off study treatment through the analysis period. - MMRM was to be used for the primary endpoint and for other continuous secondary endpoints anticipated to have normally distributed data. - For continuous endpoints expected to have non-normally distributed data, the robust regression method was to be used to test the treatment group differences and missing data was to be handled using multiple imputation approach. - For binary endpoints, logistic regression method was be used to test the treatment group differences and missing data was to be handled using multiple imputation approach. - Primary and key secondary endpoints was to also be analyzed in the mITT population to assess the drug effect during the study treatment period (on-treatment approach). - The list of key and other secondary efficacy endpoints and estimands (ITT estimand or on-treatment estimand) were adjusted. - Update language on CV events to be reported to the CEC for adjudication, and to clarify cerebrovascular events. - Clarify that LDL-C measured and calculated was to be performed at weeks 0 and 24. - Update language on collection of partner pregnancy, per the ODYSSEY program. - Update categorization of AEs (update language on how to record injection site reactions that were not related to study drug). - Make minor corrections/clarifications.

    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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