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    Clinical Trial Results:
    A Randomized, Double-Blind, Double-Dummy, Active-Controlled Study to Evaluate the Efficacy and Safety of REGN727/SAR236553 in Patients with Primary Hypercholesterolemia Who are Intolerant to Statins

    Summary
    EudraCT number
    2012-001221-27
    Trial protocol
    NO   IT   GB   AT  
    Global end of trial date

    Results information
    Results version number
    v2(current)
    This version publication date
    27 Jun 2020
    First version publication date
    07 Aug 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Minor updates

    Trial information

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    Trial identification
    Sponsor protocol code
    R727-CL-1119
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01709513
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Study Name: ODYSSEY ALTERNATIVE
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Rd., Tarrytown, United States, 10591
    Public contact
    Clinical Trial Administrator, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trial Administrator, 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
    18 Jun 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2014
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    Subjects entered 24 weeks double blind treatment period. The main objective was to demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab in comparison with ezetimibe 10 mg orally once daily (QD) after 24 weeks in subjects with primary hypercholesterolemia (heterozygous familial hypercholesterolemia [heFH] and non-familial hypercholesterolemia [FH]) who were intolerant to statins. After completion of double blind treatment period subjects entered open label treatment period wherein all subjects received alirocumab.
    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
    Lipid modifying therapies (LMT): bile acid-binding sequestrants such as cholestyramine, colestipol, and colesevelam; nicotinic acid; fenofibrate, and omega-3 fatty acids and excluded ezetimibe, statins, red yeast rice, and fibrates other than fenofibrate.
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Sep 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    United States: 214
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Israel: 33
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Norway: 6
    Worldwide total number of subjects
    314
    EEA total number of subjects
    50
    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)
    170
    From 65 to 84 years
    142
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 67 sites in 8 countries. Overall, 519 subjects were screened between 28 September 2012 and 11 Aug 2013, 158 of whom were screen failures. Screen failures were mainly due to exclusion criteria met. After screening, 361 subjects entered into single blind placebo run-in period. 314 subjects were randomized.

    Pre-assignment
    Screening details
    Randomization was stratified according to prior history of myocardial infarction or ischemic stroke. Assignment to treatment arms was done centrally in a 2:2:1 (alirocumab:ezetimibe:atorvastatin) ratio. Endpoints were not reported for statin arm as the purpose of statin arm was only to assess the statin tolerance of population.

    Period 1
    Period 1 title
    Double-Blind Treatment Period (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
    Atorvastatin
    Arm description
    Atorvastatin 20 mg QD for 24 weeks and placebo (for alirocumab) every two weeks (Q2W) for 24 weeks added to stable LMT.
    Arm type
    Statin rechallenge arm

    Investigational medicinal product name
    Atorvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Atorvastatin over­-encapsulated tablets.

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

    Arm title
    Ezetimibe
    Arm description
    Ezetimibe 10 mg QD for 24 weeks and placebo for alirocumab Q2W for 24 weeks added to stable LMT.
    Arm type
    Active comparator

    Investigational medicinal product name
    Ezetimibe
    Investigational medicinal product code
    Other name
    Zetia
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ezetimibe over­-encapsulated tablet.

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

    Arm title
    Alirocumab 75 mg/up to 150 mg
    Arm description
    Alirocumab 75 mg Q2W for 24 weeks and placebo for atorvastatin/ezetimibe QD for 24 weeks added to stable LMT. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-­C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on cardiovascular risk.
    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 SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.

    Investigational medicinal product name
    Placebo (for atorvastatin/ezetimibe)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to atorvastatin/ezetimibe over­-encapsulated tablet.

    Number of subjects in period 1
    Atorvastatin Ezetimibe Alirocumab 75 mg/up to 150 mg
    Started
    63
    125
    126
    Treated
    63
    124
    126
    Completed
    42
    82
    96
    Not completed
    21
    43
    30
         Randomized but not treated
    -
    1
    -
         Adverse event
    16
    31
    23
         poor compliance to protocol
    2
    -
    -
         Unspecified
    3
    11
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atorvastatin
    Reporting group description
    Atorvastatin 20 mg QD for 24 weeks and placebo (for alirocumab) every two weeks (Q2W) for 24 weeks added to stable LMT.

    Reporting group title
    Ezetimibe
    Reporting group description
    Ezetimibe 10 mg QD for 24 weeks and placebo for alirocumab Q2W for 24 weeks added to stable LMT.

    Reporting group title
    Alirocumab 75 mg/up to 150 mg
    Reporting group description
    Alirocumab 75 mg Q2W for 24 weeks and placebo for atorvastatin/ezetimibe QD for 24 weeks added to stable LMT. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-­C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on cardiovascular risk.

    Reporting group values
    Atorvastatin Ezetimibe Alirocumab 75 mg/up to 150 mg Total
    Number of subjects
    63 125 126 314
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.4 ± 9.5 62.8 ± 10.1 64.1 ± 9 -
    Gender categorical
    Units: Subjects
        Female
    28 58 56 142
        Male
    35 67 70 172
    Low Density Lipoprotein Cholesterol (LDL-C) in mg/dL
    Calculated LDL-C values were obtained using Friedewald formula.
    Units: mg/dL
        arithmetic mean (standard deviation)
    187.3 ± 59.5 193.5 ± 70.9 191.1 ± 72.7 -
    LDL-C in mmol/L
    Calculated LDL-C values were obtained using Friedewald formula.
    Units: mmol/L
        arithmetic mean (standard deviation)
    4.85 ± 1.54 5.011 ± 1.837 4.951 ± 1.883 -

    End points

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    End points reporting groups
    Reporting group title
    Atorvastatin
    Reporting group description
    Atorvastatin 20 mg QD for 24 weeks and placebo (for alirocumab) every two weeks (Q2W) for 24 weeks added to stable LMT.

    Reporting group title
    Ezetimibe
    Reporting group description
    Ezetimibe 10 mg QD for 24 weeks and placebo for alirocumab Q2W for 24 weeks added to stable LMT.

    Reporting group title
    Alirocumab 75 mg/up to 150 mg
    Reporting group description
    Alirocumab 75 mg Q2W for 24 weeks and placebo for atorvastatin/ezetimibe QD for 24 weeks added to stable LMT. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-­C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on cardiovascular risk.

    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 [1]
    End point description
    Calculated LDL-C values were obtained from Friedewald formula. 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 24 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 24
    Notes
    [1] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    122
    126
    Units: percent change
        least squares mean (standard error)
    -14.6 ± 2.2
    -45 ± 2.2
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    Statistical analysis description
    Alirocumab group was compared to the corresponding active control group using an appropriate contrast statement.
    Comparison groups
    Alirocumab 75 mg/up to 150 mg v Ezetimibe
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -30.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -36.6
         upper limit
    -24.2
    Notes
    [2] - 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 [3]
    End point description
    Calculated LDL-C values were obtained from Friedewald formula. 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 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first) (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 24
    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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    118
    123
    Units: percent change
        least squares mean (standard error)
    -17.1 ± 2
    -52.2 ± 2
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    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
    Ezetimibe v Alirocumab 75 mg/up to 150 mg
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -35.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -40.7
         upper limit
    -29.5
    Notes
    [4] - 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 [5]
    End point description
    Calculated LDL-C values were obtained from Friedewald formula. Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment (ITT analysis). ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    122
    126
    Units: percent change
        least squares mean (standard error)
    -15.6 ± 2
    -47 ± 1.9
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Ezetimibe v Alirocumab 75 mg/up to 150 mg
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [6]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -31.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -36.9
         upper limit
    -26.1
    Notes
    [6] - 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 [7]
    End point description
    Calculated LDL-C values were obtained from Friedewald formula. 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 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first) (on-treatment analysis). mITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [7] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    118
    123
    Units: percent change
        least squares mean (standard error)
    -18 ± 1.8
    -51.2 ± 1.7
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Ezetimibe v Alirocumab 75 mg/up to 150 mg
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [8]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -33.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -38
         upper limit
    -28.2
    Notes
    [8] - 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 [9]
    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 24 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 24
    Notes
    [9] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    116
    122
    Units: percent change
        least squares mean (standard error)
    -11.2 ± 1.7
    -36.3 ± 1.7
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Ezetimibe v Alirocumab 75 mg/up to 150 mg
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [10]
    Method
    Mixed models analysis
    Parameter type
    LS Mean difference
    Point estimate
    -25.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -29.8
         upper limit
    -20.4
    Notes
    [10] - 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 [11]
    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 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first). 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 24
    Notes
    [11] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    95
    109
    Units: percent change
        least squares mean (standard error)
    -14.4 ± 1.4
    -42.6 ± 1.3
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Ezetimibe v Alirocumab 75 mg/up to 150 mg
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [12]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -28.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -32.1
         upper limit
    -24.4
    Notes
    [12] - 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 [13]
    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 24 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 24
    Notes
    [13] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    122
    126
    Units: percent change
        least squares mean (standard error)
    -14.6 ± 1.7
    -40.2 ± 1.7
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    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 Ezetimibe
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [14]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -25.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -30.4
         upper limit
    -20.8
    Notes
    [14] - 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 [15]
    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 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first). 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 24
    Notes
    [15] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    118
    123
    Units: percent change
        least squares mean (standard error)
    -17.1 ± 1.5
    -46.9 ± 1.4
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Ezetimibe v Alirocumab 75 mg/up to 150 mg
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [16]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -29.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -33.9
         upper limit
    -25.8
    Notes
    [16] - 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 [17]
    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 24 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 24
    Notes
    [17] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    122
    126
    Units: percent change
        least squares mean (standard error)
    -10.9 ± 1.4
    -31.8 ± 1.4
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Ezetimibe v Alirocumab 75 mg/up to 150 mg
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [18]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -20.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -24.7
         upper limit
    -17
    Notes
    [18] - 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 [19]
    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 24 regardless of status on- or off-treatment. Apo B ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [19] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    116
    122
    Units: percent change
        least squares mean (standard error)
    -11.6 ± 1.5
    -36.1 ± 1.5
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Ezetimibe v Alirocumab 75 mg/up to 150 mg
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [20]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -24.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -28.7
         upper limit
    -20.4
    Notes
    [20] - 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 [21]
    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 24 regardless of status on- or off-treatment. Non-HDL-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [21] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    122
    126
    Units: percent change
        least squares mean (standard error)
    -15.8 ± 1.5
    -41.5 ± 1.5
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Ezetimibe v Alirocumab 75 mg/up to 150 mg
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [22]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -25.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -29.9
         upper limit
    -21.5
    Notes
    [22] - 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 [23]
    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 24 regardless of status on- or off-treatment. Total-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [23] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    122
    126
    Units: percent change
        least squares mean (standard error)
    -11.6 ± 1.2
    -32.7 ± 1.2
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    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 Ezetimibe
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [24]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -21.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -24.5
         upper limit
    -17.7
    Notes
    [24] - 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 Moderate 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 Moderate or High CV Risk Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis [25]
    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 24 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 24
    Notes
    [25] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    122
    126
    Units: percentage of subjects
        number (not applicable)
    4.4
    41.9
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    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
    Ezetimibe v Alirocumab 75 mg/up to 150 mg
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [26]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    19.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.9
         upper limit
    55.2
    Notes
    [26] - 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 Moderate 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 Moderate or High CV Risk Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis [27]
    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 24 i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first (on-treatment analysis). mITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    Notes
    [27] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    118
    123
    Units: percentage of subjects
        number (not applicable)
    5.6
    51.2
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    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
    Ezetimibe v Alirocumab 75 mg/up to 150 mg
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [28]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    24.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.6
         upper limit
    71.9
    Notes
    [28] - 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 [29]
    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 24 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 24
    Notes
    [29] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    122
    126
    Units: percentage of subjects
        number (not applicable)
    0.8
    32.5
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a last observation carried forward (LOCF) approach followed by exact conditional logistic regression model.
    Comparison groups
    Ezetimibe v Alirocumab 75 mg/up to 150 mg
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [30]
    Method
    Regression, Exact Conditional Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    71.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.1
         upper limit
    3022.1
    Notes
    [30] - 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 [31]
    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 24 i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first (on-treatment analysis). mITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    Notes
    [31] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    118
    123
    Units: percentage of subjects
        number (not applicable)
    0.8
    39
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a LOCF approach followed by exact conditional logistic regression model.
    Comparison groups
    Ezetimibe v Alirocumab 75 mg/up to 150 mg
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [32]
    Method
    Regression, Exact Conditional Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    109.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.5
         upper limit
    4759.3
    Notes
    [32] - 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 [33]
    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 24 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 24
    Notes
    [33] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    122
    126
    Units: percent change
        arithmetic mean (standard error)
    -7.3 ± 2.5
    -25.9 ± 2.4
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    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 Ezetimibe
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [34]
    Method
    Regression, Robust
    Parameter type
    Adjusted Mean Difference
    Point estimate
    -18.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -25.5
         upper limit
    -11.8
    Notes
    [34] - 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 [35]
    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 24 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 24
    Notes
    [35] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    122
    126
    Units: percent change
        least squares mean (standard error)
    6.8 ± 1.7
    7.7 ± 1.7
    Statistical analysis title
    Alirocumab 75 mg/up to 150 mg vs Ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Ezetimibe v Alirocumab 75 mg/up to 150 mg
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6997 [36]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.8
         upper limit
    5.6
    Notes
    [36] - 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 [37]
    End point description
    Adjusted LS means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 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 24
    Notes
    [37] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    122
    126
    Units: percent change
        least squares mean (standard error)
    -3.6 ± 2.8
    -9.3 ± 2.7
    No statistical analyses for this end point

    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 [38]
    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 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population 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 24
    Notes
    [38] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    116
    122
    Units: percent change
        least squares mean (standard error)
    2.9 ± 1.2
    4.8 ± 1.2
    No statistical analyses for this end point

    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 [39]
    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 24 regardless of status on- or off-treatment. Lipoprotein (a) ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    Notes
    [39] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    122
    126
    Units: percent change
        arithmetic mean (standard error)
    -4.5 ± 2.3
    -21.7 ± 2.2
    No statistical analyses for this end point

    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 [40]
    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 24 regardless of status on- or off-treatment. HDL-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [40] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    122
    126
    Units: percent change
        least squares mean (standard error)
    7.6 ± 1.2
    9 ± 1.2
    No statistical analyses for this end point

    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 [41]
    End point description
    Adjusted LS means and standard errors at Week 12 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Fasting triglycerides ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [41] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    122
    126
    Units: percent change
        least squares mean (standard error)
    -9.4 ± 2.6
    -8 ± 2.5
    No statistical analyses for this end point

    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 [42]
    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 24 regardless of status on- or off-treatment. Apo A-1 ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [42] - 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 main objective of the study was to compare alirocumab with ezetimibe in statin-intolerant subjects. The purpose of statin arm was only to assess whether the population was truly statin intolerant.
    End point values
    Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    116
    122
    Units: percent change
        least squares mean (standard error)
    3.9 ± 1
    5.5 ± 1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Experienced Skeletal Muscle-related Adverse Event (AE)

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    End point title
    Percentage of Subjects Who Experienced Skeletal Muscle-related Adverse Event (AE)
    End point description
    Skeletal muscle-related adverse events were a predefined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness and muscle fatigue. Events that developed during treatment emergent adverse events period (the time from the first double-blind study treatment [injection or capsules, whichever came first] up to the day of the last double-blind injection + 70 days ) are reported.
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 24
    End point values
    Atorvastatin Ezetimibe Alirocumab 75 mg/up to 150 mg
    Number of subjects analysed
    63
    124
    126
    Units: Percentage of Subjects
    number (not applicable)
        Any skeletal muscle-related AE
    46.0
    41.1
    32.5
        Leading to treatment discontinuation
    22.2
    20.2
    15.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline up to Week 24
    Adverse event reporting additional description
    Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first double-blind study treatment [injection or capsules, whichever came first] up to the day of the last double-blind injection + 70 days) are reported.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Atorvastatin
    Reporting group description
    Atorvastatin 20 mg QD for 24 weeks and placebo 'for alirocumab' Q2W for 22 weeks added to stable LMT.

    Reporting group title
    Alirocumab 75 mg/up to 150 mg
    Reporting group description
    Alirocumab 75 mg Q2W for 22 weeks and placebo for atorvastatin/ezetimibe QD for 24 weeks added to stable LMT. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-­C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on cardiovascular risk.

    Reporting group title
    Ezetimibe
    Reporting group description
    Ezetimibe 10 mg QD for 24 weeks and placebo for alirocumab Q2W for 22 weeks added to stable LMT.

    Serious adverse events
    Atorvastatin Alirocumab 75 mg/up to 150 mg Ezetimibe
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 63 (11.11%)
    12 / 126 (9.52%)
    10 / 124 (8.06%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 126 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 126 (0.00%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 126 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic arthritis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 126 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 126 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 126 (0.00%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 126 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian epithelial cancer
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 126 (0.00%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 126 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 126 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 126 (0.79%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 126 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 126 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 126 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 126 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 126 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 126 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 126 (0.00%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-Cardiac chest pain
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 126 (0.00%)
    4 / 124 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 126 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 126 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 126 (0.00%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 126 (0.00%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 126 (0.00%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 126 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 126 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 126 (0.00%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 126 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 126 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 126 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Atorvastatin Alirocumab 75 mg/up to 150 mg Ezetimibe
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 63 (55.56%)
    57 / 126 (45.24%)
    63 / 124 (50.81%)
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    4 / 63 (6.35%)
    4 / 126 (3.17%)
    0 / 124 (0.00%)
         occurrences all number
    4
    4
    0
    Headache
         subjects affected / exposed
    4 / 63 (6.35%)
    6 / 126 (4.76%)
    6 / 124 (4.84%)
         occurrences all number
    4
    7
    8
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 63 (7.94%)
    6 / 126 (4.76%)
    4 / 124 (3.23%)
         occurrences all number
    5
    6
    4
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    17 / 63 (26.98%)
    31 / 126 (24.60%)
    29 / 124 (23.39%)
         occurrences all number
    21
    35
    35
    Muscular weakness
         subjects affected / exposed
    4 / 63 (6.35%)
    1 / 126 (0.79%)
    2 / 124 (1.61%)
         occurrences all number
    4
    1
    2
    Arthralgia
         subjects affected / exposed
    5 / 63 (7.94%)
    6 / 126 (4.76%)
    9 / 124 (7.26%)
         occurrences all number
    5
    9
    10
    Muscle spasms
         subjects affected / exposed
    7 / 63 (11.11%)
    5 / 126 (3.97%)
    9 / 124 (7.26%)
         occurrences all number
    7
    7
    11
    Back pain
         subjects affected / exposed
    5 / 63 (7.94%)
    5 / 126 (3.97%)
    7 / 124 (5.65%)
         occurrences all number
    6
    6
    9
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 63 (3.17%)
    8 / 126 (6.35%)
    10 / 124 (8.06%)
         occurrences all number
    2
    8
    12
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 63 (3.17%)
    7 / 126 (5.56%)
    5 / 124 (4.03%)
         occurrences all number
    2
    7
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jan 2013
    The purpose of this amendment was to: - Add an open-label treatment period. - Change the wording of the inclusion/exclusion criteria. - Change the schedule of events. - Make changes to reflect the addition of the open-label extension.
    12 Feb 2013
    The purpose of this amendment was to: - Add contingency language to ensure the continuity of study drug supply without interruption (in the event the manufacturer faced any performance or supply issues of the auto-injector). - Increase some visit windows to allow more scheduling flexibility. - Remove hospitalization for unanticipated coronary revascularization from the list of Clinical Events Committee (CEC) adjudication categories, and add that all coronary revascularizations would be submitted to the CEC. - Make miscellaneous administrative clarifications.
    01 May 2013
    The purpose of this amendment was to: - Change vitamin D status requirements. - Clarify allowable retreatment with ezetimibe after discontinuation of study drug. - Make formatting and other corrections.
    07 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. - An 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 to 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 also to be analyzed in the mITT population to assess the drug effect during the study treatment period (on treatment approach). - The lists 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 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 data, 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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