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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of SAR236553/REGN727 in Patients With Heterozygous Familial Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy

    Summary
    EudraCT number
    		 2011-005109-56
    Trial protocol
    		 SE   GB   AT   CZ   NL   NO   ES   DK  
    Global end of trial date
    05 Dec 2014

    Results information
    Results version number
    		 v1
    This version publication date
    01 Feb 2016
    First version publication date
    06 Aug 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC12492
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01623115
    WHO universal trial number (UTN)
    		 U1111-1121-4275
    Other trial identifiers
    		 STUDY NAME: ODYSSEY FH I
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    15 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab (SAR236553/REGN727) 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).
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 All subjects had to receive a statin (simvastatin, atorvastatin or rosuvastatin) at maximally tolerated dose. Background statin therapy (including dose) was not to be changed for at least 4 weeks prior to the screening visit and throughout the whole study duration barring exceptional circumstances.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jul 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
    Canada: 32
    Country: Number of subjects enrolled
    Netherlands: 18
    Country: Number of subjects enrolled
    Norway: 4
    Country: Number of subjects enrolled
    Spain: 49
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    United Kingdom: 23
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Czech Republic: 25
    Country: Number of subjects enrolled
    Denmark: 27
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    South Africa: 91
    Country: Number of subjects enrolled
    Israel: 29
    Country: Number of subjects enrolled
    Russian Federation: 43
    Country: Number of subjects enrolled
    United States: 109
    Worldwide total number of subjects
    486
    EEA total number of subjects
    182
    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)
    405
    From 65 to 84 years
    80
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 89 centers in 14 countries. A total of 597 subjects were screened between July 2012 and April 2013, 111 of whom were screen failures.

    Pre-assignment
    Screening details
    		 Randomization was stratified according to prior history of myocardial infarction or ischemic stroke, intensity of statin treatment and geographic region. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in 1:2 (placebo:alirocumab) after confirmation of selection criteria. 486 subjects were randomized.

    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
    Blinding implementation details
    Alirocumab and placebo for alirocumab were provided in identically matched auto-injectors and packaged identically.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo for alirocumab every 2 weeks (Q2W) on top of stable maximally tolerated daily statin therapy with or without other LMT for 78 weeks.
    Arm type
    		 Placebo

    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
    1 mL subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self ­injection or by another designated person using auto­-injector.

    Arm title
    		 Alirocumab 75/Up to 150 mg Q2W
    Arm description
    		 Alirocumab 75 mg Q2W on top of stable maximally tolerated daily statin therapy with or without other LMT for 78 weeks. Alirocumab dose up-­titrated to 150 mg from Week 12 when LDL-­C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    SAR236553, REGN727
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 mL subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self ­injection or by another designated person using auto-injector.

    Number of subjects in period 1
    		Placebo Alirocumab 75/Up to 150 mg Q2W
    Started
    163
    323
    Completed
    1
    6
    Not completed
    162
    317
         Subjects moved
    -
    3
         Physician decision
    1
    -
         Other than specified here
    5
    11
         Consent withdrawn by subject
    -
    1
         Randomized but not treated
    -
    1
         Study drug auto-injector administration
    -
    1
         Treatment ongoing
    144
    280
         Adverse event
    8
    12
         Poor compliance to protocol
    4
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo for alirocumab every 2 weeks (Q2W) on top of stable maximally tolerated daily statin therapy with or without other LMT for 78 weeks.

    Reporting group title
    Alirocumab 75/Up to 150 mg Q2W
    Reporting group description
    		 Alirocumab 75 mg Q2W on top of stable maximally tolerated daily statin therapy with or without other LMT for 78 weeks. Alirocumab dose up-­titrated to 150 mg from Week 12 when LDL-­C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.

    Reporting group values
    		 Placebo Alirocumab 75/Up to 150 mg Q2W Total
    Number of subjects
    		 163 323 486
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.7 ( 12.3 ) 52.1 ( 12.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 69 143 212
        Male
    		 94 180 274
    Calculated LDL­-C in mmol/L
    Calculated LDL-C from Friedewald formula
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 3.739 ( 1.213 ) 3.749 ( 1.325 ) -
    Calculated LDL­-C in mg/dL
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 144.4 ( 46.8 ) 144.8 ( 51.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo for alirocumab every 2 weeks (Q2W) on top of stable maximally tolerated daily statin therapy with or without other LMT for 78 weeks.

    Reporting group title
    Alirocumab 75/Up to 150 mg Q2W
    Reporting group description
    		 Alirocumab 75 mg Q2W on top of stable maximally tolerated daily statin therapy with or without other LMT for 78 weeks. Alirocumab dose up-­titrated to 150 mg from Week 12 when LDL-­C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects exposed to placebo Q2W on top of stable maximally tolerated daily statin therapy with or without other LMT (mean exposure of 59 weeks).

    Subject analysis set title
    Alirocumab 75/Up to 150 mg Q2W
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects exposed to Alirocumab 75 mg/Up to 150 mg Q2W on top of stable maximally tolerated daily statin therapy with or without other LMT (mean exposure of 59 weeks).

    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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    322
    Units: percent change
        least squares mean (standard error)
    9.1 ( 2.2 )
    -48.8 ( 1.6 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Alirocumab group was compared to placebo group using an appropriate contrast statement.
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -57.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -63.3
         upper limit
    		 -52.6
    Notes
    [1] - Threshold for significance was ≤ 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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    321
    Units: percent change
        least squares mean (standard error)
    8.8 ( 2.2 )
    -49.3 ( 1.6 )
    Statistical analysis title
    		 Alirocumab 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 0.05 level.
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    484
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -58.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -63.5
         upper limit
    		 -52.7
    Notes
    [2] - Threshold for significance was ≤ 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 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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    322
    Units: percent change
        least squares mean (standard error)
    5.7 ( 2 )
    -43.5 ( 1.4 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -49.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -53.9
         upper limit
    		 -44.5
    Notes
    [3] - Threshold for significance was ≤ 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 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). mITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    321
    Units: percent change
        least squares mean (standard error)
    5.7 ( 2 )
    -43.9 ( 1.4 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    484
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -49.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.2
         upper limit
    		 -44.8
    Notes
    [4] - Threshold for significance was ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B (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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    160
    309
    Units: percent change
        least squares mean (standard error)
    4.7 ( 1.6 )
    -41.1 ( 1.2 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    469
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -45.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49.8
         upper limit
    		 -41.8
    Notes
    [5] - Threshold for significance was ≤ 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 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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    159
    308
    Units: percent change
        least squares mean (standard error)
    4.5 ( 1.7 )
    -41.4 ( 1.2 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    467
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -45.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49.9
         upper limit
    		 -41.8
    Notes
    [6] - Threshold for significance was ≤ 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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    322
    Units: percent change
        least squares mean (standard error)
    9.6 ( 2 )
    -42.8 ( 1.4 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -52.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.2
         upper limit
    		 -47.6
    Notes
    [7] - Threshold for significance was ≤ 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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    321
    Units: percent change
        least squares mean (standard error)
    9.4 ( 2 )
    -43.3 ( 1.4 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    484
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -52.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.5
         upper limit
    		 -47.8
    Notes
    [8] - Threshold for significance was ≤ 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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    322
    Units: percent change
        least squares mean (standard error)
    7.3 ( 1.5 )
    -31.4 ( 1.1 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -38.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.4
         upper limit
    		 -35
    Notes
    [9] - Threshold for significance was ≤ 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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    160
    309
    Units: percent change
        least squares mean (standard error)
    3.1 ( 1.5 )
    -34.5 ( 1.1 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    469
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -37.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.2
         upper limit
    		 -33.9
    Notes
    [10] - Threshold for significance was ≤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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    322
    Units: percent change
        least squares mean (standard error)
    5.3 ( 1.8 )
    -38.4 ( 1.3 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -43.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -48
         upper limit
    		 -39.4
    Notes
    [11] - Threshold for significance was ≤0.05.

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

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    End point title
    		 Percent Change From Baseline in Total Cholesterol (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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    322
    Units: percent change
        least squares mean (standard error)
    4.1 ( 1.4 )
    -28.3 ( 1 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant)
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -32.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35.7
         upper limit
    		 -29.2
    Notes
    [12] - Threshold for significance was ≤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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    322
    Units: percent change
        least squares mean (standard error)
    9 ( 2.6 )
    -47.1 ( 1.9 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [13]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -56.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -62.4
         upper limit
    		 -50
    Notes
    [13] - Threshold for significance was ≤ 0.05.

    Secondary: Percentage of Very High Cardiovascular (CV) Risk Subjects Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Subjects Achieving 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 Cardiovascular (CV) Risk Subjects Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Subjects Achieving 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 population.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    322
    Units: percentage of subjects
        number (not applicable)
    2.4
    72.2
    Statistical analysis title
    		 Alirocumab 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
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [14]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    156
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 48.9
         upper limit
    		 498.1
    Notes
    [14] - Threshold for significance was ≤ 0.05.

    Secondary: Percentage of Very High CV Risk Subjects Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Subjects Achieving 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 Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Subjects Achieving 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. mITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    321
    Units: percentage of subjects
        number (not applicable)
    2.4
    73
    Statistical analysis title
    		 Alirocumab 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
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    484
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [15]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    156.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 49.7
         upper limit
    		 493.7
    Notes
    [15] - Threshold for significance was ≤ 0.05.

    Secondary: Percentage of Subjects Achieving 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 Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis
    End point description
    Adjusted percentages 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 were included in the imputation model (ITT analysis). ITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    322
    Units: percentage of subjects
        number (not applicable)
    0.8
    59.8
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [16]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    244.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 34.4
         upper limit
    		 1744.4
    Notes
    [16] - Threshold for significance was ≤ 0.05.

    Secondary: Percentage of Subjects Achieving 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 Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis
    End point description
    Adjusted percentages at Week 24 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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    321
    Units: percentage of subjects
        number (not applicable)
    0.8
    60.1
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    484
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [17]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    240
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 33.9
         upper limit
    		 1700.7
    Notes
    [17] - Threshold for significance was ≤ 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 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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    322
    Units: percent change
        arithmetic mean (standard error)
    -7.5 ( 2 )
    -25.2 ( 1.4 )
    Statistical analysis title
    		 Alirocumab 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
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [18]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -17.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.6
         upper limit
    		 -12.9
    Notes
    [18] - Threshold for significance was ≤ 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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    322
    Units: percent change
        least squares mean (standard error)
    0.8 ( 1.2 )
    8.8 ( 0.9 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [19]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5
         upper limit
    		 11
    Notes
    [19] - Threshold for significance was ≤ 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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    322
    Units: percent change
        arithmetic mean (standard error)
    6.3 ( 2.2 )
    -9.6 ( 1.6 )
    Statistical analysis title
    		 Alirocumab 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
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [20]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.3
         upper limit
    		 -10.6
    Notes
    [20] - Threshold for significance was ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Apolipoprotein A-1 (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. 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 52
    End point values
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    160
    309
    Units: percent change
        least squares mean (standard error)
    0.3 ( 1 )
    5 ( 0.7 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    469
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [21]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    4.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.3
         upper limit
    		 7.2
    Notes
    [21] - Threshold for significance was ≤ 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 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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    322
    Units: percent change
        arithmetic mean (standard error)
    -3.9 ( 1.8 )
    -21.2 ( 1.3 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [22]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -17.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.5
         upper limit
    		 -13
    Notes
    [22] - Threshold for significance was ≤ 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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    322
    Units: percent change
        least squares mean (standard error)
    2.1 ( 1.2 )
    6.4 ( 0.8 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0031 [23]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    4.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.5
         upper limit
    		 7.2
    Notes
    [23] - Threshold for significance was ≤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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    163
    322
    Units: percent change
        arithmetic mean (standard error)
    1.7 ( 2.2 )
    -8 ( 1.6 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003 [24]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -9.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15
         upper limit
    		 -4.4
    Notes
    [24] - Threshold for significance was ≤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
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    160
    309
    Units: percent change
        least squares mean (standard error)
    0.1 ( 1 )
    2.9 ( 0.7 )
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Placebo v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    469
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0187 [25]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 5.2
    Notes
    [25] - Threshold for significance was ≤ 0.05.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the primary completion date regardless of seriousness or relationship to investigational medicinal product (IMP).
    Adverse event reporting additional description
    Reported adverse events and death are treatment-emergent that is AEs that developed/worsened and deaths that occurred during the ‘treatment-emergent period’ (from the first dose of double-blind IMP injection up to the day of the last dose of double-blind IMP injection +70 days).
    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
    		 Subjects exposed to placebo Q2W on top of stable maximally tolerated daily statin therapy with or without other LMT (mean exposure of 59 weeks).

    Reporting group title
    Alirocumab 75/Up to 150 mg Q2W
    Reporting group description
    		 Subjects exposed to Alirocumab 75 mg/Up to 150 mg Q2W on top of stable maximally tolerated daily statin therapy with or without other LMT (mean exposure of 59 weeks).

    Serious adverse events
    		 Placebo Alirocumab 75/Up to 150 mg Q2W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 163 (9.20%)
    39 / 322 (12.11%)
         number of deaths (all causes)
    0
    4
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acinic Cell Carcinoma Of Salivary Gland
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign Neoplasm Of Thyroid Gland
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Small Cell Lung Cancer Metastatic
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatic Carcinoma Metastatic
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Prostate Cancer Recurrent
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Cancer Metastatic
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid Adenoma
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic Stenosis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous Fistula
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Gait Disturbance
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Miscarriage Of Partner
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy Of Partner
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperventilation
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic Enzyme Increased
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International Normalised Ratio Increased
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post Lumbar Puncture Syndrome
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius Fracture
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic Vertebral Fracture
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity To Various Agents
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 163 (0.00%)
    3 / 322 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina Pectoris
         subjects affected / exposed
    0 / 163 (0.00%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    1 / 163 (0.61%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 163 (0.61%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 163 (0.00%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Chronic
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    1 / 163 (0.61%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    0 / 163 (0.00%)
    3 / 322 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Occlusion
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracardiac Thrombus
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left Ventricular Dysfunction
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral Valve Incompetence
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular Extrasystoles
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Fibrillation
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 163 (0.61%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal Artery Embolism
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         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 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical Hernia
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile Duct Stone
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis Alcoholic
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema Nummular
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary Bladder Polyp
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar Spinal Stenosis
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 163 (0.61%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 163 (0.00%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid Retention
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 322 (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/Up to 150 mg Q2W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 163 (28.22%)
    94 / 322 (29.19%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 163 (5.52%)
    13 / 322 (4.04%)
         occurrences all number
    9
    18
    General disorders and administration site conditions
    Injection Site Reaction
         subjects affected / exposed
    16 / 163 (9.82%)
    38 / 322 (11.80%)
         occurrences all number
    53
    112
    Infections and infestations
    Influenza
         subjects affected / exposed
    8 / 163 (4.91%)
    19 / 322 (5.90%)
         occurrences all number
    9
    20
    Nasopharyngitis
         subjects affected / exposed
    11 / 163 (6.75%)
    32 / 322 (9.94%)
         occurrences all number
    14
    43
    Upper Respiratory Tract Infection
         subjects affected / exposed
    11 / 163 (6.75%)
    17 / 322 (5.28%)
         occurrences all number
    13
    24

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Feb 2013
    Change in reporting of adverse events: - Addition of neurological and ophthalmologic events in the list of adverse events of special interest (AESIs). - Addition of pregnancy of male subject’s partner as an AESI with immediate notification to comply with an update in company procedures. - Safety reporting timelines were cahnged from “within 1 working day” to “within 24 hours” for serious adverse events and adverse events of special interest with immediate notification. - Change in the screening period duration and the window for the training visit. - Addition of information on a possible contingency strategy in the event the manufacturer faced any performance or supply issues of the auto-injector in order to ensure the continuity of the study treatment without interruption. - Clarification for some safety laboratory parameters. Red blood cell distribution width (RDW) and reticulocyte count added as hematology laboratory parameters. Reticulocyte count no longer assessed reflexively but rather systematically on all study samples. - Clarification was provided regarding the type of cardiovascular (CV) events to be submitted to the Clinical Events Committee (CEC) for adjudication. - Added a clarification on how to handle subjects randomized and not treated with the IMP. - Added information on the collection of family medical history. - Clarified the wording related to the possibility for a HeFH patient having completed the Double-blind treatment period to enter an open label extension (OLE).
    26 Feb 2014
    - Statistical section was changed. - Addition of the blinding procedures related to pharmacokinetic analysis. - Updated language on cardiovascular events to be reported to the CEC for adjudication and including a clarification on cerebrovascular events. - Added the following sentence “LDL-C was also be measured (via the beta-quantification method) at Week 0 and Week 24”. - Updated language on collection of information on partner pregnancy as per other protocol in the ODYSSEY phase 3 program. - Updated language on how to record injection site reactions that were not related to study drug.

    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.
    Reported results are from first step analysis conducted after all subjects completed 52 Weeks visit.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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