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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 and LDL-C higher or equal to 160 mg/dL with Their Lipid-Modifying Therapy

    Summary
    EudraCT number
    		 2012-001096-37
    Trial protocol
    		 NL  
    Global end of trial date
    06 Jan 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    12 Jun 2016
    First version publication date
    06 Aug 2015
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Addition of results: analysis of efficacy data at time points beyond the Week 52 time point (primary completion) as well as final analysis of safety data at the end of the study (Week 78)

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC12732
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01617655
    WHO universal trial number (UTN)
    		 U1111-1128-5459
    Other trial identifiers
    		 Study Name: ODYSSEY HIGH FH
    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
    Final
    Date of interim/final analysis
    06 Feb 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jan 2015
    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 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) and LDL-C higher than or equal to 160 mg/dL (4.14 mmol/L).
    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 received statins (simvastatin, atorvastatin or rosuvastatin) at maximally tolerated dose. Background statin therapy (including dose) was not to be changed 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
    06 Jun 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
    Netherlands: 11
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Russian Federation: 29
    Country: Number of subjects enrolled
    South Africa: 34
    Country: Number of subjects enrolled
    United States: 27
    Worldwide total number of subjects
    107
    EEA total number of subjects
    11
    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)
    93
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 33 centers in 5 countries. A total of 206 subjects were screened between June 2012 and May 2013, 99 of whom were screen failures. Screen failures were mainly due to exclusion criteria met.

    Pre-assignment
    Screening details
    		 Randomization was stratified according to prior history of myocardial infarction (MI) or ischemic stroke, and intensity of statin treatment. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:2 (placebo:alirocumab) ratio after confirmation of selection criteria. 107 subjects were randomized.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, 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 two 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 the auto-injector.

    Arm title
    		 Alirocumab 150 mg Q2W
    Arm description
    		 Alirocumab 150 mg Q2W on top of stable maximally tolerated daily statin therapy with or without other LMT for 78 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    SAR236553, REGN727
    Other name
    Praluent
    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 the auto-injector.

    Number of subjects in period 1
    		Placebo Alirocumab 150 mg Q2W
    Started
    35
    72
    Treated
    35
    72
    Completed
    26
    43
    Not completed
    9
    29
         Last visit outside protocol visit window
    1
    10
         Subjects moved
    -
    4
         Consent withdrawn by subject
    1
    1
         Adverse event
    2
    3
         Other than specified
    1
    2
         Poor compliance to protocol
    1
    4
         Site closure
    3
    5

    Baseline characteristics

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

    Reporting group title
    Alirocumab 150 mg Q2W
    Reporting group description
    		 Alirocumab 150 mg Q2W on top of stable maximally tolerated daily statin therapy with or without other LMT for 78 weeks.

    Reporting group values
    		 Placebo Alirocumab 150 mg Q2W Total
    Number of subjects
    		 35 72 107
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.1 ± 11.2 49.8 ± 14.2 -
    Gender categorical
    Units: Subjects
        Female
    		 13 37 50
        Male
    		 22 35 57
    Calculated low density lipprotein cholesterol (LDL-C) in mg/dL
    Calculated LDL-C from Friedewald formula (LDL cholesterol = Total cholesterol - High density lipoprotein [HDL] cholesterol - [Triglyceride/5]).
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 201 ± 43.4 196.3 ± 57.9 -
    Calculated LDL-C in mmol/L
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 5.205 ± 1.125 5.083 ± 1.499 -

    End points

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

    Reporting group title
    Alirocumab 150 mg Q2W
    Reporting group description
    		 Alirocumab 150 mg Q2W on top of stable maximally tolerated daily statin therapy with or without other LMT for 78 weeks.

    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 71 weeks)

    Subject analysis set title
    Alirocumab 150 mg Q2W
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects exposed to Alirocumab 150 mg Q2W on top of stable maximally tolerated daily statin therapy with or without other LMT (mean exposure of 68 weeks)

    Primary: Percent Change From Baseline in Calculated LDL-C at Week 24 - ITT Analysis

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 24 - 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 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        least squares mean (standard error)
    -6.6 ± 4.9
    -45.7 ± 3.5
    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 150 mg Q2W
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -39.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.1
         upper limit
    		 -27.1
    Notes
    [1] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 24 - On­ Treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis). Modified ITT population (mITT): 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 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        least squares mean (standard error)
    -6.6 ± 5
    -45.5 ± 3.5
    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 150 mg Q2W
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -38.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51
         upper limit
    		 -26.9
    Notes
    [2] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 were obtained 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 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        least squares mean (standard error)
    -6.6 ± 4.6
    -46.9 ± 3.2
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Alirocumab 150 mg Q2W
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -40.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.4
         upper limit
    		 -29.3
    Notes
    [3] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection. mITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Placebo Alirocumab 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        least squares mean (standard error)
    -6.6 ± 4.6
    -46.9 ± 3.2
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Alirocumab 150 mg Q2W
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -40.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.4
         upper limit
    		 -29.2
    Notes
    [4] - Threshold for significance ≤ 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 of the ITT population with one baseline and at least one post-baseline Apo B value 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 150 mg Q2W
    Number of subjects analysed
    34
    69
    Units: percent change
        least squares mean (standard error)
    -8.7 ± 3.8
    -39 ± 2.7
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Alirocumab 150 mg Q2W
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -30.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.7
         upper limit
    		 -20.9
    Notes
    [5] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Apo­ B at Week 24 - On-Treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 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 of mITT population with one baseline and atleast one post-baseline Apo B value on-treatment (Apo B mITT population).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Placebo Alirocumab 150 mg Q2W
    Number of subjects analysed
    34
    69
    Units: percent change
        least squares mean (standard error)
    -8.7 ± 3.9
    -38.9 ± 2.8
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Alirocumab 150 mg Q2W
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -30.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.7
         upper limit
    		 -20.7
    Notes
    [6] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline non-HDL-C value 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 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        least squares mean (standard error)
    -6.2 ± 4.3
    -41.9 ± 3.1
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Alirocumab 150 mg Q2W
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -35.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -46.3
         upper limit
    		 -25.3
    Notes
    [7] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection). Subjects of the mITT population with one baseline and at least one post-baseline non-HDL-C value on-treatment (non-HDL-C mITT population).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Placebo Alirocumab 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        least squares mean (standard error)
    -6.1 ± 4.3
    -41.7 ± 3.1
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Alirocumab 150 mg Q2W v Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -35.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -46.2
         upper limit
    		 -24.9
    Notes
    [8] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline total-C value 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 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        least squares mean (standard error)
    -4.8 ± 3.6
    -33.2 ± 2.6
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Alirocumab 150 mg Q2W
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -28.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.3
         upper limit
    		 -19.6
    Notes
    [9] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Apo B at Week 12 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Apo B ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Placebo Alirocumab 150 mg Q2W
    Number of subjects analysed
    34
    69
    Units: percent change
        least squares mean (standard error)
    -9 ± 3.7
    -39.2 ± 2.6
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Alirocumab 150 mg Q2W
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -30.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.2
         upper limit
    		 -21.1
    Notes
    [10] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Non-HDL-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Placebo Alirocumab 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        least squares mean (standard error)
    -6.9 ± 4.3
    -41.4 ± 3
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Alirocumab 150 mg Q2W
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -34.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.8
         upper limit
    		 -24.1
    Notes
    [11] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Total-C at Week 12 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Total-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Placebo Alirocumab 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        least squares mean (standard error)
    -5.2 ± 3.5
    -33 ± 2.4
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Alirocumab 150 mg Q2W
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -27.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.2
         upper limit
    		 -19.4
    Notes
    [12] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 52 from MMRM model including all available post-baseline data from week 4 to week 52 regardless of status on- or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Placebo Alirocumab 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        least squares mean (standard error)
    -3 ± 5.9
    -42.1 ± 4.2
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Alirocumab 150 mg Q2W
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [13]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -39.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -53.6
         upper limit
    		 -24.6
    Notes
    [13] - Threshold for significance ≤ 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
    Very high CV risk subjects: heFH subjects with coronary heart disease (CHD) or CHD risk equivalents. High CV risk subjects: heFH subjects without CHD or CHD risk equivalents. CHD risk equivalent: peripheral arterial disease, ischemic stroke, moderate chronic kidney disease, or diabetes mellitus (DM) plus 2 or more additional risk factors. 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 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percentage of subjects
        number (not applicable)
    5.7
    41
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Multiple imputation approach followed by logistic regression model.
    Comparison groups
    Placebo v Alirocumab 150 mg Q2W
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0016 [14]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    11.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 53.5
    Notes
    [14] - Threshold for significance ≤ 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 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 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percentage of subjects
        number (not applicable)
    5.7
    41.4
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Multiple imputation approach followed by logistic regression model.
    Comparison groups
    Placebo v Alirocumab 150 mg Q2W
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0014 [15]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    11.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.6
         upper limit
    		 54.9
    Notes
    [15] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis
    End point description
    Adjusted means and standard errors at Week 24 from a multiple imputation approach model followed by robust regression 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 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        arithmetic mean (standard error)
    -8.7 ± 5
    -23.5 ± 3.7
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Multiple imputation approach followed by robust regression model.
    Comparison groups
    Placebo v Alirocumab 150 mg Q2W
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0164 [16]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -14.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.9
         upper limit
    		 -2.7
    Notes
    [16] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline HDL-C value 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 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        least squares mean (standard error)
    3.9 ± 2.7
    7.5 ± 1.9
    Statistical analysis title
    		 Alirocumab vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Alirocumab 150 mg Q2W
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2745 [17]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 10.2
    Notes
    [17] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
    End point description
    Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression 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 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        arithmetic mean (standard error)
    -1.9 ± 4.8
    -10.5 ± 3.3
    No statistical analyses for this end point

    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 of the ITT population with one baseline and at least one post-baseline Apo A-1 value 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 150 mg Q2W
    Number of subjects analysed
    34
    69
    Units: percent change
        least squares mean (standard error)
    2 ± 2.1
    5.6 ± 1.5
    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
    End point description
    Adjusted means and standard errors at Week 12 from multiple imputation approach followed by robust regression 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 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        arithmetic mean (standard error)
    -1.5 ± 5.1
    -23.2 ± 3.6
    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
    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 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        least squares mean (standard error)
    8 ± 3.4
    7.9 ± 2.4
    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
    End point description
    Adjusted means and standard errors at Week 12 from multiple imputation approach followed by robust regression 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 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        arithmetic mean (standard error)
    -4.4 ± 5.1
    -9.4 ± 3.7
    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
    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 150 mg Q2W
    Number of subjects analysed
    34
    69
    Units: percent change
        least squares mean (standard error)
    1.1 ± 2.2
    4.6 ± 1.5
    No statistical analyses for this end point

    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 multiple imputation approach 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
    Up to Week 52
    End point values
    		 Placebo Alirocumab 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percentage of subjects
        number (not applicable)
    2.9
    32.4
    No statistical analyses for this end point

    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 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 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percentage of subjects
        number (not applicable)
    2.9
    32.6
    No statistical analyses for this end point

    Other pre-specified: Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 52 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
    Other pre-specified
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Placebo Alirocumab 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        least squares mean (standard error)
    -2.9 ± 6.1
    -42 ± 4.4
    No statistical analyses for this end point

    Other pre-specified: Percent Change From Baseline in Calculated LDL-C at Week 78 - ITT Analysis

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 78 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 78 from MMRM model including all available post-baseline data from Week 4 to Week 78 regardless of status on- or off-treatment. ITT population.
    End point type
    Other pre-specified
    End point timeframe
    From Baseline to Week 78
    End point values
    		 Placebo Alirocumab 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        least squares mean (standard error)
    1.2 ± 6.4
    -37.9 ± 4.5
    No statistical analyses for this end point

    Other pre-specified: Percent Change From Baseline in Calculated LDL-C at Week 78 - On-Treatment Analysis

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 78 - On-Treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 78 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 78 i.e. up to 21 days after last injection. mITT population.
    End point type
    Other pre-specified
    End point timeframe
    From Baseline to Week 78
    End point values
    		 Placebo Alirocumab 150 mg Q2W
    Number of subjects analysed
    35
    71
    Units: percent change
        least squares mean (standard error)
    -0.2 ± 6.2
    -40.9 ± 4.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit in the study regardless of seriousness or relationship to investigational medicinal product (IMP).
    Adverse event reporting additional description
    Reported adverse events are treatment-emergent that is AEs that developed/worsened during the 'treatment-emergent period' (from the first double-blind IMP injection up to the day of the last injection + 70 days or up to first injection in the extension study, whichever came first).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Alirocumab 150 Q2W
    Reporting group description
    		 Subjects exposed to Alirocumab 150 mg Q2W on top of stable maximally tolerated daily statin therapy with or without other LMT (mean exposure of 68 weeks).

    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 71 weeks).

    Serious adverse events
    		 Alirocumab 150 Q2W Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 72 (13.89%)
    4 / 35 (11.43%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 35 (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
    2 / 72 (2.78%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carpal Tunnel Syndrome
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic Reaction
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary Colic
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis Chronic
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Colic
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rheumatoid Arthritis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 35 (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
    		 Alirocumab 150 Q2W Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 72 (54.17%)
    20 / 35 (57.14%)
    Investigations
    Blood Uric Acid Increased
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 72 (6.94%)
    0 / 35 (0.00%)
         occurrences all number
    5
    0
    Headache
         subjects affected / exposed
    5 / 72 (6.94%)
    0 / 35 (0.00%)
         occurrences all number
    5
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 72 (6.94%)
    0 / 35 (0.00%)
         occurrences all number
    5
    0
    Injection Site Reaction
         subjects affected / exposed
    6 / 72 (8.33%)
    2 / 35 (5.71%)
         occurrences all number
    7
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 72 (5.56%)
    3 / 35 (8.57%)
         occurrences all number
    4
    5
    Dyspepsia
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    2 / 72 (2.78%)
    2 / 35 (5.71%)
         occurrences all number
    2
    2
    Vomiting
         subjects affected / exposed
    4 / 72 (5.56%)
    0 / 35 (0.00%)
         occurrences all number
    4
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    4 / 72 (5.56%)
    3 / 35 (8.57%)
         occurrences all number
    4
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 72 (5.56%)
    2 / 35 (5.71%)
         occurrences all number
    4
    2
    Influenza
         subjects affected / exposed
    9 / 72 (12.50%)
    1 / 35 (2.86%)
         occurrences all number
    9
    1
    Nasopharyngitis
         subjects affected / exposed
    10 / 72 (13.89%)
    4 / 35 (11.43%)
         occurrences all number
    12
    4
    Sinusitis
         subjects affected / exposed
    4 / 72 (5.56%)
    2 / 35 (5.71%)
         occurrences all number
    4
    2
    Upper Respiratory Tract Infection
         subjects affected / exposed
    4 / 72 (5.56%)
    0 / 35 (0.00%)
         occurrences all number
    5
    0
    Urinary Tract Infection
         subjects affected / exposed
    5 / 72 (6.94%)
    0 / 35 (0.00%)
         occurrences all number
    7
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Feb 2013
    Following changes were made: •Reporting of AEs was changed: neurological and ophthalmologic events were added in the list of Adverse Events of Special Interest (AESIs); pregnancy of male subject’s partner as an AESI with immediate notification to comply with an update in the company procedure; safety reporting timelines were changed from “within 1 working day” to “within 24 hours” for serious adverse events and AESI with immediate notification; •Screening period duration and the window for the training visit was changed; •Red blood cell distribution width (RDW) and reticulocyte count were added as hematology laboratory parameters; •Clarification was provided regarding the type of 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 subject having completed the double-blind treatment period to enter an open-label extension (OLE).
    26 Feb 2014
    •Modified the primary efficacy analysis population and the statistical analysis methodology: the primary efficacy analysis population was modified to ITT population for primary and secondary efficacy endpoints, which included assessments both on study treatment and off study treatment through the analysis period; primary and key secondary endpoints were also to be analyzed in the mITT population to assess the drug effect during the study treatment period (on-treatment approach); •Updated language on CV events to be reported to the CEC for adjudication and included a clarification on CV events; •Updated language on collection of partner pregnancy as per other protocol in the ODYSSEY Phase 3 program; •Categorization of AEs (updated language on how to record injection site reactions that were not related to IMP).

    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.
    Manual reclassification was done by the Sponsor for the "other reasons" of non-completion of study as specified in the electronic case report form (eCRF).
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