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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Evaluating the Efficacy and Safety of Alirocumab in Patients with Primary Hypercholesterolemia Not Treated With a Statin

    Summary
    EudraCT number
    		 2013-002659-14
    Trial protocol
    		 BE   NL   ES   DK  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    09 Feb 2017
    First version publication date
    09 Feb 2017
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC13786
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02023879
    WHO universal trial number (UTN)
    		 U1111-1146-3517
    Other trial identifiers
    		 Study Name: ODYSSEY CHOICE II
    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
    27 Nov 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Oct 2014
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by a regimen including an alirocumab starting dose of 150 mg every 4 weeks (Q4W) as add-on to non-statin lipid modifying background therapy or as monotherapy in comparison with placebo in subjects with primary hypercholesterolemia not treated with a statin.
    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 were to maintain a stable diet throughout the entire study duration, including the screening period. Subjects receiving background non-statin lipid modifying therapy (LMT) (ezetimibe or fenofibrate) had to continue their treatment without change (including dose) from screening through the end of 24-week double-blind treatment period barring exceptional circumstances.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Dec 2013
    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: 56
    Country: Number of subjects enrolled
    Spain: 28
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Denmark: 21
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    Canada: 27
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    United States: 71
    Worldwide total number of subjects
    233
    EEA total number of subjects
    117
    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)
    125
    From 65 to 84 years
    104
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 43 centers in 8 countries. A total of 402 subjects screened between December, 2013 and May, 2014, of whom 233 subjects were randomized and 169 were screen failures. Screen failures were mainly due to exclusion criteria met.

    Pre-assignment
    Screening details
    		 Randomization was stratified by statin intolerant status and background therapy (non-statin lipid therapy vs diet). Randomization followed a 1:2:1 ratio for placebo, alirocumab 75 mg and alirocumab 150 mg instead of 1:1:2 as initially planned due to systematic error in treatment allocation algorithm discovered after all subjects were randomized.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo Q2W
    Arm description
    		 Placebo (for alirocumab) every 2 weeks (Q2W) added to stable non-statin lipid modifying therapy (LMT) or diet alone for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    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 75 mg Q2W/Up to 150 mg Q2W (Calibrator)
    Arm description
    		 Alirocumab 75 mg Q2W added to stable non-statin LMT or diet alone for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when targeted low-density lipoprotein cholesterol (LDL-C) levels at Week 8 were not achieved i.e. LDL-C ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) depending on cardiovascular risk or <30% LDL-C reduction from baseline.
    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.

    Arm title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Arm description
    		 Alirocumab 150 mg Q4W alternating with placebo (for alirocumab) Q4W added to stable non-statin LMT or diet alone for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when targeted LDL-C levels at Week 8 were not achieved i.e. LDL-C ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) depending on cardiovascular risk or <30% LDL-C reduction from baseline.
    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.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    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 Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Started
    58
    116
    59
    Treated
    58
    115
    58
    Completed
    54
    107
    50
    Not completed
    4
    9
    9
         Consent withdrawn by subject
    1
    -
    1
         Physician decision
    -
    1
    -
         Adverse events
    2
    2
    5
         Randomized but not treated
    -
    1
    1
         Other
    1
    3
    1
         Protocol deviation
    -
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo Q2W
    Reporting group description
    		 Placebo (for alirocumab) every 2 weeks (Q2W) added to stable non-statin lipid modifying therapy (LMT) or diet alone for 24 weeks.

    Reporting group title
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator)
    Reporting group description
    		 Alirocumab 75 mg Q2W added to stable non-statin LMT or diet alone for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when targeted low-density lipoprotein cholesterol (LDL-C) levels at Week 8 were not achieved i.e. LDL-C ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) depending on cardiovascular risk or <30% LDL-C reduction from baseline.

    Reporting group title
    Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Reporting group description
    		 Alirocumab 150 mg Q4W alternating with placebo (for alirocumab) Q4W added to stable non-statin LMT or diet alone for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when targeted LDL-C levels at Week 8 were not achieved i.e. LDL-C ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) depending on cardiovascular risk or <30% LDL-C reduction from baseline.

    Reporting group values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W Total
    Number of subjects
    		 58 116 59 233
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.1 ( 10.7 ) 62.5 ( 9.9 ) 64.2 ( 10 ) -
    Gender categorical
    Units: Subjects
        Female
    		 27 47 29 103
        Male
    		 31 69 30 130
    Calculated LDL-C in mg/dL
    Calculated LDL-C from Friedewald formula (LDL-C = Total cholesterol [Total-C] - High-Density Lipoprotein Cholesterol [HDL-C] - [Triglyceride/5]).
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 158.5 ( 47.3 ) 154.5 ( 44.6 ) 163.9 ( 69.1 ) -
    Calculated LDL-C in mmol/L
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 4.106 ( 1.226 ) 4.002 ( 1.154 ) 4.245 ( 1.789 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo Q2W
    Reporting group description
    		 Placebo (for alirocumab) every 2 weeks (Q2W) added to stable non-statin lipid modifying therapy (LMT) or diet alone for 24 weeks.

    Reporting group title
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator)
    Reporting group description
    		 Alirocumab 75 mg Q2W added to stable non-statin LMT or diet alone for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when targeted low-density lipoprotein cholesterol (LDL-C) levels at Week 8 were not achieved i.e. LDL-C ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) depending on cardiovascular risk or <30% LDL-C reduction from baseline.

    Reporting group title
    Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Reporting group description
    		 Alirocumab 150 mg Q4W alternating with placebo (for alirocumab) Q4W added to stable non-statin LMT or diet alone for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when targeted LDL-C levels at Week 8 were not achieved i.e. LDL-C ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) depending on cardiovascular risk or <30% LDL-C reduction from baseline.

    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 24 regardless of status on- or off-treatment were used in the model (ITT analysis). ITT population that included all randomized subjects with one baseline and at least one post-baseline calculated LDL-C value on- or off-treatment.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    57
    115
    58
    Units: percent change
        least squares mean (standard error)
    4.7 ( 2.3 )
    -53.5 ( 1.6 )
    -51.7 ( 2.3 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W vs. Placebo
    Statistical analysis description
    Alirocumab 150 mg Q4W/up to 150 mg Q2W was compared to placebo group using an appropriate contrast statement.
    Comparison groups
    Alirocumab 150 mg Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square (LS) mean difference
    Point estimate
    -56.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -62.9
         upper limit
    		 -49.9
    Notes
    [1] - Threshold for significance at 0.05 level.

    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 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection) (on-treatment analysis). Modified ITT (mITT) population that included all randomized and treated subjects with one baseline and at least one post-baseline calculated LDL-C value on-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    56
    115
    57
    Units: percent change
        least squares mean (standard error)
    5.1 ( 2.1 )
    -55.3 ( 1.5 )
    -54.6 ( 2.1 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W 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
    Alirocumab 150 mg Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -59.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -65.6
         upper limit
    		 -53.8
    Notes
    [2] - Threshold for significance at 0.05 level.

    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 24 regardless of status on-or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    57
    115
    58
    Units: percent change
        least squares mean (standard error)
    3.2 ( 2.5 )
    -50.8 ( 1.7 )
    -41.7 ( 2.4 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W 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 Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -44.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.8
         upper limit
    		 -38.1
    Notes
    [3] - Threshold for significance at 0.05 level.

    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 24 (i.e. up to 21 days after last injection). mITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    56
    115
    57
    Units: percent change
        least squares mean (standard error)
    3.6 ( 2.3 )
    -51.5 ( 1.6 )
    -44.8 ( 2.3 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W 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 Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -48.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.8
         upper limit
    		 -41.9
    Notes
    [4] - Threshold for significance at 0.05 level.

    Secondary: Percent Change From Baseline in Calculated LDL-C to Averaged Weeks 9 to 12 - ITT- Analysis

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C to Averaged Weeks 9 to 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 24 regardless of status on-or off-treatment and assigning a weight of 0.25 for Week 9, 10, 11 and 12 time points. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    57
    115
    58
    Units: percent change
        least squares mean (standard error)
    3.2 ( 2 )
    -53.6 ( 1.4 )
    -52.3 ( 2 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W 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 Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -55.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -61.1
         upper limit
    		 -49.8
    Notes
    [5] - Threshold for significance at 0.05 level.

    Secondary: Percent Change From Baseline in Calculated LDL-C at Averaged Week 9 to 12 - On-Treatment Analysis

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Averaged Week 9 to 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 24 (i.e. up to 21 days after last injection) and assigning a weight of 0.25 for Week 9, 10, 11 and 12 time points. mITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    56
    115
    57
    Units: percent change
        least squares mean (standard error)
    3.6 ( 1.9 )
    -54.1 ( 1.3 )
    -55 ( 1.9 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W 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 Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -58.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -63.8
         upper limit
    		 -53.4
    Notes
    [6] - Threshold for significance at 0.05 level.

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

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    End point title
    		 Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment. ITT population. Number of subjects analyzed = subjects of the ITT population with available data at specified time-points.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    56
    112
    58
    Units: percent change
        least squares mean (standard error)
    7.5 ( 2.1 )
    -39.7 ( 1.5 )
    -38.9 ( 2.2 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W 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 Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -46.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -52.4
         upper limit
    		 -40.4
    Notes
    [7] - Threshold for significance at 0.05 level.

    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 24 (i.e. up to 21 days after last injection). mITT population. Number of subjects analyzed = subjects of the mITT population with available data at specified time-points.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    54
    112
    54
    Units: percent change
        least squares mean (standard error)
    7.7 ( 2 )
    -41.2 ( 1.4 )
    -40.9 ( 2.1 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W 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 Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -48.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.3
         upper limit
    		 -42.8
    Notes
    [8] - Threshold for significance at 0.05 level.

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

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    End point title
    		 Percent Change From Baseline in Non-HDL-C at Week 24 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    57
    115
    58
    Units: percent change
        least squares mean (standard error)
    4.8 ( 2.1 )
    -45.3 ( 1.5 )
    -44.2 ( 2.1 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W 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 Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.9
         upper limit
    		 -43.2
    Notes
    [9] - Threshold for significance at 0.05 level.

    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 24 (i.e. up to 21 days after last injection). mITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    56
    115
    57
    Units: percent change
        least squares mean (standard error)
    5 ( 1.9 )
    -46.9 ( 1.3 )
    -46.7 ( 1.9 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W 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 Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -51.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.1
         upper limit
    		 -46.4
    Notes
    [10] - Threshold for significance at 0.05 level.

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

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    End point title
    		 Percent Change From Baseline in Total-C at Week 24 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    57
    115
    58
    Units: percent change
        least squares mean (standard error)
    3 ( 1.6 )
    -34 ( 1.1 )
    -32.3 ( 1.6 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W 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 Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -35.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.8
         upper limit
    		 -30.8
    Notes
    [11] - Threshold for significance at 0.05 level.

    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 including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment. ITT population. Number of subjects analyzed = subjects of the ITT population with available data at specified time-points.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    56
    112
    58
    Units: percent change
        least squares mean (standard error)
    7 ( 2.2 )
    -38.4 ( 1.6 )
    -31.3 ( 2.2 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W 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 Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -38.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.3
         upper limit
    		 -32.1
    Notes
    [12] - Threshold for significance at 0.05 level.

    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 including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    57
    115
    58
    Units: percent change
        least squares mean (standard error)
    3 ( 2.2 )
    -43.4 ( 1.5 )
    -34.9 ( 2.2 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W 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 Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [13]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -37.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -43.9
         upper limit
    		 -31.8
    Notes
    [13] - Threshold for significance at 0.05 level.

    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 including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    57
    115
    58
    Units: percent change
        least squares mean (standard error)
    1.8 ( 1.6 )
    -32.6 ( 1.2 )
    -24.5 ( 1.6 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W 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 Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -26.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.9
         upper limit
    		 -21.7
    Notes
    [14] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Very High Cardiovascular (CV) Risk Subjects Achieving Calculated LDL-C <70 mg/dL (<1.81 mmol/L) or Moderate 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 Moderate or High CV Risk Subjects Achieving Calculated LDL-C <100 mg/dL (<2.59 mmol/L) at Week 24 - ITT Analysis
    End point description
    Moderate CV risk: 10-year fatal cardiovascular disease (CVD) risk Systemic Coronary Risk Evaluation (SCORE) ≥1 and <5%. High CV risk: 10-year fatal CVD risk SCORE ≥5% or moderate chronic kidney disease or type 1 or type 2 diabetes mellitus without target organ damage or familial hypercholesterolemia. Very high CV risk: history of documented coronary heart disease, ischemic stroke, peripheral artery disease, transient ischemic attack, abdominal aortic aneurysm, or carotid artery occlusion >50% without symptoms; carotid endarterectomy or carotid artery stent procedure; renal artery stenosis, or renal artery stent procedure; or type 1 or type 2 diabetes mellitus with target organ damage. Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment were included. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    57
    115
    58
    Units: percentage of subjects
        number (not applicable)
    1.8
    70.3
    63.9
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W vs. Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Statistical analysis used a multiple imputation approach followed by a logistic regression model.
    Comparison groups
    Alirocumab 150 mg Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [15]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    279.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 29.1
         upper limit
    		 2690.1
    Notes
    [15] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Very High CV Risk Subjects Achieving Calculated LDL-C< 70 mg/dL (<1.81 mmol/L) or Moderate 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 Moderate 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 multiple imputation approach including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection). mITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    56
    115
    57
    Units: percentage of subjects
        number (not applicable)
    1.8
    72.7
    67.7
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W vs. Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Statistical analysis used a multiple imputation approach followed by logistic regression model.
    Comparison groups
    Alirocumab 150 mg Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [16]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    354.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 36.2
         upper limit
    		 3479.5
    Notes
    [16] - Threshold for significance at 0.05 level.

    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 last observation carried forward (LOCF) approach including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    57
    115
    58
    Units: percentage of subjects
        number (not applicable)
    0
    60
    50
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W vs. Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Statistical analysis used a LOCF approach followed by logistic regression model.
    Comparison groups
    Alirocumab 150 mg Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [17]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    126
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 20
         upper limit
    		 9999
    Notes
    [17] - Threshold for significance at 0.05 level. Confidence interval should be read as 20.0 to >9999.

    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 LOCF approach including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection). mITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    56
    115
    57
    Units: percentage of subjects
        number (not applicable)
    0
    61.7
    50.9
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W vs. Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Statistical analysis used a LOCF approach followed by logistic regression model.
    Comparison groups
    Alirocumab 150 mg Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [18]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    141.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 22.2
         upper limit
    		 9999
    Notes
    [18] - Threshold for significance at 0.05 level. Confidence interval should be read as 20.0 to >9999.

    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 followed by robust regression model including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    57
    115
    58
    Units: percent change
        arithmetic mean (standard error)
    4.1 ( 3.7 )
    -21.8 ( 2.6 )
    -15.5 ( 3.7 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W vs. Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Statistical analysis used a Multiple imputation approach followed by robust regression model.
    Comparison groups
    Alirocumab 150 mg Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [19]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -19.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.8
         upper limit
    		 -9.4
    Notes
    [19] - Threshold for significance at 0.05 level.

    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 followed by robust regression model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    57
    115
    58
    Units: percent change
        arithmetic mean (standard error)
    2.2 ( 3.4 )
    -16.5 ( 2.4 )
    -5.7 ( 3.3 )
    Statistical analysis title
    		 Alirocumab 150 mg Q4W/Up to 150 mg Q2W vs. Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Statistical analysis used a Multiple imputation approach followed by robust regression model.
    Comparison groups
    Alirocumab 150 mg Q4W/Up to 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0892 [20]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -7.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.1
         upper limit
    		 1.2
    Notes
    [20] - Threshold for significance at 0.05 level.

    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 including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    57
    115
    58
    Units: percent change
        least squares mean (standard error)
    -2.4 ( 1.9 )
    7.4 ( 1.4 )
    7.7 ( 2 )
    No statistical analyses for this end point

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

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    End point title
    		 Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis
    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 24 regardless of status on-or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    57
    115
    58
    Units: percent change
        least squares mean (standard error)
    -0.8 ( 1.9 )
    6.8 ( 1.3 )
    8.6 ( 1.9 )
    No statistical analyses for this end point

    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 followed by robust regression model including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    57
    115
    58
    Units: percent change
        arithmetic mean (standard error)
    1.1 ( 3.8 )
    -10.6 ( 2.7 )
    -9.2 ( 3.9 )
    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 a multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    57
    115
    58
    Units: percent change
        arithmetic mean (standard error)
    2.1 ( 3.9 )
    -11.3 ( 2.7 )
    -3 ( 3.8 )
    No statistical analyses for this end point

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

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    End point title
    		 Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment. ITT population. Number of subjects analyzed = subjects of the ITT population with available data at specified time-points.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    56
    112
    58
    Units: percent change
        least squares mean (standard error)
    3.4 ( 1.5 )
    8.2 ( 1.1 )
    10 ( 1.5 )
    No statistical analyses for this end point

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

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    End point title
    		 Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis
    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 24 regardless of status on-or off-treatment. ITT population. Number of subjects analyzed = subjects of the ITT population with available data at specified time-points.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator) Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Number of subjects analysed
    56
    112
    58
    Units: percent change
        least squares mean (standard error)
    2.6 ( 1.5 )
    5.9 ( 1.1 )
    7.6 ( 1.5 )
    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 primary completion date (32 weeks) regardless of seriousness or relationship to investigational medicinal product (IMP).
    Adverse event reporting additional description
    Reported AEs & deaths are treatment-emergent, i.e.,AEs developed/worsened & deaths that occurred "on-treatment" (from 1st dose of double-blind injection up to day of last dose[active or placebo depending on Q2W or Q4W regimen]+70 days or up to the day before the first injection in open-label extension period for subjects entering extension period).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo Q2W
    Reporting group description
    		 Subjects exposed to placebo SC injection Q2W added to stable non-statin LMT or diet alone (mean exposure of 23 weeks).

    Reporting group title
    Alirocumab 150 mg Q4W/Up to 150 mg Q2W
    Reporting group description
    		 Subjects exposed to alirocumab 150 mg Q4W/up to 150 mg Q2W SC injection added to stable non-statin LMT or diet alone (mean exposure of 22 weeks).

    Reporting group title
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator)
    Reporting group description
    		 Subjects exposed to alirocumab 75 mg Q2W/up to 150 mg Q2W SC injection added to stable non-statin LMT or diet alone (mean exposure of 23 weeks).

    Serious adverse events
    		 Placebo Q2W Alirocumab 150 mg Q4W/Up to 150 mg Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 58 (6.90%)
    7 / 58 (12.07%)
    6 / 115 (5.22%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Meningioma
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple Fractures
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive Crisis
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary Colic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis Bacterial
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salpingitis
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Q2W Alirocumab 150 mg Q4W/Up to 150 mg Q2W Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 58 (34.48%)
    25 / 58 (43.10%)
    51 / 115 (44.35%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
    6 / 115 (5.22%)
         occurrences all number
    1
    0
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 58 (6.90%)
    4 / 58 (6.90%)
    1 / 115 (0.87%)
         occurrences all number
    4
    4
    1
    Headache
         subjects affected / exposed
    3 / 58 (5.17%)
    5 / 58 (8.62%)
    10 / 115 (8.70%)
         occurrences all number
    4
    5
    10
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 58 (0.00%)
    4 / 58 (6.90%)
    5 / 115 (4.35%)
         occurrences all number
    0
    4
    5
    Injection Site Reaction
         subjects affected / exposed
    0 / 58 (0.00%)
    8 / 58 (13.79%)
    4 / 115 (3.48%)
         occurrences all number
    0
    25
    6
    Oedema Peripheral
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 58 (0.00%)
    3 / 115 (2.61%)
         occurrences all number
    4
    0
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 58 (1.72%)
    5 / 115 (4.35%)
         occurrences all number
    4
    1
    5
    Nausea
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 58 (5.17%)
    6 / 115 (5.22%)
         occurrences all number
    2
    3
    6
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 58 (5.17%)
    1 / 115 (0.87%)
         occurrences all number
    0
    3
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 58 (3.45%)
    7 / 58 (12.07%)
    7 / 115 (6.09%)
         occurrences all number
    2
    8
    7
    Back Pain
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 58 (3.45%)
    6 / 115 (5.22%)
         occurrences all number
    0
    2
    6
    Muscle Spasms
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 58 (5.17%)
    8 / 115 (6.96%)
         occurrences all number
    0
    3
    8
    Myalgia
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 58 (5.17%)
    7 / 115 (6.09%)
         occurrences all number
    3
    3
    10
    Pain In Extremity
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 58 (5.17%)
    4 / 115 (3.48%)
         occurrences all number
    1
    3
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 58 (5.17%)
    5 / 58 (8.62%)
    10 / 115 (8.70%)
         occurrences all number
    3
    7
    11
    Urinary Tract Infection
         subjects affected / exposed
    1 / 58 (1.72%)
    4 / 58 (6.90%)
    4 / 115 (3.48%)
         occurrences all number
    1
    4
    4
    Upper Respiratory Tract Infection
         subjects affected / exposed
    4 / 58 (6.90%)
    3 / 58 (5.17%)
    4 / 115 (3.48%)
         occurrences all number
    5
    5
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Oct 2013
    -Changes were made to the exclusion criterion for consistency with the 2004 adult treatment panel (ATP) III guidelines. -Timing of the primary endpoint was changed (at Week 24, to be consistent with the rest of the phase 3 program). –Changes were made to the analysis of the primary and secondary endpoints (use of an ITT approach). -Added collection of measured LDL-C at Week 0 and Week 24.
    25 Aug 2014
    -Adjusted the list of key and other secondary efficacy endpoints and estimands (ITT estimand and on-treatment estimand). -Added time points (Week 9, Week 10 and Week 11) in the model for the primary efficacy analysis endpoint. -Specified sensitivity analyses to be performed on the primary efficacy endpoint.

    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.
    The systematic randomization error was not anticipated to have an impact on the power of the study. The sample size to detect a difference in efficacy endpoints was reached (it was increased to obtain additional safety data) and blind was maintained.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27625344
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