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    Clinical Trial Results:
    A Randomized, Double-Blind Study of the Efficacy and Safety of REGN727 Added on to Rosuvastatin versus Ezetimibe Added-on to Rosuvastatin versus Rosuvastatin Dose Increase in Patients Who are Not Controlled on Rosuvastatin

    Summary
    EudraCT number
    2012-002333-11
    Trial protocol
    DE   ES   GB   IT  
    Global end of trial date
    08 May 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    08 Apr 2020
    First version publication date
    06 Aug 2015
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    R727-CL-1118
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01730053
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Study ID: ODYSSEY OPTIONS II
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Rd., Tarrytown, United States, 10591
    Public contact
    Clinical Trial Management, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trial Management, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Jun 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on therapy to rosuvastatin in comparison with ezetimibe as add-on therapy to rosuvastatin, and in comparison with doubling the rosuvastatin dose, after 24 weeks of treatment in subjects with hypercholesterolemia at high cardiovascular (CV) risk.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    Lipid-modifying therapies (LMT) that were allowed as background therapy included fish oils with ≥1000 mg of omega-3 fatty acids, fenofibrate, bile acid-binding sequestrates (eg, cholestyramine), and niacin. Doses of these medications were to remain stable for at least 4 weeks (at least 6 weeks for fenofibrate) before the screening visit, during the screening period, and during the double-blind treatment period.
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Oct 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
    Spain: 29
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    United States: 183
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Mexico: 12
    Worldwide total number of subjects
    305
    EEA total number of subjects
    71
    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)
    188
    From 65 to 84 years
    115
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 79 sites in 8 countries. Overall, 672 subjects were screened between 29 October 2012 and 27 September 2013, 367 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 or ischemic stroke, and intensity of statin treatment (rosuvastatin 10 or 20 mg). Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:1:1:1:1:1 ratio after confirmation of selection criteria.

    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
    Investigator, Subject, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Rosuvastatin 20 mg
    Arm description
    Subjects, who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every two weeks (Q2W), and placebo for ezetimibe QD added to stable Lipid-Modifying Therapy (LMT) for 24 weeks.
    Arm type
    Active comparator

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

    Investigational medicinal product name
    Placebo (for Alirocumab and Ezetimibe)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Solution for injection
    Routes of administration
    Oral use, Subcutaneous use
    Dosage and administration details
    Placebo matched to alirocumab administered as a SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm. Placebo matched to ezetimibe over-encapsulated tablet.

    Arm title
    Ezetimibe 10 mg + Rosuvastatin 10 mg
    Arm description
    Subjects, who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.
    Arm type
    Active comparator

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

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

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

    Arm title
    Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Arm description
    Subjects, who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Arm type
    Experimental

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

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

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

    Arm title
    Rosuvastatin 40 mg
    Arm description
    Subjects, who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks.
    Arm type
    Active comparator

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

    Investigational medicinal product name
    Placebo (for Alirocumab and Ezetimibe)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Solution for injection
    Routes of administration
    Oral use, Subcutaneous use
    Dosage and administration details
    Placebo matched to alirocumab administered as a SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm. Placebo matched to ezetimibe over-encapsulated tablet.

    Arm title
    Ezetimibe 10 mg + Rosuvastatin 20 mg
    Arm description
    Subjects, who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.
    Arm type
    Active comparator

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

    Investigational medicinal product name
    Rosuvastatin
    Investigational medicinal product code
    Other name
    Crestor
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Rosuvastatin 20 mg over-encapsulated tablets.

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

    Arm title
    Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm description
    Subjects, who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Arm type
    Experimental

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

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

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

    Number of subjects in period 1
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Started
    48
    48
    49
    53
    53
    54
    Treated
    48
    48
    49
    53
    53
    54
    Completed
    43
    34
    38
    45
    44
    41
    Not completed
    5
    14
    11
    8
    9
    13
         Subject moved
    -
    -
    1
    -
    -
    -
         Physician decision
    -
    -
    -
    1
    -
    -
         Other than specified
    2
    6
    5
    4
    7
    9
         Adverse event
    2
    6
    3
    3
    2
    2
         Poor compliance to protocol
    1
    2
    2
    -
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rosuvastatin 20 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every two weeks (Q2W), and placebo for ezetimibe QD added to stable Lipid-Modifying Therapy (LMT) for 24 weeks.

    Reporting group title
    Ezetimibe 10 mg + Rosuvastatin 10 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.

    Reporting group title
    Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.

    Reporting group title
    Rosuvastatin 40 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks.

    Reporting group title
    Ezetimibe 10 mg + Rosuvastatin 20 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.

    Reporting group title
    Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.

    Reporting group values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg Total
    Number of subjects
    48 48 49 53 53 54 305
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    61.5 ± 11.15 60.4 ± 10.38 62.2 ± 11.11 60.6 ± 10.11 63.1 ± 10.2 57.9 ± 8.86 -
    Gender categorical
    Units: Subjects
        Female
    15 22 18 15 22 26 118
        Male
    33 26 31 38 31 28 187
    Low density lipoprotein cholesterol (LDL-C) in mg/dL
    Calculated LDL-C from Friedewald formula.
    Units: mg/dL
        arithmetic mean (standard deviation)
    105.9 ± 36 102.4 ± 41.9 107.3 ± 26.4 112.9 ± 43.3 119 ± 48 118.3 ± 32.2 -
    LDL-C in mmol/L
    Units: mmol/L
        arithmetic mean (standard deviation)
    2.743 ± 0.933 2.653 ± 1.085 2.78 ± 0.684 2.924 ± 1.122 3.082 ± 1.243 3.065 ± 0.834 -

    End points

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    End points reporting groups
    Reporting group title
    Rosuvastatin 20 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every two weeks (Q2W), and placebo for ezetimibe QD added to stable Lipid-Modifying Therapy (LMT) for 24 weeks.

    Reporting group title
    Ezetimibe 10 mg + Rosuvastatin 10 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.

    Reporting group title
    Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.

    Reporting group title
    Rosuvastatin 40 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks.

    Reporting group title
    Ezetimibe 10 mg + Rosuvastatin 20 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.

    Reporting group title
    Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.

    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
    Calculated LDL-C values were obtained using the Friedewald formula. Adjusted Least-squares (LS) means and standard errors at Week 24 were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data. All available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment were used in the model (ITT analysis). ITT population: all randomized subjects with one baseline and at least one post-baseline calculated LDL-C value on- or off-treatment.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 24
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    47
    48
    52
    50
    53
    Units: percent change
        least squares mean (standard error)
    -16.3 ± 4.1
    -14.4 ± 4.4
    -50.6 ± 4.2
    -15.9 ± 7.1
    -11 ± 7.2
    -36.3 ± 7.1
    Statistical analysis title
    Alirocumab v Rosuvastatin 20 mg
    Statistical analysis description
    Alirocumab group was compared to the corresponding active control group using an appropriate contrast statement.
    Comparison groups
    Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -34.2
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -49.2
         upper limit
    -19.3
    Notes
    [1] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab v Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    As described in statistical analysis 1 of the endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -36.1
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -51.5
         upper limit
    -20.7
    Notes
    [2] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab v Rosuvastatin 40 mg
    Statistical analysis description
    As described in statistical analysis 1 of the endpoint.
    Comparison groups
    Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg v Rosuvastatin 40 mg
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0453 [3]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -20.3
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -45.8
         upper limit
    5.1
    Notes
    [3] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab v Ezetimibe 10 mg + Rosuvastatin 20 mg
    Statistical analysis description
    As described in statistical analysis 1 of the endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0136 [4]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -25.3
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -50.9
         upper limit
    0.3
    Notes
    [4] - Threshold for significance ≤ 0.0125.

    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
    Calculated LDL-C values were obtained using the Friedewald formula. Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule [rosuvastatin or ezetimibe], whichever came first) (on-treatment analysis). Modified ITT (mITT) population: all randomized and treated subjects with one baseline and at least one post-baseline calculated LDL-C value on-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    46
    48
    50
    50
    51
    Units: percent change
        least squares mean (standard error)
    -18.3 ± 3.3
    -20.3 ± 3.6
    -53.5 ± 3.5
    -17 ± 6.9
    -16.5 ± 6.9
    -41.5 ± 6.9
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    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 1.25 % level.
    Comparison groups
    Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [5]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -35.2
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -47.4
         upper limit
    -23
    Notes
    [5] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [6]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -33.2
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -45.9
         upper limit
    -20.5
    Notes
    [6] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Rosuvastatin 40 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Rosuvastatin 40 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0131 [7]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -24.5
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -49.2
         upper limit
    0.2
    Notes
    [7] - Threshold for significance ≤ 0.0125.

    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
    Calculated LDL-C values were obtained using the Friedewald formula. Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment (ITT analysis). ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    47
    48
    52
    50
    53
    Units: percent change
        least squares mean (standard error)
    -17.1 ± 4.1
    -17.4 ± 4.2
    -49.6 ± 4.1
    -22.1 ± 5.3
    -19.3 ± 5.4
    -32.3 ± 5.2
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Comparison groups
    Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [8]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -35.2
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -47.4
         upper limit
    -17.9
    Notes
    [8] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [9]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -32.2
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -47
         upper limit
    -17.5
    Notes
    [9] - Threshold for significance ≤ 0.0125.

    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
    Calculated LDL-C values were obtained using the Friedewald formula. Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule [rosuvastatin or ezetimibe], whichever came first) (on-treatment analysis). mITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    46
    48
    50
    50
    51
    Units: percent change
        least squares mean (standard error)
    -17.2 ± 3.6
    -20.3 ± 3.8
    -52.6 ± 3.6
    -22.9 ± 5.2
    -21.8 ± 5.2
    -35.1 ± 5.2
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Comparison groups
    Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [10]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -35.3
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -48.2
         upper limit
    -22.5
    Notes
    [10] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [11]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -32.3
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -45.6
         upper limit
    -19
    Notes
    [11] - Threshold for significance ≤ 0.0125.

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

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    End point title
    Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline Apo B value on- or off-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    44
    44
    44
    51
    48
    49
    Units: percent change
        least squares mean (standard error)
    -7.3 ± 3
    -9.7 ± 3.1
    -36.5 ± 3.1
    -9.8 ± 4.1
    -11.2 ± 4.3
    -28.3 ± 4.3
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Comparison groups
    Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg v Rosuvastatin 20 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [12]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -29.2
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -40.1
         upper limit
    -18.3
    Notes
    [12] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg v Ezetimibe 10 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [13]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -26.8
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -37.9
         upper limit
    -15.7
    Notes
    [13] - Threshold for significance ≤ 0.0125.

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

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    End point title
    Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule [rosuvastatin or ezetimibe], whichever came first). Subjects analyzed: subjects of the mITT population with one baseline and at least one post-baseline Apo B value on-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    44
    42
    43
    50
    47
    48
    Units: percent change
        least squares mean (standard error)
    -8.8 ± 2.6
    -11.2 ± 2.7
    -39.5 ± 2.6
    -12.7 ± 4
    -12.6 ± 4.1
    -30.4 ± 4.2
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Comparison groups
    Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [14]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -30.7
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -40.1
         upper limit
    -21.3
    Notes
    [14] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [15]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -28.3
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -38
         upper limit
    -18.7
    Notes
    [15] - Threshold for significance ≤ 0.0125.

    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 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline non-HDL-C value on- or off-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    47
    48
    52
    50
    53
    Units: percent change
        least squares mean (standard error)
    -11.3 ± 3.4
    -13.4 ± 3.7
    -42.7 ± 3.5
    -11.2 ± 5.1
    -12.9 ± 5.2
    -31.4 ± 5.2
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Comparison groups
    Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [16]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -31.4
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -43.9
         upper limit
    -18.9
    Notes
    [16] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [17]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -29.3
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -42.1
         upper limit
    -16.4
    Notes
    [17] - Threshold for significance ≤ 0.0125.

    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 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule [rosuvastatin or ezetimibe], whichever came first). Subjects analyzed: subjects of the mITT population with one baseline and at least one post-baseline Non-HDL-C value on-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    46
    48
    50
    50
    51
    Units: percent change
        least squares mean (standard error)
    -12.9 ± 2.8
    -17.5 ± 3.1
    -45.7 ± 2.9
    -14.9 ± 4.2
    -18.2 ± 4.2
    -35.6 ± 4.3
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Comparison groups
    Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [18]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -32.8
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -43.2
         upper limit
    -22.4
    Notes
    [18] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [19]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -28.2
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -39.1
         upper limit
    -17.3
    Notes
    [19] - Threshold for significance ≤ 0.0125.

    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 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline Total-C value on- or off-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    47
    48
    52
    50
    53
    Units: percent change
        least squares mean (standard error)
    -8.3 ± 2.4
    -8.7 ± 2.6
    -28.9 ± 2.5
    -8.5 ± 3.6
    -12.4 ± 3.6
    -20.6 ± 3.6
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Comparison groups
    Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [20]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -20.6
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -29.4
         upper limit
    -11.8
    Notes
    [20] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [21]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -20.3
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -29.3
         upper limit
    -11.2
    Notes
    [21] - Threshold for significance ≤ 0.0125.

    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 24 regardless of status on- or off-treatment. Apo B ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    44
    44
    44
    51
    48
    49
    Units: percent change
        least squares mean (standard error)
    -8.1 ± 3.2
    -12.1 ± 3.3
    -36.1 ± 3.2
    -13.7 ± 3.3
    -14.3 ± 3.3
    -29 ± 3.3
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Comparison groups
    Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [22]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -28.1
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -39.7
         upper limit
    -16.5
    Notes
    [22] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [23]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -24
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -35.7
         upper limit
    -12.3
    Notes
    [23] - Threshold for significance ≤ 0.0125.

    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 24 regardless of status on- or off-treatment. Non-HDL-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    47
    48
    52
    50
    53
    Units: percent change
        least squares mean (standard error)
    -11.7 ± 3.5
    -16.3 ± 3.6
    -41.2 ± 3.5
    -18 ± 3.6
    -18.7 ± 3.7
    -29.8 ± 3.6
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Comparison groups
    Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001 [24]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -29.5
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -42.1
         upper limit
    -16.9
    Notes
    [24] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001 [25]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -24.9
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -37.7
         upper limit
    -12.2
    Notes
    [25] - Threshold for significance ≤ 0.0125.

    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 24 regardless of status on- or off-treatment. Total-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    47
    48
    52
    50
    53
    Units: percent change
        least squares mean (standard error)
    -8.9 ± 2.6
    -11.8 ± 2.7
    -29 ± 2.6
    -13.8 ± 2.8
    -13.9 ± 2.8
    -19.4 ± 2.7
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Comparison groups
    Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [26]
    Method
    Mixed models analysis
    Parameter type
    LS Mean difference
    Point estimate
    -20.1
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -29.4
         upper limit
    -10.7
    Notes
    [26] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [27]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -17.2
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -26.7
         upper limit
    -7.7
    Notes
    [27] - Threshold for significance ≤ 0.0125.

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

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    End point title
    Percentage of Very High CV Risk Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis
    End point description
    Calculated LDL-C values were obtained from Friedewald formula. Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to week 24 regardless of status on- or off-treatment were included in the imputation model. (ITT analysis). ITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    47
    48
    52
    50
    53
    Units: percentage of subjects
        number (not applicable)
    45
    57.2
    84.9
    40.1
    52.2
    66.7
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
    Comparison groups
    Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg v Rosuvastatin 20 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [28]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    12.4
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    2.6
         upper limit
    59.5
    Notes
    [28] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007 [29]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    8.4
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    1.8
         upper limit
    40.5
    Notes
    [29] - Threshold for significance ≤ 0.0125.

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

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    End point title
    Percentage of Very High CV Risk Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis
    End point description
    Calculated LDL-C values were obtained from Friedewald formula. Adjusted percentages at Week 24 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 24 i.e. up to 21 days after last injection or 3 days after the last capsule [rosuvastatin or ezetimibe], whichever came first (on-treatment analysis). mITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    46
    48
    50
    50
    51
    Units: percentage of subjects
        number (not applicable)
    47
    60.5
    86.4
    41.3
    54.8
    70.4
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
    Comparison groups
    Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [30]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    15.6
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    2.58
         upper limit
    88.2
    Notes
    [30] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [31]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    9.9
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    1.7
         upper limit
    56.7
    Notes
    [31] - Threshold for significance ≤ 0.0125.

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

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    End point title
    Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis
    End point description
    Calculated LDL-C values were obtained from Friedewald formula. Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to week 24 regardless of status on- or off-treatment were included in the imputation model (ITT analysis). ITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    47
    48
    52
    50
    53
    Units: percentage of subjects
        number (not applicable)
    31.3
    43.1
    77.8
    29.9
    43.6
    60.1
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
    Comparison groups
    Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [32]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    18.6
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    3.6
         upper limit
    96.2
    Notes
    [32] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [33]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    11.6
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    2.5
         upper limit
    53.1
    Notes
    [33] - Threshold for significance ≤ 0.0125.

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

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    End point title
    Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis
    End point description
    Calculated LDL-C values were obtained from Friedewald formula. Adjusted percentages at Week 24 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 24 i.e. up to 21 days after last injection or 3 days after the last capsule [rosuvastatin or ezetimibe], whichever came first (on-treatment analysis). mITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    46
    48
    50
    50
    51
    Units: percentage of subjects
        number (not applicable)
    34.8
    46.7
    76.5
    30.6
    45.1
    66.1
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
    Comparison groups
    Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [34]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    20.3
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    2.4
         upper limit
    67.7
    Notes
    [34] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002 [35]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    12.7
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    2.4
         upper limit
    67.7
    Notes
    [35] - Threshold for significance ≤ 0.0125.

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

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    End point title
    Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis
    End point description
    Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    47
    48
    52
    50
    53
    Units: percent change
        arithmetic mean (standard error)
    -4 ± 4.3
    -4.3 ± 4.5
    -27.9 ± 4.1
    -5.2 ± 4.8
    -5.8 ± 4.6
    -22.7 ± 5.1
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification). Statistical analysis used a multiple imputation approach followed by a robust regression model.
    Comparison groups
    Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [36]
    Method
    Regression, Robust
    Parameter type
    Adjusted Mean Difference
    Point estimate
    -23.9
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -38.6
         upper limit
    -9.1
    Notes
    [36] - Threshold for significance ≤ 0.0125.
    Statistical analysis title
    Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg
    Statistical analysis description
    Analysis description as per the statistical analysis 1 of this endpoint.
    Comparison groups
    Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001 [37]
    Method
    Regression, Robust
    Parameter type
    Adjusted Mean Difference
    Point estimate
    -23.6
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -39
         upper limit
    -8.2
    Notes
    [37] - Threshold for significance ≤ 0.0125.

    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 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline HDL-C value on- or off-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    47
    48
    52
    50
    53
    Units: percent change
        least squares mean (standard error)
    1.7 ± 2.4
    4 ± 2.5
    9.1 ± 2.4
    1.5 ± 2.3
    -1.8 ± 2.3
    7.2 ± 2.3
    Statistical analysis title
    Alirocumab vs Rosuvastatin 20 mg
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification). Statistical analysis used a multiple imputation approach followed by a robust regression model.
    Comparison groups
    Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg v Rosuvastatin 20 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0311 [38]
    Method
    Regression, Robust
    Parameter type
    Adjusted Mean Difference
    Point estimate
    7.4
    Confidence interval
         level
    98.75%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    16.1
    Notes
    [38] - Threshold for significance ≤ 0.0125.

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

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    End point title
    Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
    End point description
    Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    47
    48
    52
    50
    53
    Units: percent change
        least squares mean (standard error)
    -1.8 ± 4.5
    -8.3 ± 4.8
    -11.2 ± 4.6
    -9.9 ± 4.1
    -11.1 ± 4.3
    -8.7 ± 4.5
    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 model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline Apo A-1 value on- or off-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    44
    44
    44
    51
    48
    49
    Units: percent change
        least squares mean (standard error)
    5.4 ± 1.9
    5 ± 1.9
    6.7 ± 1.9
    2.9 ± 1.9
    -0.9 ± 1.9
    6.7 ± 2
    No statistical analyses for this end point

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

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    End point title
    Percent Change From Baseline in Lipoprotein(a) at Week 12 - ITT Analysis
    End point description
    Adjusted means and standard errors at Week 12 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Lipoprotein (a) ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    47
    48
    52
    50
    53
    Units: percent change
        arithmetic mean (standard error)
    -0.7 ± 3.5
    -3.9 ± 3.6
    -20.7 ± 3.5
    3.5 ± 4.2
    7.9 ± 4.1
    -16 ± 4.2
    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 model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. HDL-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    47
    48
    52
    50
    53
    Units: percent change
        least squares mean (standard error)
    0.7 ± 2.1
    0.2 ± 2.2
    5.9 ± 2.1
    0.6 ± 2.5
    3.1 ± 2.5
    8 ± 2.5
    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 model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Fasting triglycerides ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    48
    47
    48
    52
    50
    53
    Units: percent change
        least squares mean (standard error)
    8.1 ± 4.1
    -8.2 ± 4.2
    -14 ± 4.1
    -2.7 ± 4
    -12.4 ± 4
    -10.1 ± 4
    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 24 regardless of status on- or off-treatment. Apo A-1 ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Number of subjects analysed
    44
    44
    44
    51
    48
    49
    Units: percent change
        least squares mean (standard error)
    4 ± 1.6
    2.6 ± 1.6
    4.3 ± 1.6
    0.9 ± 1.8
    1.8 ± 1.8
    9.1 ± 1.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline to Week 24
    Adverse event reporting additional description
    Treatment emergent adverse events that developed during treatment emergent adverse events period (the time period from the first double-blind injection of study drug up to the day of last injection + 70 days) are reported.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Rosuvastatin 20 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks.

    Reporting group title
    Ezetimibe 10 mg + Rosuvastatin 10 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.

    Reporting group title
    Alirocumab 75/up to 150 + Rosuvastatin 20 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.

    Reporting group title
    Rosuvastatin 40 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks.

    Reporting group title
    Ezetimibe 10 mg + Rosuvastatin 20 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.

    Reporting group title
    Alirocumab 75/up to 150 + Rosuvastatin 10 mg
    Reporting group description
    Subjects, who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.

    Serious adverse events
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75/up to 150 + Rosuvastatin 20 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75/up to 150 + Rosuvastatin 10 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 48 (8.33%)
    5 / 48 (10.42%)
    4 / 54 (7.41%)
    4 / 53 (7.55%)
    3 / 53 (5.66%)
    2 / 49 (4.08%)
         number of deaths (all causes)
    0
    0
    0
    0
    1
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Renal cell carcinoma
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Small cell lung cancer metastatic
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-Cardiac chest pain
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychotic disorder
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Obesity
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Spinal cord infection
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75/up to 150 + Rosuvastatin 20 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75/up to 150 + Rosuvastatin 10 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 48 (22.92%)
    11 / 48 (22.92%)
    15 / 54 (27.78%)
    20 / 53 (37.74%)
    12 / 53 (22.64%)
    11 / 49 (22.45%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 54 (0.00%)
    3 / 53 (5.66%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    4
    0
    0
    Dizziness
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 48 (2.08%)
    2 / 54 (3.70%)
    2 / 53 (3.77%)
    1 / 53 (1.89%)
    1 / 49 (2.04%)
         occurrences all number
    4
    1
    2
    2
    1
    1
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 48 (0.00%)
    3 / 54 (5.56%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    3
    0
    5
    0
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 48 (4.17%)
    2 / 54 (3.70%)
    3 / 53 (5.66%)
    0 / 53 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    0
    2
    2
    3
    0
    0
    Nausea
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 48 (2.08%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
    3 / 49 (6.12%)
         occurrences all number
    1
    3
    0
    1
    1
    3
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 48 (6.25%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    1
    3
    0
    0
    0
    1
    Arthralgia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    0 / 54 (0.00%)
    2 / 53 (3.77%)
    1 / 53 (1.89%)
    4 / 49 (8.16%)
         occurrences all number
    1
    0
    0
    2
    1
    4
    Myalgia
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 48 (6.25%)
    4 / 54 (7.41%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
    0 / 49 (0.00%)
         occurrences all number
    2
    3
    5
    1
    1
    0
    Pain in extremity
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 48 (2.08%)
    0 / 54 (0.00%)
    5 / 53 (9.43%)
    2 / 53 (3.77%)
    2 / 49 (4.08%)
         occurrences all number
    3
    1
    0
    5
    2
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 48 (4.17%)
    2 / 54 (3.70%)
    6 / 53 (11.32%)
    3 / 53 (5.66%)
    2 / 49 (4.08%)
         occurrences all number
    1
    2
    2
    6
    3
    2
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 48 (0.00%)
    4 / 54 (7.41%)
    6 / 53 (11.32%)
    4 / 53 (7.55%)
    2 / 49 (4.08%)
         occurrences all number
    3
    0
    4
    7
    4
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Feb 2013
    The purpose of this amendment was to: - Redefine the exclusion of subjects with HbA 1c >8.5% to HbA 1c >9%. - Clarify that a repeat lab was allowed for Thyroid-stimulating hormone (TSH) eligibility laboratory results. - Clarify fulfillment of applicable local regulatory requirements through the informed consent form or a local protocol addendum in women of childbearing potential and add a definition for the duration of required contraception use after discontinuation of the study drug. - Clarify LMTs that were allowed as background therapy. - Add contingency language to ensure the continuity of study drug treatment without interruption (in the event the manufacturer faced any performance or supply issues of the auto-injector). - Remove hospitalization for unanticipated coronary revascularization from the list of Clinical Events Committee (CEC) adjudication categories, and add that all coronary revascularizations would be submitted to the CEC. - Clarify that reporting of Adverse event of special interest (AESI) that required accelerated reporting would be done within 24 hours of learning of the event. - Make miscellaneous administrative clarifications.
    08 Apr 2014
    The purpose of this amendment was to: - Modify the primary efficacy analysis population to the ITT population for the primary and secondary efficacy endpoints, which would include assessments both on study treatment and off study treatment through the analysis period. - An MMRM would be used for the primary endpoint and for other continuous secondary endpoints anticipated to have normally distributed data. - For continuous endpoints expected to have non-normally distributed data, the robust regression method would be used to test the treatment group differences and missing data would be handled using multiple imputation approach. - For binary endpoints, logistic regression method would be used to test the treatment group differences and missing data would be handled using multiple imputation approach. - Supportive analyses had been added for the primary and secondary efficacy endpoints, pooling treatment arms across the dose regimens. - Primary and key secondary endpoints would also be analyzed in the mITT population to assess the drug effect during the study treatment period (on-treatment approach). - The list of key and other secondary efficacy endpoints and estimands (ITT estimand or on-treatment estimand) were adjusted. - For safety, the initial review of data would be based on the pooled dose regimens, with the individual treatment groups within the rosuvastatin dose regimens as supportive. - Update language on cardiovascular events to be reported to the CEC for adjudication, and to clarify cerebrovascular events. - Clarify that LDL-C measured and calculated would be performed at weeks 0 and 24. - Update language on collection of partner pregnancy data, per the ODYSSEY program. - Update categorization of AEs (update language on how to record injection site reactions that were not related to study drug). - Make minor corrections/clarifications.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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