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    Clinical Trial Results:
    A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety and Efficacy of Evolocumab (AMG 145) in Combination With Statin Therapy in Diabetic Subjects With Hyperlipidemia or Mixed Dyslipidemia (BERSON)

    Summary
    EudraCT number
    		 2013-000723-14
    Trial protocol
    		 FR  
    Global end of trial date
    06 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Dec 2018
    First version publication date
    19 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20120119
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02662569
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the effect of 12 weeks of subcutaneous evolocumab in combination with daily oral atorvastatin, compared with placebo and daily atorvastatin, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in diabetic subjects with hyperlipidemia or mixed dyslipidemia.
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations and guidelines. The study and all amendments were reviewed by an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) at each center. The investigator or his/her designee informed the subject of all aspects pertaining to the subject’s participation in the study before any screening procedures were performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Apr 2016
    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
    China: 453
    Country: Number of subjects enrolled
    Korea, Republic of: 38
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Russian Federation: 227
    Country: Number of subjects enrolled
    Turkey: 31
    Country: Number of subjects enrolled
    Argentina: 58
    Country: Number of subjects enrolled
    Brazil: 112
    Country: Number of subjects enrolled
    Colombia: 25
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    United States: 33
    Worldwide total number of subjects
    986
    EEA total number of subjects
    3
    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)
    620
    From 65 to 84 years
    366
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at 102 study centers and randomized at 98 centers in Argentina, Brazil, Canada, China, Colombia, France, Republic of Korea, Russian Federation, Turkey, and the United States from 14 April 2016 to 28 July 2017.

    Pre-assignment
    Screening details
    		 After undergoing screening procedures, including laboratory assessments and a screening placebo injection, participants meeting eligibility criteria and completing at least 4 weeks of lipid stabilization on atorvastatin 20 mg daily were randomized in a 1:1:2:2 ratio. Randomization was stratified by entry statin therapy and geographic region.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo Q2W
    Arm description
    		 Participants received placebo subcutaneous injection once every 2 weeks (Q2W) and 20 mg atorvastatin orally once a day for up to 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to evolocumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously once every 2 weeks

    Investigational medicinal product name
    Atorvastatin
    Investigational medicinal product code
    Other name
    Lipitor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day

    Arm title
    		 Placebo QM
    Arm description
    		 Participants received placebo subcutaneous injection once a month (QM) and 20 mg atorvastatin orally once a day for up to 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to evolocumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously once every month

    Investigational medicinal product name
    Atorvastatin
    Investigational medicinal product code
    Other name
    Lipitor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day

    Arm title
    		 Evolocumab Q2W
    Arm description
    		 Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks and 20 mg atorvastatin orally once a day for up to 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atorvastatin
    Investigational medicinal product code
    Other name
    Lipitor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day

    Investigational medicinal product name
    Evolocumab
    Investigational medicinal product code
    AMG 145
    Other name
    Repatha
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously once every 2 weeks

    Arm title
    		 Evolocumab QM
    Arm description
    		 Participants received 420 mg evolocumab by subcutaneous injection once a month and 20 mg atorvastatin orally once a day for up to 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atorvastatin
    Investigational medicinal product code
    Other name
    Lipitor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day

    Investigational medicinal product name
    Evolocumab
    Investigational medicinal product code
    AMG 145
    Other name
    Repatha
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously once every month

    Number of subjects in period 1
    		Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Started
    166
    161
    327
    332
    Received Study Drug
    164
    160
    325
    332
    Completed
    159
    160
    321
    328
    Not completed
    7
    1
    6
    4
         Consent withdrawn by subject
    6
    1
    6
    4
         Lost to follow-up
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo Q2W
    Reporting group description
    		 Participants received placebo subcutaneous injection once every 2 weeks (Q2W) and 20 mg atorvastatin orally once a day for up to 12 weeks.

    Reporting group title
    Placebo QM
    Reporting group description
    		 Participants received placebo subcutaneous injection once a month (QM) and 20 mg atorvastatin orally once a day for up to 12 weeks.

    Reporting group title
    Evolocumab Q2W
    Reporting group description
    		 Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks and 20 mg atorvastatin orally once a day for up to 12 weeks.

    Reporting group title
    Evolocumab QM
    Reporting group description
    		 Participants received 420 mg evolocumab by subcutaneous injection once a month and 20 mg atorvastatin orally once a day for up to 12 weeks.

    Reporting group values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM Total
    Number of subjects
    		 166 161 327 332 986
    Age, Customized
    Units: Subjects
        18 - 64 years
    		 105 101 206 208 620
        65 - 84 years
    		 61 60 121 124 366
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.6 ( 8.8 ) 61.0 ( 8.8 ) 61.0 ( 8.5 ) 61.6 ( 8.4 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 102 94 178 190 564
        Male
    		 64 67 149 142 422
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1 0 2
        Asian
    		 82 80 164 166 492
        Black or African American
    		 7 6 11 18 42
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        White
    		 72 68 140 140 420
        Multiple
    		 5 6 11 8 30
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 29 34 65 67 195
        Not Hispanic or Latino
    		 137 127 262 265 791
        Unknown or Not Reported
    		 0 0 0 0 0
    Stratification Factor: Statin Therapy at Study Entry
    Intensive: at least one of the following recorded for the last 4 weeks prior to screening: atorvastatin ≥ 40 mg once daily (QD); rosuvastatin ≥ 20 mg QD; simvastatin ≥ 80 mg QD; any statin (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) QD plus ezetimibe. Non-intensive: Subject has been taking any dose of a statin at least weekly for the last 4 weeks prior to screening and is not included in the intensive statin usage. No statin: Subject is not included in the intensive statin usage or non-intensive statin usage.
    Units: Subjects
        Intensive statin usage
    		 16 15 31 32 94
        Non-intensive statin usage
    		 83 80 167 166 496
        No statin
    		 67 66 129 134 396
    Stratification Factor: Geographic Region
    Units: Subjects
        China
    		 76 75 150 152 453
        South Korea
    		 6 5 14 13 38
        Other countries
    		 84 81 163 167 495
    Low-density Lipoprotein Cholesterol (LDL-C) Concentration
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), 164, 160, 325, and 332 subjects in each treatment group respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 92.2 ( 32.0 ) 91.0 ( 30.7 ) 92.4 ( 33.8 ) 93.5 ( 33.6 ) -
    Non-high-density Lipoprotein Cholesterol (non-HDL-C) Concentration
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), 164, 160, 325, and 332 subjects in each treatment group respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 119.2 ( 38.2 ) 119.4 ( 36.0 ) 121.3 ( 38.1 ) 121.2 ( 37.0 ) -
    Apolipoprotein B100 Concentration
    Apolipoprotein B100 is the primary apolipoprotein of low-density lipoprotein cholesterol particles, and plays a role in moving cholesterol around the body. Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), and with available baseline data, 162, 158, 325, and 332 subjects in each treatment group respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 82.1 ( 23.1 ) 83.4 ( 22.3 ) 84.8 ( 23.0 ) 84.4 ( 21.8 ) -
    Total Cholesterol
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), 164, 160, 325, and 332 subjects in each treatment group respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 166.5 ( 38.6 ) 169.3 ( 37.5 ) 167.8 ( 38.9 ) 168.9 ( 38.9 ) -
    Total Cholesterol/High-density Lipoprotein Cholesterol(HDL-C) Ratio
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), 164, 160, 325, and 332 subjects in each treatment group respectively.
    Units: ratio
        arithmetic mean (standard deviation)
    		 3.717 ( 1.337 ) 3.598 ( 1.071 ) 3.804 ( 1.273 ) 3.725 ( 1.201 ) -
    Apolipoprotein B100/Apolipoprotein A1 Ratio
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), and with available baseline data, 162, 158, 325, and 332 subjects in each treatment group respectively.
    Units: ratio
        arithmetic mean (standard deviation)
    		 0.573 ( 0.192 ) 0.563 ( 0.161 ) 0.601 ( 0.200 ) 0.586 ( 0.185 ) -
    Lipoprotein(a)
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), 164, 160, 325, and 332 subjects in each treatment group respectively.
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 67.0 ( 90.9 ) 71.8 ( 96.5 ) 65.6 ( 92.5 ) 73.2 ( 95.9 ) -
    Triglycerides Concentration
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), 164, 160, 325, and 332 subjects in each treatment group respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 137.3 ( 77.3 ) 150.6 ( 154.6 ) 145.9 ( 67.5 ) 139.7 ( 64.9 ) -
    High-density Lipoprotein Cholesterol (HDL-C) Concentration
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), 164, 160, 325, and 332 subjects in each treatment group respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 47.3 ( 11.9 ) 49.9 ( 15.2 ) 46.5 ( 11.5 ) 47.6 ( 12.3 ) -
    Very Low-density Lipoprotein Cholesterol (VLDL-C) Concentration
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), 164, 160, 325, and 332 subjects in each treatment group respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 27.3 ( 14.9 ) 28.4 ( 16.2 ) 28.7 ( 12.6 ) 27.8 ( 12.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo Q2W
    Reporting group description
    		 Participants received placebo subcutaneous injection once every 2 weeks (Q2W) and 20 mg atorvastatin orally once a day for up to 12 weeks.

    Reporting group title
    Placebo QM
    Reporting group description
    		 Participants received placebo subcutaneous injection once a month (QM) and 20 mg atorvastatin orally once a day for up to 12 weeks.

    Reporting group title
    Evolocumab Q2W
    Reporting group description
    		 Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks and 20 mg atorvastatin orally once a day for up to 12 weeks.

    Reporting group title
    Evolocumab QM
    Reporting group description
    		 Participants received 420 mg evolocumab by subcutaneous injection once a month and 20 mg atorvastatin orally once a day for up to 12 weeks.

    Primary: Percent Change From Baseline in LDL-C at the Mean of Weeks 10 and 12

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    End point title
    		 Percent Change From Baseline in LDL-C at the Mean of Weeks 10 and 12
    End point description
    End point type
    Primary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    4.94 ( 3.48 )
    0.99 ( 3.31 )
    -65.35 ( 3.09 )
    -69.05 ( 2.96 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -70.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -75.43
         upper limit
    		 -65.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.61
    Notes
    [1] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [2] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -70.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -74.67
         upper limit
    		 -65.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.35
    Notes
    [3] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [4] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit

    Primary: Percent Change From Baseline in LDL-C at Week 12

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    End point title
    		 Percent Change From Baseline in LDL-C at Week 12
    End point description
    End point type
    Primary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    7.10 ( 3.66 )
    2.63 ( 3.41 )
    -64.66 ( 3.20 )
    -62.30 ( 3.02 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -71.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -77.61
         upper limit
    		 -65.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.97
    Notes
    [5] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [6] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.0001 [8]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -64.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -69.97
         upper limit
    		 -59.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.56
    Notes
    [7] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [8] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit

    Secondary: Change From Baseline in LDL-C at the Mean of Weeks 10 and 12

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    End point title
    		 Change From Baseline in LDL-C at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: mg/dL
        least squares mean (standard error)
    -2.1 ( 4.1 )
    -8.8 ( 4.0 )
    -64.6 ( 3.6 )
    -71.9 ( 3.6 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.0001 [10]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -62.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -68.2
         upper limit
    		 -56.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.9
    Notes
    [9] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [10] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.0001 [12]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -63.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -68.4
         upper limit
    		 -57.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.7
    Notes
    [11] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [12] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.

    Secondary: Change From Baseline in LDL-C at Week 12

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    End point title
    		 Change From Baseline in LDL-C at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: mg/dL
        least squares mean (standard error)
    -0.3 ( 4.2 )
    -7.3 ( 4.1 )
    -63.9 ( 3.7 )
    -66.1 ( 3.7 )
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 < 0.0001 [14]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -58.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -64.3
         upper limit
    		 -53.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.8
    Notes
    [13] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [14] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 < 0.0001 [16]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -63.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -69.7
         upper limit
    		 -57.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.1
    Notes
    [15] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [16] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit

    Secondary: Percent Change From Baseline in Non-HDL-C at the Mean of Weeks 10 and 12

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    End point title
    		 Percent Change From Baseline in Non-HDL-C at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    4.33 ( 3.05 )
    0.33 ( 2.95 )
    -56.57 ( 2.70 )
    -59.08 ( 2.63 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 < 0.0001 [18]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -60.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -65.51
         upper limit
    		 -56.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.35
    Notes
    [17] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [18] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 < 0.0001 [20]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -59.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -63.52
         upper limit
    		 -55.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.09
    Notes
    [19] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [20] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.

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

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    End point title
    		 Percent Change From Baseline in Non-HDL-C at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    5.87 ( 3.20 )
    1.30 ( 3.03 )
    -55.76 ( 2.79 )
    -59.92 ( 2.69 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 < 0.0001 [22]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -61.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -66.82
         upper limit
    		 -56.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.64
    Notes
    [21] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [22] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 < 0.0001 [24]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -54.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -58.7
         upper limit
    		 -49.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.28
    Notes
    [23] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [24] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.

    Secondary: Percent Change From Baseline in Apolipoprotein B100 at the Mean of Weeks 10 and 12

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B100 at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    1.97 ( 3.31 )
    -1.52 ( 2.99 )
    -54.96 ( 3.07 )
    -56.37 ( 2.72 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 < 0.0001 [26]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -56.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -60.93
         upper limit
    		 -52.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.03
    Notes
    [25] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [26] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 < 0.0001 [28]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -54.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -58.52
         upper limit
    		 -51.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.87
    Notes
    [27] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [28] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.

    Secondary: Percent Change From Baseline in Apolipoprotein B100 at Week 12

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B100 at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    3.17 ( 3.42 )
    -0.26 ( 3.03 )
    -53.90 ( 3.14 )
    -49.68 ( 2.75 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 < 0.0001 [30]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -57.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -61.59
         upper limit
    		 -52.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.3
    Notes
    [29] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [30] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 < 0.0001 [32]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -49.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -53.31
         upper limit
    		 -45.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.98
    Notes
    [31] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [32] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit

    Secondary: Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 10 and 12

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    End point title
    		 Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    2.89 ( 2.30 )
    -0.25 ( 2.18 )
    -38.64 ( 2.04 )
    -39.74 ( 1.95 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 < 0.0001 [34]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -41.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.95
         upper limit
    		 -38.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.74
    Notes
    [33] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [34] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 < 0.0001 [36]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -39.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.47
         upper limit
    		 -36.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.51
    Notes
    [35] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [36] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit

    Secondary: Percent Change From Baseline in Total Cholesterol at Week 12

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    End point title
    		 Percent Change From Baseline in Total Cholesterol at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    4.40 ( 2.40 )
    0.67 ( 2.24 )
    -37.82 ( 2.10 )
    -35.22 ( 1.99 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 < 0.0001 [38]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -42.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -46.02
         upper limit
    		 -38.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.93
    Notes
    [37] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [38] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 < 0.0001 [40]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -35.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.12
         upper limit
    		 -32.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.64
    Notes
    [39] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [40] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.

    Secondary: Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at the Mean of Weeks 10 and 12

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    End point title
    		 Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    3.03 ( 2.38 )
    -2.03 ( 2.41 )
    -41.06 ( 2.11 )
    -45.70 ( 2.17 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 < 0.0001 [42]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -44.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -47.64
         upper limit
    		 -40.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.81
    Notes
    [41] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [42] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 < 0.0001 [44]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -43.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -46.9
         upper limit
    		 -40.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.64
    Notes
    [43] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [44] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.

    Secondary: Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at Week 12

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    End point title
    		 Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    3.22 ( 2.49 )
    -1.22 ( 2.47 )
    -40.72 ( 2.18 )
    -41.78 ( 2.21 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 < 0.0001 [46]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -43.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -47.9
         upper limit
    		 -39.97
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.02
    Notes
    [45] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [46] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [47]
    P-value
    		 < 0.0001 [48]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -40.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.08
         upper limit
    		 -37.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.79
    Notes
    [47] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [48] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit

    Secondary: Percent Change From Baseline in Apolipoprotein B100/Apolipoprotein A1 Ratio at the Mean of Weeks 10 and 12

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B100/Apolipoprotein A1 Ratio at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    2.60 ( 3.30 )
    -1.02 ( 3.09 )
    -55.60 ( 3.07 )
    -57.75 ( 2.82 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [49]
    P-value
    		 < 0.0001 [50]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -58.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -62.15
         upper limit
    		 -54.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.01
    Notes
    [49] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [50] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [51]
    P-value
    		 < 0.0001 [52]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -56.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -60.53
         upper limit
    		 -52.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.93
    Notes
    [51] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [52] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.

    Secondary: Percent Change From Baseline in Apolipoprotein B100/Apolipoprotein A1 Ratio at Week 12

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B100/Apolipoprotein A1 Ratio at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    3.23 ( 3.39 )
    -0.10 ( 3.16 )
    -54.98 ( 3.12 )
    -51.80 ( 2.86 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [53]
    P-value
    		 < 0.0001 [54]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -58.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -62.59
         upper limit
    		 -53.84
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.23
    Notes
    [53] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [54] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [55]
    P-value
    		 < 0.0001 [56]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -51.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -55.81
         upper limit
    		 -47.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.09
    Notes
    [55] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [56] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.

    Secondary: Percentage of Participants With Mean LDL-C at Weeks 10 and 12 of Less Than 70 mg/dL (1.8 mmol/L)

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    End point title
    		 Percentage of Participants With Mean LDL-C at Weeks 10 and 12 of Less Than 70 mg/dL (1.8 mmol/L)
    End point description
    End point type
    Secondary
    End point timeframe
    Weeks 10 and 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percentage of participants
        number (confidence interval 95%)
    21.7 (15.9 to 28.7)
    19.4 (13.9 to 26.3)
    90.1 (86.2 to 92.9)
    91.3 (87.6 to 93.9)
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [57]
    P-value
    		 < 0.0001 [58]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    68.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 60.4
         upper limit
    		 74.8
    Notes
    [57] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [58] - Cochran-Mantel Haenszel test stratified by entry statin therapy and geographic region.
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [59]
    P-value
    		 < 0.0001 [60]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    71.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 64.1
         upper limit
    		 77.9
    Notes
    [59] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [60] - Cochran-Mantel Haenszel test stratified by entry statin therapy and geographic region.

    Secondary: Percentage of Participants With LDL-C Less Than 70 mg/dL (1.8 mmol/L) at Week 12

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    End point title
    		 Percentage of Participants With LDL-C Less Than 70 mg/dL (1.8 mmol/L) at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percentage of participants
        number (confidence interval 95%)
    20.9 (15.2 to 28.2)
    21.3 (15.5 to 28.6)
    88.2 (84.0 to 91.4)
    90.2 (86.2 to 93.1)
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [61]
    P-value
    		 < 0.0001 [62]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    67.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 58.9
         upper limit
    		 73.9
    Notes
    [61] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [62] - Cochran-Mantel Haenszel test stratified by entry statin therapy and geographic region.
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [63]
    P-value
    		 < 0.0001 [64]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    68.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 60.6
         upper limit
    		 75.3
    Notes
    [63] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [64] - Cochran-Mantel Haenszel test stratified by entry statin therapy and geographic region.

    Secondary: Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 10 and 12

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    End point title
    		 Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    16.89 ( 17.49 )
    8.48 ( 9.49 )
    -38.63 ( 13.67 )
    -42.29 ( 8.49 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [65]
    P-value
    		 < 0.0001 [66]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -55.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -92.64
         upper limit
    		 -18.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.85
    Notes
    [65] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [66] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [67]
    P-value
    		 < 0.0001 [68]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -50.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -63.82
         upper limit
    		 -37.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.63
    Notes
    [67] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [68] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.

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

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    End point title
    		 Percent Change From Baseline in Lipoprotein(a) at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    26.53 ( 21.78 )
    7.47 ( 10.40 )
    -35.93 ( 16.47 )
    -37.85 ( 9.02 )
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [69]
    P-value
    		 < 0.0001 [70]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -45.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -61.87
         upper limit
    		 -28.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.42
    Notes
    [69] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [70] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [71]
    P-value
    		 < 0.0001 [72]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -62.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -110.89
         upper limit
    		 -14.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    24.64
    Notes
    [71] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [72] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.

    Secondary: Percent Change From Baseline in Triglycerides at the Mean of Weeks 10 and 12

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    End point title
    		 Percent Change From Baseline in Triglycerides at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    11.54 ( 5.27 )
    8.48 ( 4.48 )
    -6.48 ( 4.70 )
    -7.15 ( 4.02 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [73]
    P-value
    		 = 0.0002 [74]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -18.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.89
         upper limit
    		 -10.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.01
    Notes
    [73] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [74] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [75]
    P-value
    		 < 0.0001 [76]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -15.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.69
         upper limit
    		 -9.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.08
    Notes
    [75] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [76] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.

    Secondary: Percent Change From Baseline in Triglycerides at Week 12

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    End point title
    		 Percent Change From Baseline in Triglycerides at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    10.50 ( 5.36 )
    8.07 ( 4.57 )
    -5.91 ( 4.75 )
    -4.24 ( 4.09 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [77]
    P-value
    		 = 0.0002 [78]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -16.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.63
         upper limit
    		 -8.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    14.18
    Notes
    [77] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [78] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [79]
    P-value
    		 < 0.0001 [80]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -12.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.76
         upper limit
    		 -5.86
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.28
    Notes
    [79] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [80] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.

    Secondary: Percent Change From Baseline in HDL-C at the Mean of Weeks 10 and 12

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    End point title
    		 Percent Change From Baseline in HDL-C at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    1.25 ( 2.19 )
    5.88 ( 2.11 )
    7.59 ( 1.99 )
    13.75 ( 1.90 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [81]
    P-value
    		 = 0.0003 [82]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    6.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.36
         upper limit
    		 9.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.52
    Notes
    [81] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [82] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [83]
    P-value
    		 < 0.0001 [84]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    7.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.1
         upper limit
    		 10.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.41
    Notes
    [83] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [84] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.

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

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    End point title
    		 Percent Change From Baseline in HDL-C at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    2.57 ( 2.29 )
    6.04 ( 2.18 )
    8.45 ( 2.04 )
    14.18 ( 1.95 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [85]
    P-value
    		 = 0.0003 [86]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    5.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.49
         upper limit
    		 9.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.72
    Notes
    [85] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [86] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [87]
    P-value
    		 < 0.0001 [88]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    8.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.03
         upper limit
    		 11.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.58
    Notes
    [87] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [88] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.

    Secondary: Percent Change From Baseline in VLDL-C at the Mean of Weeks 10 and 12

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    End point title
    		 Percent Change From Baseline in VLDL-C at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Q2W Placebo QM Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    164
    160
    325
    332
    Units: percent change
        least squares mean (standard error)
    9.63 ( 4.70 )
    7.92 ( 4.43 )
    -17.55 ( 4.19 )
    -16.09 ( 3.99 )
    Statistical analysis title
    		 Evolocumab Q2W vs Placebo Q2W
    Comparison groups
    Placebo Q2W v Evolocumab Q2W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [89]
    P-value
    		 < 0.0001 [90]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -27.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.2
         upper limit
    		 -20.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.57
    Notes
    [89] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [90] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit
    Statistical analysis title
    		 Evolocumab QM vs Placebo QM
    Comparison groups
    Placebo QM v Evolocumab QM
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [91]
    P-value
    		 < 0.0001 [92]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -24.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.88
         upper limit
    		 -18.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.99
    Notes
    [91] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [92] - The model includes treatment group, entry statin therapy and geographic region, scheduled visit, and the interaction of treatment with scheduled visit.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug (evolocumab or placebo) to 30 days after the last dose; up to 14 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo Q2W
    Reporting group description
    		 Participants received placebo subcutaneous injection once every 2 weeks (Q2W) and 20 mg atorvastatin orally once a day for up to 12 weeks.

    Reporting group title
    Evolocumab Q2W
    Reporting group description
    		 Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks and 20 mg atorvastatin orally once a day for up to 12 weeks.

    Reporting group title
    Evolocumab QM
    Reporting group description
    		 Participants received 420 mg evolocumab by subcutaneous injection once a month and 20 mg atorvastatin orally once a day for up to 12 weeks.

    Reporting group title
    Placebo QM
    Reporting group description
    		 Participants received placebo subcutaneous injection once a month (QM) and 20 mg atorvastatin orally once a day for up to 12 weeks.

    Serious adverse events
    		 Placebo Q2W Evolocumab Q2W Evolocumab QM Placebo QM
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 164 (3.66%)
    10 / 325 (3.08%)
    22 / 332 (6.63%)
    5 / 160 (3.13%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    0 / 332 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 325 (0.00%)
    0 / 332 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 325 (0.31%)
    0 / 332 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cyst
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 325 (0.31%)
    0 / 332 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 325 (0.31%)
    0 / 332 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 325 (0.00%)
    2 / 332 (0.60%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    0 / 332 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 325 (0.31%)
    0 / 332 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 164 (0.00%)
    2 / 325 (0.62%)
    0 / 332 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    0 / 332 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lacunar stroke
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 325 (0.31%)
    0 / 332 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular encephalopathy
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 325 (0.31%)
    0 / 332 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 325 (0.31%)
    0 / 332 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 325 (0.31%)
    0 / 332 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephropathy
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Herpes zoster cutaneous disseminated
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 325 (0.00%)
    0 / 332 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    0 / 332 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 325 (0.31%)
    0 / 332 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 325 (0.31%)
    0 / 332 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 325 (0.31%)
    1 / 332 (0.30%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    0 / 332 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 325 (0.00%)
    3 / 332 (0.90%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo Q2W Evolocumab Q2W Evolocumab QM Placebo QM
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 164 (17.07%)
    45 / 325 (13.85%)
    49 / 332 (14.76%)
    22 / 160 (13.75%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 164 (3.66%)
    8 / 325 (2.46%)
    5 / 332 (1.51%)
    3 / 160 (1.88%)
         occurrences all number
    6
    8
    5
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 164 (2.44%)
    1 / 325 (0.31%)
    6 / 332 (1.81%)
    2 / 160 (1.25%)
         occurrences all number
    4
    1
    6
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 164 (0.61%)
    3 / 325 (0.92%)
    3 / 332 (0.90%)
    4 / 160 (2.50%)
         occurrences all number
    1
    8
    3
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 164 (3.66%)
    9 / 325 (2.77%)
    11 / 332 (3.31%)
    6 / 160 (3.75%)
         occurrences all number
    8
    9
    13
    7
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 164 (3.66%)
    9 / 325 (2.77%)
    13 / 332 (3.92%)
    5 / 160 (3.13%)
         occurrences all number
    8
    9
    13
    5
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    2 / 164 (1.22%)
    15 / 325 (4.62%)
    15 / 332 (4.52%)
    4 / 160 (2.50%)
         occurrences all number
    2
    15
    15
    4
    Hypoglycaemia
         subjects affected / exposed
    5 / 164 (3.05%)
    2 / 325 (0.62%)
    2 / 332 (0.60%)
    0 / 160 (0.00%)
         occurrences all number
    5
    2
    2
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Dec 2013
    • added MMTT with 1 time point for all subjects • replaced “AMG 145” with “evolocumab” throughout the protocol • updated the contraception language
    29 Jul 2015
    Steroid analyte testing was added for Chinese subjects, following a request from China Food and Drug Administration to include this as part of the study, since steroid hormones are synthesized from cholesterol precursors, theoretically very low circulating cholesterol could be associated with steroid hormone deficiency.
    11 Nov 2015
    • removed potential endpoint adjudication by a clinical events committee • added/updated safety language on the reporting of adverse device effects to include assessment of such events for subjects on Q2W investigational product during the end-of-study contact (eg, phone call) at week 14 and clarify assessment of these events throughout the study • clarified use of effective birth control • clarified definition of product complaint • updated pregnancy and lactation reporting procedures

    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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