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    Clinical Trial Results:
    A Double-blind, Randomized, Multicenter Study to Evaluate Safety and Efficacy of AMG 145, Compared With Ezetimibe, in Hypercholesterolemic Subjects Unable to Tolerate an Effective Dose of a HMG-CoA Reductase Inhibitor

    Summary
    EudraCT number
    		 2012-001364-30
    Trial protocol
    		 BE   ES   DK   NL   PL   GB   DE  
    Global end of trial date
    19 Nov 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2016
    First version publication date
    30 Jul 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20110116
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01763905
    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
    19 Nov 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab every 2 weeks (Q2W) and monthly (QM), compared with ezetimibe, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic subjects unable to tolerate an effective dose of a statin.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations and guidelines, and Food and Drug Administration (FDA) regulations, and guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jan 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    United States: 99
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Denmark: 35
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Netherlands: 36
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Australia: 39
    Country: Number of subjects enrolled
    Hong Kong: 2
    Worldwide total number of subjects
    307
    EEA total number of subjects
    147
    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)
    180
    From 65 to 84 years
    127
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Men and women ≥ 18 to ≤ 80 years of age who have tried at least 2 statins and were unable to tolerate any dose or increase in statin dose due to muscle-related side effects were eligible for this study. The first participant was enrolled on 24 January 2013 and the last participant enrolled on 29 August 2013.

    Pre-assignment
    Screening details
    		 Participants received subcutaneous placebo corresponding to the once monthly dose volume during a 6-week screening period. Those who completed the screening period and met final eligibility criteria were randomized 1:1:2:2 into 4 treatment groups. Randomization was stratified by LDL-C level (< 180 mg/dL vs ≥ 180 mg/dL) and statin use (yes vs no).

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ezetimibe (Q2W)
    Arm description
    		 Participants received placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe orally once a day for up to 12 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ezetimibe
    Investigational medicinal product code
    Other name
    Zetia
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg administered orally once a day

    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 by subcutaneous injection

    Arm title
    		 Ezetimibe (QM)
    Arm description
    		 Participants received placebo subcutaneous injection once a month and 10 mg ezetimibe orally once a day for up to 12 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ezetimibe
    Investigational medicinal product code
    Other name
    Zetia
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg administered orally once a day

    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 by subcutaneous injection

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

    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 by subcutaneous injection

    Investigational medicinal product name
    Placebo to Ezetimibe
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Self-administered orally once daily

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

    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 by subcutaneous injection

    Investigational medicinal product name
    Placebo to Ezetimibe
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Self-administered orally once daily

    Number of subjects in period 1
    		Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Started
    51
    51
    103
    102
    Completed
    45
    50
    94
    101
    Not completed
    6
    1
    9
    1
         Consent withdrawn by subject
    1
    1
    -
    1
         Lost to follow-up
    -
    -
    1
    -
         Decision by sponsor
    5
    -
    8
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ezetimibe (Q2W)
    Reporting group description
    		 Participants received placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe orally once a day for up to 12 weeks.

    Reporting group title
    Ezetimibe (QM)
    Reporting group description
    		 Participants received placebo subcutaneous injection once a month and 10 mg ezetimibe 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 placebo tablets 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 placebo tablets once a day for up to 12 weeks.

    Reporting group values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM Total
    Number of subjects
    		 51 51 103 102 307
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.7 ( 10.1 ) 60.2 ( 8.7 ) 60.5 ( 9.7 ) 62.9 ( 10.2 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 27 22 46 46 141
        Male
    		 24 29 57 56 166
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 1 3 5 1 10
        Black or African American
    		 0 1 3 3 7
        Native Hawaiian or Other Pacific Islander
    		 0 0 1 0 1
        White
    		 49 46 94 98 287
        Other
    		 1 1 0 0 2
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 1 2 3 1 7
        Not Hispanic or Latino
    		 50 49 100 101 300
    Stratification Factor: Low-density Lipoprotein Cholesterol (LDL-C)
    Units: Subjects
        < 180 mg/dL
    		 26 26 52 52 156
        ≥ 180 mg/dL
    		 25 25 51 50 151
    Stratification Factor: Baseline Statin Use
    Units: Subjects
        No
    		 41 42 84 82 249
        Yes
    		 10 9 19 20 58
    LDL-C Concentration
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 194.7 ( 63.8 ) 195.2 ( 51.8 ) 192 ( 57 ) 192.2 ( 61.2 ) -
    Non-High-Density Lipoprotein Cholesterol (non-HDL-C) Concentration
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 231.4 ( 66 ) 232.9 ( 57 ) 227.9 ( 56.6 ) 222.1 ( 63.2 ) -
    Apolipoprotein B Concentration
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 140 ( 37 ) 140 ( 31.1 ) 140.2 ( 32.1 ) 133.1 ( 32.2 ) -
    Total Cholesterol/High-Density Lipoprotein Cholesterol Ratio
    Units: ratio
        arithmetic mean (standard deviation)
    		 5.989 ( 2.19 ) 6.137 ( 1.787 ) 5.912 ( 1.929 ) 5.506 ( 1.925 ) -
    Apolipoprotein B/Apolipoprotein A1 Ratio
    Units: ratio
        arithmetic mean (standard deviation)
    		 0.943 ( 0.282 ) 1.005 ( 0.294 ) 0.98 ( 0.318 ) 0.901 ( 0.283 ) -
    Lipoprotein(a) Concentration
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 106.3 ( 101 ) 76.6 ( 96.7 ) 66.2 ( 72.5 ) 70.9 ( 99.9 ) -
    Triglyceride Concentration
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 183.4 ( 79.8 ) 187 ( 81.5 ) 179.8 ( 80 ) 149.3 ( 63.1 ) -
    Very Low-density Lipoprotein Cholesterol (VLDL-C) Concentration
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 36.7 ( 16 ) 37.1 ( 15.8 ) 35.2 ( 14.5 ) 29.9 ( 12.6 ) -
    High-Density Lipoprotein Cholesterol (HDL-C)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 52.4 ( 18.3 ) 48 ( 11 ) 51.1 ( 16.4 ) 54 ( 16 ) -

    End points

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    End points reporting groups
    Reporting group title
    Ezetimibe (Q2W)
    Reporting group description
    		 Participants received placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe orally once a day for up to 12 weeks.

    Reporting group title
    Ezetimibe (QM)
    Reporting group description
    		 Participants received placebo subcutaneous injection once a month and 10 mg ezetimibe 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 placebo tablets 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 placebo tablets once a day for up to 12 weeks.

    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
    Calculated LDL-C was determined based on the Friedewald equation.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -18.08 ( 2.52 )
    -15.05 ( 2.13 )
    -56.14 ( 1.91 )
    -52.6 ( 1.58 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Statistical analysis description
    The null hypothesis was that there is no mean difference in the percent change from Baseline at Week 12 in LDL-C between evolocumab and ezetimibe, and the alternative hypothesis is that a mean difference does exist.
    Comparison groups
    Evolocumab Q2W v Ezetimibe (Q2W)
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [1]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -38.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -43.73
         upper limit
    		 -32.99
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.87
    Notes
    [1] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Statistical analysis description
    The null hypothesis was that there is no mean difference in the percent change from baseline at Week 12 in LDL-C between evolocumab and ezetimibe, and the alternative hypothesis is that a mean difference does exist.
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [2]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -37.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.16
         upper limit
    		 -32.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.33
    Notes
    [2] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

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

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    End point title
    		 Mean Percent Change From Baseline in LDL-C at Weeks 10 and 12
    End point description
    Calculated LDL-C was determined based on the Friedewald equation.
    End point type
    Primary
    End point timeframe
    Baseline and Weeks 10 and 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -19.21 ( 2.4 )
    -16.62 ( 2.03 )
    -56.11 ( 1.83 )
    -55.31 ( 1.53 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Statistical analysis description
    The null hypothesis was that there is no mean difference in the mean percent change from Baseline at Weeks 10 and 12 in LDL-C between evolocumab and ezetimibe, and the alternative hypothesis is that a mean difference does exist.
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [3]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -36.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.26
         upper limit
    		 -31.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.71
    Notes
    [3] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Statistical analysis description
    The null hypothesis was that there is no mean difference in the percent change from baseline at Week 12 in LDL-C between evolocumab and ezetimibe, and the alternative hypothesis is that a mean difference does exist.
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [4]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -38.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -43.06
         upper limit
    		 -34.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.21
    Notes
    [4] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

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

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    End point title
    		 Mean Change From Baseline in LDL-C at Weeks 10 and 12
    End point description
    Calculated LDL-C was determined based on the Friedewald equation.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 10 and 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: mg/dL
        least squares mean (standard error)
    -39.1 ( 5.1 )
    -33 ( 4.5 )
    -105.4 ( 3.9 )
    -103.6 ( 3.4 )
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [5]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -70.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -80.5
         upper limit
    		 -60.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    5
    Notes
    [5] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [6]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -66.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -77.9
         upper limit
    		 -54.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.9
    Notes
    [6] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

    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
    Calculated LDL-C was determined based on the Friedewald equation.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: mg/dL
        least squares mean (standard error)
    -36.2 ( 5.4 )
    -30.2 ( 4.7 )
    -106 ( 4.1 )
    -99 ( 3.5 )
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [7]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -68.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -79.2
         upper limit
    		 -58.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.3
    Notes
    [7] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [8]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -69.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -82
         upper limit
    		 -57.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.2
    Notes
    [8] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

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

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    End point title
    		 Mean Percentage of Participants with LDL-C < 70 mg/dL (1.8 mmol/L) at Weeks 10 and 12
    End point description
    Mean low density lipoprotein-cholesterol response at Weeks 10 and 12 (low density lipoprotein-cholesterol < 70 mg/dL [1.8 mmol/L]).
    End point type
    Secondary
    End point timeframe
    Weeks 10 and 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percentage of participants
        number (confidence interval 95%)
    2 (0.4 to 10.5)
    0 (0 to 7.3)
    45.5 (36.2 to 55.2)
    42 (32.8 to 51.8)
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    43.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 30.9
         upper limit
    		 53.4
    Notes
    [9] - Cochran-Mantel Haenszel test stratified by baseline LDL-C and statin use. For testing, non-achievement was imputed for participants with missing data. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 30.3
         upper limit
    		 51.8
    Notes
    [10] - Cochran-Mantel Haenszel test stratified by baseline LDL-C and statin use. For testing, non-achievement was imputed for participants with missing data. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

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

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    End point title
    		 Percentage of Participants with LDL-C < 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
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percentage of participants
        number (confidence interval 95%)
    2 (0.4 to 10.7)
    0 (0 to 7.9)
    50 (40.3 to 59.7)
    37.5 (28.5 to 47.5)
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [11]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 35
         upper limit
    		 57.8
    Notes
    [11] - Cochran-Mantel Haenszel test stratified by baseline LDL-C and statin use. For testing, non-achievement was imputed for participants with missing data. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [12]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    37.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25.5
         upper limit
    		 47.5
    Notes
    [12] - Cochran-Mantel Haenszel test stratified by baseline LDL-C and statin use. For testing, non-achievement was imputed for participants with missing data. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05

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

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    End point title
    		 Mean Percent Change From Baseline in Non-HDL-C at Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 10 and 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -17.18 ( 2.15 )
    -14.54 ( 1.86 )
    -48.72 ( 1.64 )
    -49.13 ( 1.4 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [13]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -31.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.34
         upper limit
    		 -26.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.43
    Notes
    [13] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [14]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -34.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.63
         upper limit
    		 -30.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.05
    Notes
    [14] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

    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
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -16.53 ( 2.3 )
    -13.16 ( 1.93 )
    -48.62 ( 1.74 )
    -46.15 ( 1.43 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [15]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -32.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.28
         upper limit
    		 -26.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.63
    Notes
    [15] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [16]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -32.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.19
         upper limit
    		 -28.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.12
    Notes
    [16] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

    Secondary: Mean Percent Change From Baseline in Apolipoprotein B at Weeks 10 and 12

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    End point title
    		 Mean Percent Change From Baseline in Apolipoprotein B at Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 10 and 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -13.67 ( 2.15 )
    -11.02 ( 2.21 )
    -45.88 ( 1.68 )
    -46.01 ( 1.65 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [17]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -32.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.92
         upper limit
    		 -27.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.39
    Notes
    [17] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [18]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -34.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.59
         upper limit
    		 -30.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.33
    Notes
    [18] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

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

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -12.95 ( 2.32 )
    -9.97 ( 2.34 )
    -45.81 ( 1.79 )
    -43.07 ( 1.73 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [19]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -32.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.04
         upper limit
    		 -27.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.62
    Notes
    [19] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [20]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -33.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.04
         upper limit
    		 -28.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.5
    Notes
    [20] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

    Secondary: Mean Percent Change From Baseline in the Total Cholesterol/High Density Lipoprotein Cholesterol Ratio at Weeks 10 and 12

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    End point title
    		 Mean Percent Change From Baseline in the Total Cholesterol/High Density Lipoprotein Cholesterol Ratio at Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 10 and 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -13.44 ( 2.14 )
    -11.2 ( 2.16 )
    -40.83 ( 1.65 )
    -41.14 ( 1.62 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [21]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -27.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.11
         upper limit
    		 -22.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.39
    Notes
    [21] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [22]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -29.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.72
         upper limit
    		 -25.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.42
    Notes
    [22] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

    Secondary: Percent Change From Baseline in the Total Cholesterol/High Density Lipoprotein Cholesterol Ratio at Week 12

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    End point title
    		 Percent Change From Baseline in the Total Cholesterol/High Density Lipoprotein Cholesterol Ratio at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -14.13 ( 2.3 )
    -9.92 ( 2.34 )
    -40.42 ( 1.75 )
    -38.57 ( 1.73 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [23]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -26.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.42
         upper limit
    		 -21.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.6
    Notes
    [23] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [24]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -28.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.88
         upper limit
    		 -23.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.64
    Notes
    [24] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

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

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    End point title
    		 Mean Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 10 and 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -13 ( 2.27 )
    -11.94 ( 2.56 )
    -47.86 ( 1.77 )
    -48.31 ( 1.92 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [25]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -34.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.84
         upper limit
    		 -29.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.52
    Notes
    [25] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [26]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -36.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.73
         upper limit
    		 -31.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.71
    Notes
    [26] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

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

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -13.14 ( 2.47 )
    -11.37 ( 2.71 )
    -47.66 ( 1.9 )
    -45.51 ( 2.01 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [27]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -34.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.05
         upper limit
    		 -29
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.79
    Notes
    [27] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [28]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -34.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.87
         upper limit
    		 -28.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.91
    Notes
    [28] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

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

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    End point title
    		 Mean Percent Change From Baseline in Lipoprotein (a) at Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 10 and 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -2.3 ( 3.36 )
    1.55 ( 4.01 )
    -26.2 ( 2.64 )
    -23.72 ( 2.97 )
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [29]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -25.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.75
         upper limit
    		 -16.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.3
    Notes
    [29] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [30]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -23.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.27
         upper limit
    		 -16.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.73
    Notes
    [30] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

    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
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -1.74 ( 3.58 )
    5.81 ( 5.1 )
    -27.03 ( 2.78 )
    -22.07 ( 3.66 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [31]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -25.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.26
         upper limit
    		 -17.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.03
    Notes
    [31] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [32]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -27.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.21
         upper limit
    		 -16.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.73
    Notes
    [32] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

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

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    End point title
    		 Mean Percent Change From Baseline in Triglycerides at Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 10 and 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -3.74 ( 3.88 )
    -0.32 ( 4.65 )
    -6.32 ( 2.94 )
    -6.73 ( 3.44 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.97 [33]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -2.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.38
         upper limit
    		 6.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.45
    Notes
    [33] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Ezetimibe (QM) v Evolocumab QM
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33 [34]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -6.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.55
         upper limit
    		 3.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.13
    Notes
    [34] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

    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
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -5.47 ( 4.25 )
    2.16 ( 5.52 )
    -3.88 ( 3.18 )
    -2.53 ( 3.98 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.97 [35]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    1.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.14
         upper limit
    		 11.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.92
    Notes
    [35] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33 [36]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -4.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.04
         upper limit
    		 7.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.25
    Notes
    [36] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

    Secondary: Mean Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Weeks 10 and 12

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    End point title
    		 Mean Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 10 and 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    0.33 ( 1.98 )
    1.44 ( 2.03 )
    5.48 ( 1.51 )
    7.18 ( 1.51 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.068 [37]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    5.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 9.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.23
    Notes
    [37] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13 [38]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    5.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.23
         upper limit
    		 10.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.28
    Notes
    [38] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

    Secondary: Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 12

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    End point title
    		 Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    1.77 ( 2.22 )
    1.64 ( 2.22 )
    5.34 ( 1.67 )
    6.47 ( 1.63 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.068 [39]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    3.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.49
         upper limit
    		 8.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.56
    Notes
    [39] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13 [40]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    4.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 9.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.52
    Notes
    [40] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

    Secondary: Mean Percent Change From Baseline in Very Low-Density Lipoprotein Cholesterol at Weeks 10 and 12

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    End point title
    		 Mean Percent Change From Baseline in Very Low-Density Lipoprotein Cholesterol at Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 10 and 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -5.76 ( 3.8 )
    -2.93 ( 4.41 )
    -7.6 ( 2.89 )
    -6.46 ( 3.21 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.97 [41]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -1.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.43
         upper limit
    		 6.75
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.35
    Notes
    [41] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33 [42]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -3.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.12
         upper limit
    		 6.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.85
    Notes
    [42] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

    Secondary: Percent Change From Baseline in Very Low-Density Lipoprotein Cholesterol at Week 12

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    End point title
    		 Percent Change From Baseline in Very Low-Density Lipoprotein Cholesterol at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Number of subjects analysed
    51
    51
    103
    102
    Units: percent change
        least squares mean (standard error)
    -5.49 ( 4.05 )
    -2.25 ( 5.11 )
    -6.16 ( 3.08 )
    -2.18 ( 3.6 )
    Statistical analysis title
    		 Evolocumab Q2W vs Ezetimibe (Q2W)
    Comparison groups
    Ezetimibe (Q2W) v Evolocumab Q2W
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.97 [43]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.96
         upper limit
    		 8.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.7
    Notes
    [43] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    Statistical analysis title
    		 Evolocumab QM vs Ezetimibe (QM)
    Comparison groups
    Ezetimibe (QM) v Evolocumab QM
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33 [44]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.24
         upper limit
    		 11.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.72
    Notes
    [44] - The model includes treatment group, baseline LDL-C level and statin use, scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug until 28 days after the last dose (12 weeks).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Ezetimibe (Q2W)
    Reporting group description
    		 Participants received placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe orally once a day for up to 12 weeks.

    Reporting group title
    Ezetimibe (QM)
    Reporting group description
    		 Participants received placebo subcutaneous injection once a month and 10 mg ezetimibe 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 placebo tablets 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 placebo tablets once a day for up to 12 weeks.

    Serious adverse events
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 51 (5.88%)
    5 / 103 (4.85%)
    1 / 102 (0.98%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma stage III
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (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
    Lipoma
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (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
    Neuroendocrine carcinoma metastatic
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (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
    Surgical and medical procedures
    Cartilage graft
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         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
    Osteotomy
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         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
    Spinal decompression
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
    0 / 103 (0.00%)
    0 / 102 (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
    Gastrointestinal disorders
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
    0 / 103 (0.00%)
    0 / 102 (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
    Inguinal hernia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
    0 / 103 (0.00%)
    0 / 102 (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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (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
    Infections and infestations
    Kidney infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
    0 / 103 (0.00%)
    0 / 102 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ezetimibe (Q2W) Ezetimibe (QM) Evolocumab Q2W Evolocumab QM
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 51 (39.22%)
    29 / 51 (56.86%)
    28 / 103 (27.18%)
    42 / 102 (41.18%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 51 (5.88%)
    6 / 51 (11.76%)
    4 / 103 (3.88%)
    12 / 102 (11.76%)
         occurrences all number
    3
    9
    7
    12
    Paraesthesia
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 51 (7.84%)
    0 / 103 (0.00%)
    2 / 102 (1.96%)
         occurrences all number
    1
    4
    0
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 51 (7.84%)
    6 / 51 (11.76%)
    3 / 103 (2.91%)
    6 / 102 (5.88%)
         occurrences all number
    4
    7
    3
    6
    Injection site erythema
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 51 (5.88%)
    2 / 103 (1.94%)
    2 / 102 (1.96%)
         occurrences all number
    0
    3
    2
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 51 (5.88%)
    4 / 51 (7.84%)
    3 / 103 (2.91%)
    2 / 102 (1.96%)
         occurrences all number
    3
    4
    4
    2
    Nausea
         subjects affected / exposed
    2 / 51 (3.92%)
    5 / 51 (9.80%)
    3 / 103 (2.91%)
    6 / 102 (5.88%)
         occurrences all number
    2
    5
    4
    9
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 51 (5.88%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 51 (1.96%)
    5 / 103 (4.85%)
    8 / 102 (7.84%)
         occurrences all number
    6
    1
    7
    9
    Myalgia
         subjects affected / exposed
    7 / 51 (13.73%)
    11 / 51 (21.57%)
    7 / 103 (6.80%)
    9 / 102 (8.82%)
         occurrences all number
    7
    15
    10
    12
    Pain in extremity
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
    2 / 103 (1.94%)
    12 / 102 (11.76%)
         occurrences all number
    0
    1
    2
    19
    Infections and infestations
    Influenza
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 51 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences all number
    4
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 51 (0.00%)
    5 / 103 (4.85%)
    2 / 102 (1.96%)
         occurrences all number
    3
    0
    5
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Aug 2012
    - added testing for prior or existing HCV infection in high risk individuals and evaluation of viral load in those who show evidence thereof - strengthened the definition of statin-intolerance by requiring subjects to have failed 2 statins instead of 1 - clarified that subjects with a known sensitivity to the “active substances or their excipients” were excluded - added urine pregnancy testing at day 1, week 4, and week 8 for women of childbearing potential - implemented minor clarifications and error corrections
    10 Oct 2012
    - added the GAUSS-2 study acronym and short title - made minor modification of LDL-C inclusion limits in accordance with NCEP ATP III risk categories - added new evolocumab formulation and autoinjectors to allow administration of investigational product in a home-use setting - revised schedule of assessment and description of procedures in Section 7 to replace weeks 4 and 6 visits with home-use IP administration - added reporting requirements for product/device complaints - updated program status in evolocumab background section - provided instruction regarding missed ezetimibe doses - added subjects with a history of HCV infection to the ones at high risk of HCV injection to the HCV antibody testing and viral load monitoring, if positive - updated sections on collection and reporting of adverse events and serious adverse events, including adding device-related adverse events, and the eSAE contingency form - moved change from baseline in VLDL-C at week 12 from tertiary to secondary endpoints - added transient ischemic attacks and non-coronary revascularization as exploratory endpoints - implemented minor clarifications and error corrections
    10 Dec 2012
    - added the LDL-C endpoint of mean percent change from baseline at weeks 10 and 12 as a co-primary endpoint - added the means of weeks 10 and 12 as co-secondary endpoints to all secondary endpoints for the same reason as above - added alert threshold for elevated triglycerides - added publication references for primary result publications of phase 2 studies MENDEL and LAPLACE - introduced the simplified terminology of once monthly (QM) dosing - implemented minor clarifications and error corrections

    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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