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    Clinical Trial Results:
    A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Long-term Tolerability and Durable Efficacy of AMG 145 on LDL-C in Hyperlipidemic Subjects

    Summary
    EudraCT number
    		 2011-003827-37
    Trial protocol
    		 CZ   HU   BE   AT   DK  
    Global end of trial date
    07 Nov 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    20110109
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01516879
    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
    07 Nov 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Nov 2013
    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 52 weeks of subcutaneous evolocumab monthly (QM), compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) when added to background lipid-lowering therapy.
    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
    		 All eligible subjects received 1 of 4 background therapies based upon their LDL-C goal derived from National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP) risk, screening LDL-C, current lipid lowering therapy, and level of LDL-C lowering required to achieve their individual LDL-C goal: 1. no drug therapy required - diet alone 2. low dose drug therapy required - diet plus atorvastatin 10 mg orally once daily 3. high dose drug therapy required - diet plus atorvastatin 80 mg orally once daily 4. maximal drug therapy required - diet plus atorvastatin 80 mg plus ezetimibe 10 mg orally once daily.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jan 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 155
    Country: Number of subjects enrolled
    United States: 369
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Czech Republic: 102
    Country: Number of subjects enrolled
    Denmark: 87
    Country: Number of subjects enrolled
    Hungary: 33
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    South Africa: 121
    Worldwide total number of subjects
    905
    EEA total number of subjects
    243
    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)
    699
    From 65 to 84 years
    206
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Adults with fasting low-density lipoprotein cholesterol (LDL-C) ≥ 75 mg/dL and triglycerides ≤ 400 mg/dL were eligible. The first patient enrolled on 5 January 2012 and the last patient enrolled on 12 October 2012. All patients were counseled on the National Cholesterol Education Program Adult Treatment Panel III Therapeutic Lifestyle Changes diet.

    Pre-assignment
    Screening details
    		 Patients were assigned to 1 of 4 background lipid-lowering regimens for a 4-12 week stabilization period: diet alone, diet and 10 mg atorvastatin daily, diet and 80 mg atorvastatin daily, or diet, 80 mg atorvastatin and 10 mg ezetimibe daily. Patients meeting criteria were randomized 2:1 to evolocumab or placebo, stratified by background therapy.

    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
    		 Placebo
    Arm description
    		 Participants received placebo subcutaneously once a month for 52 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo subcutaneous injection one a month

    Arm title
    		 Evolocumab
    Arm description
    		 Participants received evolocumab 420 mg subcutaneously once a month for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evolocumab
    Investigational medicinal product code
    AMG 145
    Other name
    Repatha
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Evolocumab 420 mg subcutaneously once a month

    Number of subjects in period 1
    		Placebo Evolocumab
    Started
    303
    602
    Received Treatment
    302
    599
    Completed
    287
    568
    Not completed
    16
    34
         Consent withdrawn by subject
    9
    11
         Other
    5
    10
         Death
    -
    2
         Lost to follow-up
    2
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneously once a month for 52 weeks.

    Reporting group title
    Evolocumab
    Reporting group description
    		 Participants received evolocumab 420 mg subcutaneously once a month for 52 weeks.

    Reporting group values
    		 Placebo Evolocumab Total
    Number of subjects
    		 303 602 905
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.6 ± 10.3 55.9 ± 10.9 -
    Gender, Male/Female
    Units: participants
        Female
    		 162 312 474
        Male
    		 141 290 431
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 3 3
        Asian
    		 16 41 57
        Black or African American
    		 23 53 76
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        White
    		 249 478 727
        Other
    		 13 26 39
        Mixed Race
    		 2 0 2
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic/Latino
    		 17 33 50
        Not Hispanic/Latino
    		 286 569 855
    Background Therapy
    Units: Subjects
        Diet Only
    		 38 74 112
        Diet + Atorvastatin 10 mg
    		 129 256 385
        Diet + Atorvastatin 80 mg
    		 73 146 219
        Diet + Atorvastatin 80 mg + Ezetimibe 10 mg
    		 63 126 189
    Low-density Lipoprotein Cholesterol (LDL-C) Concentration
    Cholesterol was measured by means of ultracentrifugation. Data are provided for the Full Analysis Set (all participants who were randomized and received at least 1 dose of study treatment).
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 104 ± 21.6 104.2 ± 22.1 -
    Total Cholesterol
    Data are provided for the Full Analysis Set
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 179.1 ± 27.2 176.8 ± 27.5 -
    Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) Concentration
    Data are provided for the Full Analysis Set
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 125.6 ± 26.9 124.2 ± 25.6 -
    Apolipoprotein B Concentration
    Data are provided for the Full Analysis Set
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 87.5 ± 16.3 87 ± 16.3 -
    Total Cholesterol/High Density Lipoprotein-Cholesterol (HDL-C) Ratio
    Data are provided for the Full Analysis Set
    Units: ratio
        arithmetic mean (standard deviation)
    		 3.603 ± 1.11 3.597 ± 1.04 -
    Apolipoprotein B/Apolipoprotein A-1 Ratio
    Data are provided for the Full Analysis Set
    Units: ratio
        arithmetic mean (standard deviation)
    		 0.586 ± 0.17 0.593 ± 0.17 -
    Lipoprotein(a) Concentration
    Data are provided for the Full Analysis Set
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 89.3 ± 108.6 84 ± 98.5 -
    Triglycerides Concentration
    Data are provided for the Full Analysis Set
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 127.8 ± 65.8 119.8 ± 63.2 -
    High-density Lipoprotein Cholesterol (HDL-C) Concentration
    Data are providedfor the Full Analysis Set
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 53.5 ± 16.1 52.6 ± 15.5 -
    Very Low-density Lipoprotein Cholesterol (VLDL-C) Concentration
    Data are provided for the Full Analysis Set
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 21.5 ± 13.4 20 ± 11.4 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneously once a month for 52 weeks.

    Reporting group title
    Evolocumab
    Reporting group description
    		 Participants received evolocumab 420 mg subcutaneously once a month for 52 weeks.

    Primary: Percent Change from Baseline in LDL-C at Week 52

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    End point title
    		 Percent Change from Baseline in LDL-C at Week 52
    End point description
    Cholesterol was measured by means of ultracentrifugation. The full analysis set (FAS) included all randomized subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    302 [1]
    599 [2]
    Units: percent change
        least squares mean (standard error)
    6.83 ± 1.75
    -50.14 ± 1.24
    Notes
    [1] - Full Analysis Set
    [2] - Full Analysis Set
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    The null hypothesis was that there was no mean difference in the percent change from Baseline at Week 52 in LDL-C between evolocumab 420 mg and placebo, and the alternative hypothesis was that a mean difference did exist.
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    901
    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
    -56.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -61.08
         upper limit
    		 -52.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1
    Notes
    [3] - The model includes treatment group, stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates.

    Secondary: Change from Baseline in LDL-C at Week 52

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    End point title
    		 Change from Baseline in LDL-C at Week 52
    End point description
    Cholesterol was measured by means of ultracentrifugation.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    302 [4]
    599 [5]
    Units: mg/dL
        least squares mean (standard error)
    5.1 ± 1.9
    -52.7 ± 1.4
    Notes
    [4] - Full Analysis Set
    [5] - Full Analysis Set
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    901
    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
    -57.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -62.3
         upper limit
    		 -53.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.3
    Notes
    [6] - The model includes treatment group, stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates.

    Secondary: Percentage of Participants with an LDL-C Response at Week 52

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    End point title
    		 Percentage of Participants with an LDL-C Response at Week 52
    End point description
    An LDL-C response is defined as LDL-C level < 70 mg/dL (1.8 mmol/L) at Week 52.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    302 [7]
    599 [8]
    Units: percentage of participants
        number (confidence interval 95%)
    6.4 (4.1 to 10.1)
    82.3 (78.8 to 85.3)
    Notes
    [7] - Full Analysis Set
    [8] - Full Analysis Set
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    901
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    75.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 70.8
         upper limit
    		 79.7
    Notes
    [9] - Based on CMH test stratified by the stratification factor. For testing, non-achievement was imputed for subjects with a missing value at Week 52.

    Secondary: 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
    Cholesterol was measured by means of ultracentrifugation.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    302 [10]
    599 [11]
    Units: percent change
        least squares mean (standard error)
    3.17 ± 1.31
    -54.35 ± 0.96
    Notes
    [10] - Full analysis set
    [11] - Full analysis set
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    901
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [12]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -57.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -60.57
         upper limit
    		 -54.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.56
    Notes
    [12] - The model includes treatment group, stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates.

    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 Evolocumab
    Number of subjects analysed
    302 [13]
    599 [14]
    Units: percent change
        least squares mean (standard error)
    2.85 ± 0.87
    -32.3 ± 0.63
    Notes
    [13] - Full Analysis Set
    [14] - Full Analysis Set
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    901
    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
    -35.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.19
         upper limit
    		 -33.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.04
    Notes
    [15] - The model includes treatment group, stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates.

    Secondary: Percent Change from Baseline in Total Cholesterol at Week 52

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    End point title
    		 Percent Change from Baseline in Total Cholesterol at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    302 [16]
    599 [17]
    Units: percent change
        least squares mean (standard error)
    5.26 ± 1.16
    -28.18 ± 0.84
    Notes
    [16] - Full Analysis Set
    [17] - Full Analysis Set
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    901
    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
    -33.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.21
         upper limit
    		 -30.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.41
    Notes
    [18] - The model includes treatment group, stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates.

    Secondary: Percent Change from Baseline in Non-High-Density Lipoprotein Cholesterol (non-HDL-C) at Week 52

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    End point title
    		 Percent Change from Baseline in Non-High-Density Lipoprotein Cholesterol (non-HDL-C) at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    302 [19]
    599 [20]
    Units: percent change
        least squares mean (standard error)
    8.44 ± 1.68
    -41.82 ± 1.21
    Notes
    [19] - Full Analysis Set
    [20] - Full Analysis Set
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    901
    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
    -50.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.25
         upper limit
    		 -46.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.03
    Notes
    [21] - The model includes treatment group, stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates.

    Secondary: Percent Change from Baseline in Apolipoprotein B at Week 52

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    End point title
    		 Percent Change from Baseline in Apolipoprotein B at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    302 [22]
    599 [23]
    Units: percent change
        least squares mean (standard error)
    2.94 ± 1.41
    -41.26 ± 1.02
    Notes
    [22] - Full Analysis Set
    [23] - Full Analysis Set
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    901
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.004 [24]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -44.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -47.56
         upper limit
    		 -40.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.71
    Notes
    [24] - The model includes treatment group, stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates.

    Secondary: Percent Change from Baseline in the Total Cholesterol/HDL-C Ratio at Week 52

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    End point title
    		 Percent Change from Baseline in the Total Cholesterol/HDL-C Ratio at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    302 [25]
    599 [26]
    Units: percent change
        least squares mean (standard error)
    6.47 ± 1.37
    -30.67 ± 0.99
    Notes
    [25] - Full Analysis Set
    [26] - Full Analysis Set
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    901
    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
    -37.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.41
         upper limit
    		 -33.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.67
    Notes
    [27] - The model includes treatment group, stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates.

    Secondary: Percent Change from Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 52

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    End point title
    		 Percent Change from Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    302 [28]
    599 [29]
    Units: percent change
        least squares mean (standard error)
    4.46 ± 1.5
    -41.75 ± 1.09
    Notes
    [28] - Full Analysis Set
    [29] - Full Analysis Set
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    901
    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
    -46.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49.79
         upper limit
    		 -42.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.82
    Notes
    [30] - The model includes treatment group, stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates.

    Secondary: Percent Change from Baseline in Lipoprotein(a) at Week 52

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    End point title
    		 Percent Change from Baseline in Lipoprotein(a) at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    302 [31]
    599 [32]
    Units: percent change
        least squares mean (standard error)
    -5.37 ± 1.62
    -27.72 ± 1.19
    Notes
    [31] - Full Analysis Set
    [32] - Full Analysis Set
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    901
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [33]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -22.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.15
         upper limit
    		 -18.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.94
    Notes
    [33] - The model includes treatment group, stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates.

    Secondary: Percent Change from Baseline in Triglycerides at Week 52

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    End point title
    		 Percent Change from Baseline in Triglycerides at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    302 [34]
    599 [35]
    Units: percent change
        least squares mean (standard error)
    8.99 ± 2.39
    -2.55 ± 1.72
    Notes
    [34] - Full analysis set
    [35] - Full analysis set
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    901
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [36]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -11.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.21
         upper limit
    		 -5.86
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.89
    Notes
    [36] - The model includes treatment group, stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates.

    Secondary: Percent Change from Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 52

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    End point title
    		 Percent Change from Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    302 [37]
    599 [38]
    Units: percent change
        least squares mean (standard error)
    0.35 ± 0.9
    5.77 ± 0.65
    Notes
    [37] - Full Analysis Set
    [38] - Full Analysis Set
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    901
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [39]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    5.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.28
         upper limit
    		 7.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.09
    Notes
    [39] - The model includes treatment group, stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates.

    Secondary: Percent Change from Baseline in Very Low-Density Lipoprotein Cholesterol (VLDL-C) at Week 52

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    End point title
    		 Percent Change from Baseline in Very Low-Density Lipoprotein Cholesterol (VLDL-C) at Week 52
    End point description
    Cholesterol was measured by means of ultracentrifugation.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    302 [40]
    599 [41]
    Units: percent change
        least squares mean (standard error)
    31.89 ± 4.69
    2.74 ± 3.36
    Notes
    [40] - Full Analysis Set
    [41] - Full Analysis Set
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    901
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [42]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -29.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.23
         upper limit
    		 -18.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.64
    Notes
    [42] - The model includes treatment group, stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates.

    Secondary: Percent Change from Week 12 to Week 52 in LDL-C

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    End point title
    		 Percent Change from Week 12 to Week 52 in LDL-C
    End point description
    Cholesterol was measured by means of ultracentrifugation. Analysis was peformed in the effect durability analysis set which included subjects in the FAS who adhered to the scheduled study drug and have nonmissing LDL-C values at Baseline, Week 12 and Week 52.
    End point type
    Secondary
    End point timeframe
    Week 12 and Week 52
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    253 [43]
    514 [44]
    Units: percent change
        least squares mean (standard error)
    2.57 ± 1.56
    2.44 ± 1.14
    Notes
    [43] - Effect Durability Analysis Set
    [44] - Effect Durability Analysis Set
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    767
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94 [45]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.76
         upper limit
    		 3.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.84
    Notes
    [45] - Model includes treatment group and stratification factor as covariates

    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 (52 weeks).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Evolocumab
    Reporting group description
    		 Participants received evolocumab 420 mg subcutaneously once a month for 52 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneously once a month for 52 weeks.

    Serious adverse events
    		 Evolocumab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 599 (5.51%)
    13 / 302 (4.30%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Renal neoplasm
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Breast prosthesis implantation
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 599 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device breakage
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    2 / 599 (0.33%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 599 (0.17%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 599 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Joint injury
         subjects affected / exposed
    0 / 599 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 599 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 599 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 599 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 599 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 599 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 599 (0.33%)
    2 / 302 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Palpitations
         subjects affected / exposed
    2 / 599 (0.33%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 599 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    2 / 599 (0.33%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 599 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine with aura
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 599 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    2 / 599 (0.33%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exostosis of external ear canal
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract disorder
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 599 (0.33%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 599 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    1 / 599 (0.17%)
    0 / 302 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Evolocumab Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    177 / 599 (29.55%)
    76 / 302 (25.17%)
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    36 / 599 (6.01%)
    17 / 302 (5.63%)
         occurrences all number
    38
    17
    Infections and infestations
    Influenza
         subjects affected / exposed
    45 / 599 (7.51%)
    19 / 302 (6.29%)
         occurrences all number
    54
    21
    Upper respiratory tract infection
         subjects affected / exposed
    56 / 599 (9.35%)
    19 / 302 (6.29%)
         occurrences all number
    66
    21
    Nasopharyngitis
         subjects affected / exposed
    63 / 599 (10.52%)
    29 / 302 (9.60%)
         occurrences all number
    66
    34

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Feb 2012
    - added a vitamin E substudy - updated the study schema - added additional clarity on the definition of CHD risk equivalents - removed the term “absolute” from all endpoints - added information on drug dispensation and reconciliation - added information on retesting - added a rescreening cap - added steroid testing at day 1 and weeks 12, 24, and 52 - added a process for updating the DMC for consecutive LDL values below 25 mg/dl - better defined end of study (EOS) - updated blood pressure and waist circumference language to add additional clarity - clarified that doses should be split - updated the interim analysis guidelines
    03 May 2012
    - changed the sample size from 600 to 900 subjects in order to increase long-term safety and tolerability data supporting registration - updated the evolocumab background section with the most currently available data - added information to the 420 mg dose selection with data from the most recent evolocumab interim analysis - changed “hypercholesterolemia” to “hyperlipidemia” to be consistent with Amgen’s phase 3 protocols - updated the statistics section to align the hypothesis-testing secondary endpoints with Amgen’s phase 3 protocols, adjusted for multiplicity - added language that allowed Amgen to limit the enrollment of patients in certain NCEP risk categories or background therapy arms in order to prevent overly skewed enrollment in these groups - allowed down titration for subjects randomized to maximal background therapy who overshoot the LDL entry cutoff - updated the vital sign and waist circumference sections to align the language with that used in Amgen’s phase 3 protocols - changed the SAE reporting requirements from 1 business day to 24 hours - added additional information on pregnancy and lactation
    09 Dec 2012
    - requirements reclassified the study from a phase 2 study to a phase 3 study - changed the dosing terminology from Q4W to QM - updated the list of completed and ongoing studies
    21 Feb 2013
    - updated three secondary endpoints - updated the study schema - added an alert threshold for elevated triglycerides - added new Amgen safety template AE & SAE language

    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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