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    Clinical Trial Results:
    A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability, and Efficacy of Evolocumab (AMG 145) on LDL-C in Subjects With Type 2 Diabetes Mellitus and Hypercholesterolemia/Mixed Dyslipidemia (BANTING)

    Summary
    EudraCT number
    		 2015-004711-21
    Trial protocol
    		 PL   BE   ES   IT  
    Global end of trial date
    05 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Aug 2018
    First version publication date
    18 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20130287
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02739984
    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
    03 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the effect of 12 weeks of subcutaneous evolocumab once a month (QM) compared with placebo QM on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed dyslipidemia on maximally tolerated dose of statin of at least moderate-intensity oral daily.
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines, and Food and Drug Administration (FDA) regulations and guidelines set forth in 21 Code of Federal Regulations parts 11, 50, 54, 56, and 312. The study and all amendments were reviewed by an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) at each center. The investigator or his/her designee informed the subject of all aspects pertaining to the subject’s participation in the study before any screening procedures were performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 May 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 23
    Country: Number of subjects enrolled
    United States: 327
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Poland: 27
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    Mexico: 10
    Worldwide total number of subjects
    424
    EEA total number of subjects
    64
    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)
    245
    From 65 to 84 years
    179
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Of 853 patients screened, a total of 424 participants were randomized at 58 centers in Belgium, Canada, Italy, Mexico, Poland, Spain and the United States from 17 May 2016 to 05 May 2017.

    Pre-assignment
    Screening details
    		 Participants received subcutaneous placebo during a 6-week screening period. Participants who completed the screening period and met final eligibility criteria were randomized in a 1:2 ratio to placebo or evolocumab. Randomization was stratified by low-density lipoprotein cholesterol (LDL-C) level (> or < 130 mg/dL).

    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 subcutaneous injection once every month (QM) for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    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 once a month

    Arm title
    		 Evolocumab
    Arm description
    		 Participants received 420 mg evolocumab subcutaneous injection once every month (QM) for 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 once a month

    Number of subjects in period 1
    		Placebo Evolocumab
    Started
    143
    281
    Received Study Drug
    141
    280
    Completed
    138
    279
    Not completed
    5
    2
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    1
    1
         Sponsor Decision
    1
    -
         Lost to follow-up
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneous injection once every month (QM) for 12 weeks.

    Reporting group title
    Evolocumab
    Reporting group description
    		 Participants received 420 mg evolocumab subcutaneous injection once every month (QM) for 12 weeks.

    Reporting group values
    		 Placebo Evolocumab Total
    Number of subjects
    		 143 281 424
    Age, Customized
    Units: Subjects
        < 65 years
    		 86 159 245
        65 - < 85 years
    		 57 122 179
        ≥ 85 years
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.3 ± 8.5 62.5 ± 8.5 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 65 121 186
        Male
    		 78 160 238
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 7 8 15
        Asian
    		 2 4 6
        Black (or African American)
    		 32 41 73
        Native Hawaiian or Other Pacific Islander
    		 0 2 2
        White
    		 102 223 325
        Multiple
    		 0 1 1
        Other
    		 0 2 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 24 54 78
        Not Hispanic or Latino
    		 119 227 346
        Unknown or Not Reported
    		 0 0 0
    Stratification Factor: Low-density Lipoprotein Cholesterol (LDL-C) Level
    Units: Subjects
        < 130 mg/dL
    		 108 213 321
        ≥ 130 mg/dL
    		 35 68 103
    LDL-C Concentration
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), 141 and 280 subjects in each treatment group respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 110.4 ± 33.0 108.6 ± 31.0 -
    Non-High-density Lipoprotein Cholesterol (non-HDL-C) Concentration
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), 141 and 280 subjects in each treatment group respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 145.5 ± 33.9 144.6 ± 34.9 -
    Apolipoprotein B Concentration
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), and with available baseline data, 138 and 272 subjects in each treatment group respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 98.1 ± 22.1 97.1 ± 23.3 -
    Total Cholesterol Concentration
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), 141 and 280 subjects in each treatment group respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 190.7 ± 35.0 188.2 ± 36.8 -
    Lipoprotein(a) Concentration
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), and with available baseline data, 137 and 273 subjects in each treatment group respectively.
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 99.4 ± 122.8 88.0 ± 111.5 -
    Triglycerides Concentration
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), 141 and 280 subjects in each treatment group respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 177.3 ± 89.2 184.2 ± 102.2 -
    High-density Lipoprotein Cholesterol (HDL-C) Concentraion
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), 141 and 280 subjects in each treatment group respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 45.2 ± 12.2 43.6 ± 12.9 -
    Very Low-density Lipoprotein Cholesterol (VLDL-C) Concentration
    Data are reported for all participants in the full analysis set, consisting of randomized participants who received at least 1 dose of the study drug (placebo or evolocumab), and with available baseline data, 138 and 276 subjects in each treatment group respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 33.6 ± 14.3 34.8 ± 15.4 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneous injection once every month (QM) for 12 weeks.

    Reporting group title
    Evolocumab
    Reporting group description
    		 Participants received 420 mg evolocumab subcutaneous injection once every month (QM) for 12 weeks.

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

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    End point title
    		 Percent Change From Baseline in LDL-C at the Mean of Weeks 10 and 12
    End point description
    End point type
    Primary
    End point timeframe
    Baseline and Weeks 10 and 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percent change
        least squares mean (standard error)
    -0.84 ± 1.76
    -64.98 ± 1.31
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -64.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -68.16
         upper limit
    		 -60.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.05
    Notes
    [1] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [2] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

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

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    End point title
    		 Percent Change From Baseline in LDL-C at Week 12
    End point description
    End point type
    Primary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percent change
        least squares mean (standard error)
    -1.14 ± 1.92
    -54.28 ± 1.42
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -53.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.56
         upper limit
    		 -48.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.25
    Notes
    [3] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [4] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

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

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    End point title
    		 Change From Baseline in LDL-C at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: mg/dL
        least squares mean (standard error)
    -8.3 ± 2.2
    -75.5 ± 1.6
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -67.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -72.1
         upper limit
    		 -62.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.5
    Notes
    [5] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [6] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

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

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    End point title
    		 Change From Baseline in LDL-C at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: mg/dL
        least squares mean (standard error)
    -8.6 ± 2.3
    -64.4 ± 1.7
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.0001 [8]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -55.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -61
         upper limit
    		 -50.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.7
    Notes
    [7] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [8] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

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

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    End point title
    		 Percent Change From Baseline in Non-HDL-C at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percent change
        least squares mean (standard error)
    -0.05 ± 1.63
    -56.62 ± 1.21
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.0001 [10]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -56.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -60.28
         upper limit
    		 -52.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.89
    Notes
    [9] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [10] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

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

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    End point title
    		 Percent Change From Baseline in Non-HDL-C at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percent change
        least squares mean (standard error)
    -0.60 ± 1.79
    -46.89 ± 1.33
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.0001 [12]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -46.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -50.42
         upper limit
    		 -42.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1
    Notes
    [11] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [12] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

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

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percent change
        least squares mean (standard error)
    2.31 ± 1.58
    -50.17 ± 1.18
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 < 0.0001 [14]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -52.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -56.1
         upper limit
    		 -48.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.85
    Notes
    [13] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [14] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

    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
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percent change
        least squares mean (standard error)
    1.78 ± 1.73
    -40.34 ± 1.29
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 < 0.0001 [16]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -42.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -46.13
         upper limit
    		 -38.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.04
    Notes
    [15] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [16] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

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

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    End point title
    		 Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percent change
        least squares mean (standard error)
    -1.13 ± 1.24
    -42.19 ± 0.92
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 < 0.0001 [18]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -41.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -43.9
         upper limit
    		 -38.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.44
    Notes
    [17] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [18] - The model includes treatment group, stratification factor (screening LDL-C level), 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
    141
    280
    Units: percent change
        least squares mean (standard error)
    -1.23 ± 1.36
    -34.97 ± 1.01
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 < 0.0001 [20]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -33.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.87
         upper limit
    		 -30.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.59
    Notes
    [19] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [20] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

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

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    End point title
    		 Percentage of Participants With Mean LDL-C at Weeks 10 and 12 of Less Than 70 mg/dL (1.8 mmol/L)
    End point description
    End point type
    Secondary
    End point timeframe
    Weeks 10 and 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percentage of participants
        number (confidence interval 95%)
    14.8 (9.8 to 21.8)
    92.7 (89.0 to 95.2)
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 < 0.0001 [22]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    77.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 70
         upper limit
    		 83.5
    Notes
    [21] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [22] - Cochran Mantel Haenszel (CMH) test adjusted by the stratification factor (screening LDL-C level).

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

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    End point title
    		 Percentage of Participants With LDL-C at Week 12 of Less Than 70 mg/dL (1.8 mmol/L)
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percentage of participants
        number (confidence interval 95%)
    15.4 (10.2 to 22.6)
    84.5 (79.5 to 88.5)
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 < 0.0001 [24]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    69.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 60.4
         upper limit
    		 75.7
    Notes
    [23] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [24] - Cochran Mantel Haenszel (CMH) test adjusted by the stratification factor (screening LDL-C level).

    Secondary: Percentage of Participants With at Least a 50% Reduction from Baseline in Mean LDL-C at Weeks 10 and 12

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    End point title
    		 Percentage of Participants With at Least a 50% Reduction from Baseline in Mean LDL-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
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percentage of participants
        number (confidence interval 95%)
    0.7 (0.1 to 4.1)
    84.2 (79.5 to 88.1)
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 < 0.0001 [26]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    83.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 77.7
         upper limit
    		 87.4
    Notes
    [25] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [26] - Cochran Mantel Haenszel (CMH) test adjusted by the stratification factor (screening LDL-C level).

    Secondary: Percentage of Participants With at Least a 50% Reduction from Baseline in LDL-C at Week 12

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    End point title
    		 Percentage of Participants With at Least a 50% Reduction from Baseline in LDL-C at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percentage of participants
        number (confidence interval 95%)
    0.8 (0.1 to 4.2)
    65.5 (59.4 to 71.1)
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 < 0.0001 [28]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    64.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 57.7
         upper limit
    		 70.3
    Notes
    [27] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [28] - Cochran Mantel Haenszel (CMH) test adjusted by the stratification factor (screening LDL-C level).

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

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    End point title
    		 Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percent change
        least squares mean (standard error)
    9.63 ± 3.29
    -30.87 ± 2.43
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 < 0.0001 [30]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -40.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -48.11
         upper limit
    		 -32.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.87
    Notes
    [29] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [30] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

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

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    End point title
    		 Percent Change From Baseline in Lipoprotein(a) at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percent change
        least squares mean (standard error)
    7.38 ± 3.06
    -25.18 ± 2.28
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 < 0.0001 [32]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -32.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.58
         upper limit
    		 -25.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.57
    Notes
    [31] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [32] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

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

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    End point title
    		 Percent Change From Baseline in Triglycerides at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percent change
        least squares mean (standard error)
    6.61 ± 2.94
    -12.64 ± 2.19
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 < 0.0001 [34]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -19.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.95
         upper limit
    		 -12.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.41
    Notes
    [33] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [34] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

    Secondary: Percent Change From Baseline in Triglycerides at Week 12

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    End point title
    		 Percent Change From Baseline in Triglycerides at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percent change
        least squares mean (standard error)
    4.81 ± 3.41
    -8.90 ± 2.52
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 < 0.0001 [36]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -13.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.6
         upper limit
    		 -5.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.02
    Notes
    [35] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [36] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

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

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    End point title
    		 Percent Change From Baseline in HDL-C at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percent change
        least squares mean (standard error)
    -2.57 ± 1.25
    7.23 ± 0.93
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 < 0.0001 [38]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    9.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.95
         upper limit
    		 12.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.45
    Notes
    [37] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [38] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

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

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    End point title
    		 Percent Change From Baseline in HDL-C at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percent change
        least squares mean (standard error)
    -1.41 ± 1.38
    5.96 ± 1.02
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 < 0.0001 [40]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    7.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.19
         upper limit
    		 10.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.62
    Notes
    [39] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [40] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

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

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    End point title
    		 Percent Change From Baseline in VLDL-C at the Mean of Weeks 10 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 10 and 12
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    141
    280
    Units: percent change
        least squares mean (standard error)
    3.42 ± 2.57
    -13.64 ± 1.89
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 < 0.0001 [42]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -17.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.91
         upper limit
    		 -11.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.98
    Notes
    [41] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [42] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

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

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    End point title
    		 Percent Change From Baseline in VLDL-C 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
    141
    280
    Units: percent change
        least squares mean (standard error)
    3.02 ± 2.94
    -10.31 ± 2.15
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 < 0.0001 [44]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -13.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.09
         upper limit
    		 -6.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.44
    Notes
    [43] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.
    [44] - The model includes treatment group, stratification factor (screening LDL-C level), scheduled visit and the interaction of treatment with scheduled visit as covariates.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug (placebo or evolocumab) to week 12.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneous injection once every month (QM) for 12 weeks.

    Reporting group title
    Evolocumab
    Reporting group description
    		 Participants received 420 mg evolocumab subcutaneous injection once every month (QM) for 12 weeks.

    Serious adverse events
    		 Placebo Evolocumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 141 (1.42%)
    14 / 280 (5.00%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 280 (0.36%)
         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
    Fracture displacement
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 280 (0.36%)
         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 / 141 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden cardiac death
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Peptic ulcer
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 280 (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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 141 (0.00%)
    4 / 280 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis chronic
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 280 (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
    0 / 141 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo Evolocumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 141 (13.48%)
    37 / 280 (13.21%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 141 (0.00%)
    11 / 280 (3.93%)
         occurrences all number
    0
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 141 (2.13%)
    6 / 280 (2.14%)
         occurrences all number
    3
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 141 (2.84%)
    6 / 280 (2.14%)
         occurrences all number
    9
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 141 (2.13%)
    2 / 280 (0.71%)
         occurrences all number
    3
    2
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    3 / 141 (2.13%)
    0 / 280 (0.00%)
         occurrences all number
    3
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 141 (1.42%)
    6 / 280 (2.14%)
         occurrences all number
    2
    6
    Viral upper respiratory tract infection
         subjects affected / exposed
    4 / 141 (2.84%)
    5 / 280 (1.79%)
         occurrences all number
    4
    5
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    5 / 141 (3.55%)
    8 / 280 (2.86%)
         occurrences all number
    5
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jan 2016
    - clarified timing of randomization in relation to first dose. - added clarification that subjects must tolerate SC injection of placebo with device anticipated to be used (either AI/pen or AMD) - added clinical research associate as an additional contact for the investigator prior to unblinding of subject’s treatment assignment. - added non-clinic investigational product injection at Week 4 to the Schedule of Assessments table for clarity. - removed text specifying kilograms and centimeters for body weight and height so sites can record in pounds and inches. - added that triglycerides > 1000 mg/dL would be reported to the investigators to allow appropriate follow-up to be initiated. - revised reasons for removal from treatment to be consistent with template text. - updated reporting requirements for adverse events for consistency throughout the protocol. - added appendix E of Child-Pugh Score to provide additional information.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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