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    Clinical Trial Results:
    Double-blind, Randomized, Multicenter, Placebo-controlled, Parallel Group Study to Characterize the Efficacy, Safety, and Tolerability of 24 Weeks of Evolocumab for Low Density Lipoprotein-cholesterol (LDL-C) Reduction, as Add-on to Diet and Lipid-lowering Therapy, in Pediatric Subjects 10 to 17 Years of Age With Heterozygous Familial Hypercholesterolemia (HeFH)

    Summary
    EudraCT number
    		 2014-002277-11
    Trial protocol
    		 CZ   BE   ES   IT   Outside EU/EEA   GR   NL   GB   AT   HU   SI   PT   PL   NO   RO  
    Global end of trial date
    25 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jun 2020
    First version publication date
    07 Jun 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20120123
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02392559
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001268-PIP01-05
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the effect of 24 weeks of subcutaneous (SC) evolocumab compared with placebo, when added to standard of care, on percent change from baseline in LDL-C in pediatric subjects 10 to 17 years of age with HeFH.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations and guidelines, and Food and Drug Administration (FDA) regulations, and guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    Netherlands: 22
    Country: Number of subjects enrolled
    Norway: 8
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    Slovenia: 1
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Brazil: 20
    Country: Number of subjects enrolled
    Colombia: 6
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Malaysia: 1
    Country: Number of subjects enrolled
    South Africa: 2
    Worldwide total number of subjects
    158
    EEA total number of subjects
    97
    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)
    39
    Adolescents (12-17 years)
    119
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled from 24 March 2016 to 30 May 2019 at 8 research centers in North America, 30 research centers in Europe, 6 research centers in Latin America, and 3 research centers in Asia Pacific.

    Pre-assignment
    Screening details
    		 Participants were randomized in a 2:1 ratio to receive 24 weeks of monthly (QM) evolocumab or placebo. Randomization was stratified by screening low-density lipoprotein cholesterol (LDL-C; < 160 mg/dL vs ≥ 160 mg/dL) and age (< 14 years vs ≥ 14 years).

    Pre-assignment period milestones
    Number of subjects started
    		 158
    Number of subjects completed
    		 157

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Randomized, not dosed: 1
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Matching subcutaneous injection QM
    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
    Each QM administration of investigational product consists of 3 injections of placebo in 1.0 mL (administration by prefilled AI/Pen) for a total of 3.0 mL placebo administered.

    Arm title
    		 EvoMab 420 mg QM
    Arm description
    		 Evolocumab subcutaneous injection QM
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evolocumab
    Investigational medicinal product code
    AMG 145
    Other name
    EvoMab
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each QM administration of investigational product consists of 3 injections of 140 mg evolocumab in 1.0 mL (administration by prefilled AI/Pen) for a total of 3.0 mL (420 mg evolocumab) administered.

    Number of subjects in period 1 [1]
    		Placebo EvoMab 420 mg QM
    Started
    53
    104
    Completed
    53
    104
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1 enrolled and randomized participant was not dosed.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching subcutaneous injection QM

    Reporting group title
    EvoMab 420 mg QM
    Reporting group description
    		 Evolocumab subcutaneous injection QM

    Reporting group values
    		 Placebo EvoMab 420 mg QM Total
    Number of subjects
    		 53 104 157
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 13.7 ± 2.5 13.7 ± 2.3 -
    Sex: Female, Male
    Units:
        Female
    		 27 61 88
        Male
    		 26 43 69
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 7 6 13
        Not Hispanic or Latino
    		 46 98 144
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 0 2 2
        Black (or African American)
    		 0 2 2
        White
    		 44 89 133
        Other, Not Specified
    		 9 11 20
    Stratification Factor: Age Group
    Units: Subjects
        < 14 years
    		 25 48 73
        ≥ 14 years
    		 28 56 84
    Stratification Factor: Screening LDL-C Level
    Units: Subjects
        < 160 mg/dL
    		 16 33 49
        ≥ 160 mg/dL
    		 37 71 108
    LDL-C
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 183.0 ± 47.2 185.0 ± 45.0 -
    Non-High-Density Lipoprotein Cholesterol (Non-HDL-C)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 200.2 ± 48.2 203.8 ± 47.3 -
    Total Cholesterol/HDL-C Ratio
    Units: ratio
        arithmetic mean (standard deviation)
    		 5.517 ± 1.492 5.702 ± 1.791 -
    Apolipoprotein B (ApoB)
    participants with an assessment at baseline (n=154)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 119.4 ± 27.9 123.3 ± 27.1 -
    ApoB/Apolipoprotein A1 (ApoA1) Ratio
    participants with an assessment at baseline (n=154)
    Units: ratio
        arithmetic mean (standard deviation)
    		 0.938 ± 0.255 0.970 ± 0.302 -
    Systolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 112.0 ± 12.1 110.8 ± 11.5 -
    Diastolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 67.2 ± 8.7 66.3 ± 7.7 -
    Heart Rate
    Units: beats per minute
        arithmetic mean (standard deviation)
    		 74.3 ± 11.7 74.5 ± 11.1 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching subcutaneous injection QM

    Reporting group title
    EvoMab 420 mg QM
    Reporting group description
    		 Evolocumab subcutaneous injection QM

    Primary: Percent Change From Baseline to Week 24 in LDL-C

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    End point title
    		 Percent Change From Baseline to Week 24 in LDL-C
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, stratification factors of age and screening LDL-C (from interactive voice response system [IVRS]), scheduled visit and the interaction of treatment with scheduled visit as covariates. The model uses an unstructured covariance.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo EvoMab 420 mg QM
    Number of subjects analysed
    53
    104
    Units: percent change
        least squares mean (standard error)
    -6.23 ± 3.08
    -44.53 ± 2.17
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v EvoMab 420 mg QM
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 repeated measures model
    Parameter type
    		 treatment difference
    Point estimate
    -38.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -45.54
         upper limit
    		 -31.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.66
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v EvoMab 420 mg QM
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 sequential testing/Hochberg procedure
    Confidence interval
    Notes
    [1] - Adjusted p-value based on a combination of sequential testing and the Hochberg procedure to control the overall significance level for all primary and secondary endpoints.

    Secondary: Mean Percent Change from Baseline to Mean of Weeks 22 and 24 in LDL-C

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    End point title
    		 Mean Percent Change from Baseline to Mean of Weeks 22 and 24 in LDL-C
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, stratification factors of age and screening LDL-C (from IVRS), scheduled visit and the interaction of treatment with scheduled visit as covariates.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 22, Week 24
    End point values
    		 Placebo EvoMab 420 mg QM
    Number of subjects analysed
    53
    104
    Units: percent change
        least squares mean (standard error)
    -5.87 ± 2.66
    -47.95 ± 1.92
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v EvoMab 420 mg QM
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 repeated measures model
    Parameter type
    		 treatment difference
    Point estimate
    -42.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -48.34
         upper limit
    		 -35.83
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.17
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v EvoMab 420 mg QM
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 sequential testing/Hochberg procedure
    Confidence interval
    Notes
    [2] - Adjusted p-value based on a combination of sequential testing and the Hochberg procedure to control the overall significance level for all primary and secondary endpoints.

    Secondary: Change From Baseline to Week 24 in LDL-C

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    End point title
    		 Change From Baseline to Week 24 in LDL-C
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, stratification factors of age and screening LDL-C (from IVRS), scheduled visit and the interaction of treatment with scheduled visit as covariates.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo EvoMab 420 mg QM
    Number of subjects analysed
    53
    104
    Units: mg/dL
        least squares mean (standard error)
    -9.0 ± 6.2
    -77.5 ± 4.4
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v EvoMab 420 mg QM
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 repeated measures model
    Parameter type
    		 treatment difference
    Point estimate
    -68.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -83.1
         upper limit
    		 -54
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.3
    Notes
    [3] - Treatment difference uses placebo as the reference.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v EvoMab 420 mg QM
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 sequential testing/Hochberg procedure
    Confidence interval
    Notes
    [4] - Adjusted p-value based on a combination of sequential testing and the Hochberg procedure to control the overall significance level for all primary and secondary endpoints.

    Secondary: Percent Change From Baseline to Week 24 in Non-HDL-C

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    End point title
    		 Percent Change From Baseline to Week 24 in Non-HDL-C
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, stratification factors of age and screening LDL-C (from IVRS), scheduled visit and the interaction of treatment with scheduled visit as covariates
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo EvoMab 420 mg QM
    Number of subjects analysed
    53
    104
    Units: percent change
        least squares mean (standard error)
    -6.14 ± 2.87
    -41.19 ± 2.01
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v EvoMab 420 mg QM
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 repeated measures model
    Parameter type
    		 treatment difference
    Point estimate
    -35.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.79
         upper limit
    		 -28.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.41
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v EvoMab 420 mg QM
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 sequential testing/Hochberg procedure
    Confidence interval
    Notes
    [5] - Adjusted p-value based on a combination of sequential testing and the Hochberg procedure to control the overall significance level for all primary and secondary endpoints.

    Secondary: Percent Change From Baseline to Week 24 in Apoliprotein-B (ApoB)

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    End point title
    		 Percent Change From Baseline to Week 24 in Apoliprotein-B (ApoB)
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, stratification factors of age and screening LDL-C (from IVRS), scheduled visit and the interaction of treatment with scheduled visit as covariates.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo EvoMab 420 mg QM
    Number of subjects analysed
    53
    104
    Units: percent change
        least squares mean (standard error)
    -2.37 ± 2.70
    -34.85 ± 1.88
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v EvoMab 420 mg QM
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 repeated measures model
    Parameter type
    		 treatment difference
    Point estimate
    -32.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.82
         upper limit
    		 -26.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.21
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v EvoMab 420 mg QM
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 sequential testing/Hochberg procedure
    Confidence interval
    Notes
    [6] - Adjusted p-value based on a combination of sequential testing and the Hochberg procedure to control the overall significance level for all primary and secondary endpoints.

    Secondary: Percent Change From Baseline to Week 24 in Total Cholesterol/HDL-C Ratio

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    End point title
    		 Percent Change From Baseline to Week 24 in Total Cholesterol/HDL-C Ratio
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, stratification factors of age and screening LDL-C (from IVRS), scheduled visit and the interaction of treatment with scheduled visit as covariates.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo EvoMab 420 mg QM
    Number of subjects analysed
    53
    104
    Units: percent change
        least squares mean (standard error)
    -4.66 ± 2.60
    -34.96 ± 1.82
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v EvoMab 420 mg QM
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 repeated measures model
    Parameter type
    		 treatment difference
    Point estimate
    -30.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.4
         upper limit
    		 -24.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.09
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v EvoMab 420 mg QM
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 sequential testing/Hochberg procedure
    Confidence interval
    Notes
    [7] - Adjusted p-value based on a combination of sequential testing and the Hochberg procedure to control the overall significance level for all primary and secondary endpoints.

    Secondary: Percent Change From Baseline to Week 24 in ApoB:ApoA1 Ratio

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    End point title
    		 Percent Change From Baseline to Week 24 in ApoB:ApoA1 Ratio
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, stratification factors of age and screening LDL-C (from IVRS), scheduled visit and the interaction of treatment with scheduled visit as covariates.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo EvoMab 420 mg QM
    Number of subjects analysed
    53
    104
    Units: percent change
        least squares mean (standard error)
    -0.63 ± 2.80
    -37.02 ± 1.95
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v EvoMab 420 mg QM
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 repeated measures model
    Parameter type
    		 treatment difference
    Point estimate
    -36.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.97
         upper limit
    		 -29.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.33
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v EvoMab 420 mg QM
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 sequential testing/Hochberg procedure
    Confidence interval
    Notes
    [8] - Adjusted p-value based on a combination of sequential testing and the Hochberg procedure to control the overall significance level for all primary and secondary endpoints.

    Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation (DC), Fatal TEAEs, and Device-Related TEAEs

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation (DC), Fatal TEAEs, and Device-Related TEAEs
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. An SAE is defined as an adverse event that: is fatal; is a life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or other medically important serious event. Events were graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grading scale (1=mild; 2=moderate; 3=severe; 4=life-threatening; 5=death). Events were defined as treatment emergent if they occurred after the first dose of study drug and up to and including 30 days after the last dose or the end of study date, whichever is earlier.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to and including 30 days after the last dose or end of study date (Week 24), whichever was earlier. Mean (SD) duration on study was 5.664 (0.278) and 5.608 (0.137) months for Placebo and EvoMab arms, respectively.
    End point values
    		 Placebo EvoMab 420 mg QM
    Number of subjects analysed
    53
    104
    Units: participants
        All TEAEs
    34
    64
        Grade ≥ 2 TEAEs
    22
    46
        Grade ≥ 3 TEAEs
    0
    4
        Grade ≥ 4 TEAEs
    0
    0
        Serious TEAEs
    0
    1
        TEAEs Leading to DC of Study Drug
    0
    1
        Serious TEAEs Leading to DC of Study Drug
    0
    0
        Non-Serious TEAEs Leading to DC of Study Drug
    0
    1
        Fatal TEAEs
    0
    0
        Device-Related TEAEs
    2
    3
        Device-Related Grade ≥ 2 TEAEs
    0
    0
        Device-Related Grade ≥ 3 TEAEs
    0
    0
        Device-Related Grade ≥ 4 TEAEs
    0
    0
        Serious Device-Related TEAEs
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Maximum Post-Baseline Laboratory Toxicities of Grade ≥ 3

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    End point title
    		 Number of Participants With Maximum Post-Baseline Laboratory Toxicities of Grade ≥ 3
    End point description
    Laboratory toxicity grading was based on NCI CTCAE grading; Grade 3 indicates severe toxicity and Grade 4 indicates life-threatening toxicity. Values representing a worsening from baseline are shown.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo EvoMab 420 mg QM
    Number of subjects analysed
    53
    104
    Units: participants
        High Total Bilirubin - Grade 3
    1
    0
        High Total Cholesterol - Grade 3
    1
    1
        High Uric Acid - Grade 3
    2
    8
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in Systolic Blood Pressure

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    End point title
    		 Change From Baseline Over Time in Systolic Blood Pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 12, Week 20, Week 22, Week 24
    End point values
    		 Placebo EvoMab 420 mg QM
    Number of subjects analysed
    53
    104
    Units: mmHg
    arithmetic mean (standard deviation)
        Change at Week 4
    -0.1 ± 11.3
    -0.7 ± 9.4
        Change at Week 12
    -0.6 ± 10.3
    0.3 ± 9.6
        Change at Week 20
    -2.1 ± 7.7
    0.1 ± 10.1
        Change at Week 22
    1.0 ± 10.9
    1.1 ± 10.0
        Change at Week 24
    -0.6 ± 11.4
    0.6 ± 10.7
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in Diastolic Blood Pressure

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    End point title
    		 Change From Baseline Over Time in Diastolic Blood Pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 12, Week 20, Week 22, Week 24
    End point values
    		 Placebo EvoMab 420 mg QM
    Number of subjects analysed
    53
    104
    Units: mmHg
    arithmetic mean (standard deviation)
        Change at Week 4
    -2.5 ± 9.5
    -1.5 ± 7.3
        Change at Week 12
    -2.2 ± 10.0
    0.5 ± 8.9
        Change at Week 20
    -3.3 ± 7.6
    -0.6 ± 7.7
        Change at Week 22
    -1.5 ± 9.3
    2.9 ± 8.0
        Change at Week 24
    -0.5 ± 9.0
    0.3 ± 8.6
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in Heart Rate

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    End point title
    		 Change From Baseline Over Time in Heart Rate
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 12, Week 20, Week 22, Week 24
    End point values
    		 Placebo EvoMab 420 mg QM
    Number of subjects analysed
    53
    104
    Units: beats per minute
    arithmetic mean (standard deviation)
        Change at Week 4
    2.1 ± 11.0
    0.1 ± 10.8
        Change at Week 12
    -0.5 ± 11.5
    -1.3 ± 10.2
        Change at Week 20
    -1.1 ± 10.3
    1.1 ± 11.5
        Change at Week 22
    1.3 ± 13.5
    -0.6 ± 11.3
        Change at Week 24
    0.2 ± 13.0
    -1.8 ± 11.8
    No statistical analyses for this end point

    Secondary: Number of Participants Testing Positive for Anti-Evolocumab Antibodies

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    End point title
    		 Number of Participants Testing Positive for Anti-Evolocumab Antibodies
    End point description
    End point type
    Secondary
    End point timeframe
    up to Week 24
    End point values
    		 Placebo EvoMab 420 mg QM
    Number of subjects analysed
    0 [9]
    104
    Units: participants
        Binding antibody positive at anytime
    0
        Neutralizing antibody positive at anytime
    0
    Notes
    [9] - Participants receiving evolocumab only were assessed.
    No statistical analyses for this end point

    Secondary: Serum Evolocumab Concentrations Over Time

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    End point title
    		 Serum Evolocumab Concentrations Over Time [10]
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12, Week 22, Week 24
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Serum concentration assessments are limited to participants who received evolocumab.
    End point values
    		 EvoMab 420 mg QM
    Number of subjects analysed
    99
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 12
    22400 ± 14700
        Week 22
    64900 ± 34400
        Week 24
    25800 ± 19200
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Fatal AEs: from first dose date to the end of study date (Week 24). Non-fatal AEs: from first dose of study drug up to and including 30 days after the last dose or end of study date, whichever was earlier.
    Adverse event reporting additional description
    Mean (SD) duration on study was 5.664 (0.278) and 5.608 (0.137) months for the Placebo and EvoMab arms, respectively.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    EvoMab 420 mg QM
    Reporting group description
    		 Evolocumab subcutaneous injection QM

    Reporting group title
    Placebo QM
    Reporting group description
    		 Matching subcutaneous injection QM

    Serious adverse events
    		 EvoMab 420 mg QM Placebo QM
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 53 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 53 (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: 2%
    Non-serious adverse events
    		 EvoMab 420 mg QM Placebo QM
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 104 (39.42%)
    19 / 53 (35.85%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 104 (0.96%)
    2 / 53 (3.77%)
         occurrences all number
    1
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 104 (10.58%)
    1 / 53 (1.89%)
         occurrences all number
    17
    1
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    3 / 104 (2.88%)
    0 / 53 (0.00%)
         occurrences all number
    3
    0
    Pyrexia
         subjects affected / exposed
    3 / 104 (2.88%)
    3 / 53 (5.66%)
         occurrences all number
    3
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 104 (2.88%)
    0 / 53 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 104 (1.92%)
    3 / 53 (5.66%)
         occurrences all number
    2
    3
    Oropharyngeal pain
         subjects affected / exposed
    7 / 104 (6.73%)
    0 / 53 (0.00%)
         occurrences all number
    8
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 104 (0.00%)
    2 / 53 (3.77%)
         occurrences all number
    0
    2
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    5 / 104 (4.81%)
    4 / 53 (7.55%)
         occurrences all number
    5
    4
    Influenza
         subjects affected / exposed
    6 / 104 (5.77%)
    2 / 53 (3.77%)
         occurrences all number
    6
    5
    Nasopharyngitis
         subjects affected / exposed
    12 / 104 (11.54%)
    6 / 53 (11.32%)
         occurrences all number
    14
    6
    Rhinitis
         subjects affected / exposed
    0 / 104 (0.00%)
    2 / 53 (3.77%)
         occurrences all number
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 104 (5.77%)
    1 / 53 (1.89%)
         occurrences all number
    6
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 May 2015
    • added hematology, urinalysis, and anti-evolocumab antibody assessments at week 12 • added exclusion of apheresis subjects to synopsis • added documentation of historical lipid therapies • added assessments of cognitive function to schedule of assessments and as an exploratory endpoint • clarification that the calculation of sample size accounts for 20% of randomized subjects discontinuing investigational product prior to completion of the study • deleted the exploratory endpoint of “categorical change from baseline in high sensitivity C-reactive protein”
    01 Sep 2015
    • added explicit exclusion of homozygous familial hypercholesterolemia subjects • added adverse device effects (ADE) and disease-related events (DRE) as safety assessments • removed cogstate neurocognitive battery as an exploratory endpoint and added it as a other safety endpoint. • added low-fat diet as background therapy to be maintained throughout the study • added explicit exclusion subjects receiving lipid apheresis • added definition of product complaints to the schedule of assessments • added the primary estimand • added statistical methodology for reporting vital signs, antibody data, and pharmacokinetic data

    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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