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    Clinical Trial Results:
    A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability, and Efficacy on LDL-C of Evolocumab (AMG 145) in Subjects With HIV and With Hyperlipidemia and/or Mixed Dyslipidemia

    Summary
    EudraCT number
    		 2015-004735-12
    Trial protocol
    		 FR   PT   GB   BE   ES   GR   PL   IT  
    Global end of trial date
    27 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jan 2021
    First version publication date
    28 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20130286
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02833844
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oks, California, United States,
    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
    27 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jan 2020
    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 24 weeks of subcutaneous (SC) evolocumab administered once monthly (QM) compared with placebo QM on percent change from baseline in low density lipoprotein cholesterol (LDL-C) in human immunodeficiency virus (HIV)-positive subjects with hyperlipidemia and/or mixed dyslipidemia.
    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 regulations and guidelines set forth in 21 Code of Federal Regulations parts 11, 50, 54, 56, and 312. 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
    22 May 2017
    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
    Australia: 28
    Country: Number of subjects enrolled
    South Africa: 20
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    France: 49
    Country: Number of subjects enrolled
    Greece: 31
    Country: Number of subjects enrolled
    Italy: 27
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Portugal: 24
    Country: Number of subjects enrolled
    Romania: 18
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    Switzerland: 25
    Country: Number of subjects enrolled
    United Kingdom: 26
    Country: Number of subjects enrolled
    Brazil: 25
    Country: Number of subjects enrolled
    Canada: 32
    Country: Number of subjects enrolled
    United States: 121
    Worldwide total number of subjects
    467
    EEA total number of subjects
    190
    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)
    390
    From 65 to 84 years
    77
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 72 centers in Australia, Belgium, Brazil, Canada, France, Greece, Italy, Poland, Portugal, Romania, South Africa, Spain, Switzerland, United Kingdom, and United States. The first participant was enrolled on 22 May 2017, and the last participant was enrolled on 23 January 2019.

    Pre-assignment
    Screening details
    		 Participants were randomized in a 2:1 ratio to evolocumab or placebo, respectively, in a double-blind manner. Randomization was stratified by entry statin treatment and hepatitis C status.

    Period 1
    Period 1 title
    Double-Blind Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Blinded individuals did not have access to unblinded information until the study was formally unblinded. Unblinding and potentially unblinding information was not distributed to the study team, investigators or subjects prior to the study being formally unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double-Blind Placebo
    Arm description
    		 Double-blind placebo subcutaneous (SC) injection every 4 weeks (QM) for 24 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
    Matching placebo administered QM at day 1 and weeks 4, 8, 12, 16, and 20 as an SC injection.

    Arm title
    		 Double-Blind Evolocumab
    Arm description
    		 Double-blind evolocumab SC injection QM for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evolocumab
    Investigational medicinal product code
    AMG 145
    Other name
    EvoMab Repatha
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Evolocumab 420 mg administered QM at day 1 and weeks 4, 8, 12, 16, and 20 as an SC injection.

    Number of subjects in period 1
    		Double-Blind Placebo Double-Blind Evolocumab
    Started
    157
    310
    Randomized and Treated
    157
    307
    Completed
    155
    303
    Not completed
    2
    7
         Consent withdrawn by subject
    2
    3
         Protocol deviation
    -
    4
    Period 2
    Period 2 title
    Open-Label Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double-Blind Placebo/Open-Label Evolocumab
    Arm description
    		 Participants originally randomized to placebo in the double-blind period then received open-label evolocumab 420 mg SC QM for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evolocumab
    Investigational medicinal product code
    AMG 145
    Other name
    EvoMab Repatha
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Evolocumab 420 mg QM at weeks 24, 28, 32, 36, 40, 44, and 48 as an SC injection.

    Arm title
    		 Double-Blind Evolocumab/Open-Label Evolocumab
    Arm description
    		 Participants originally randomized to evolocumab in the double-blind period then received open-label evolocumab 420 mg SC QM for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evolocumab
    Investigational medicinal product code
    AMG 145
    Other name
    EvoMab Repatha
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Evolocumab 420 mg QM at weeks 24, 28, 32, 36, 40, 44, and 48 as an SC injection.

    Number of subjects in period 2 [1]
    		Double-Blind Placebo/Open-Label Evolocumab Double-Blind Evolocumab/Open-Label Evolocumab
    Started
    152
    303
    Received Open-Label Study Drug
    152
    299 [2]
    Completed
    150
    301
    Not completed
    2
    2
         Adverse event, serious fatal
    -
    2
         Consent withdrawn by subject
    1
    -
         Lost to follow-up
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 3 participants did not continue into the open-label period.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 4 participants did not receive open-label study drug.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double-Blind Placebo
    Reporting group description
    		 Double-blind placebo subcutaneous (SC) injection every 4 weeks (QM) for 24 weeks.

    Reporting group title
    Double-Blind Evolocumab
    Reporting group description
    		 Double-blind evolocumab SC injection QM for 24 weeks.

    Reporting group values
    		 Double-Blind Placebo Double-Blind Evolocumab Total
    Number of subjects
    		 157 310 467
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.2 ± 8.0 56.5 ± 9.1 -
    Sex: Female, Male
    Units:
        Female
    		 37 45 82
        Male
    		 120 265 385
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 21 41 62
        Not Hispanic or Latino
    		 136 269 405
        Unknown or Not Reported
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 3 3 6
        Black or African American
    		 25 54 79
        White
    		 125 246 371
        Multiple Races
    		 1 0 1
        Other, Not Specified
    		 3 7 10
    Stratification Factor: Statin Use at Baseline
    Units: Subjects
        Statin Use = Yes
    		 128 256 384
        Statin Use = No
    		 29 54 83
    Stratification Factor: Hepatitis C Virus (HCV) Status at Baseline
    Units: Subjects
        HCV = Yes
    		 7 10 17
        HCV = No
    		 150 300 450
    Low-Density Lipoprotein Cholesterol (LDL-C)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 133.26 ± 39.97 133.25 ± 40.25 -

    End points

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    End points reporting groups
    Reporting group title
    Double-Blind Placebo
    Reporting group description
    		 Double-blind placebo subcutaneous (SC) injection every 4 weeks (QM) for 24 weeks.

    Reporting group title
    Double-Blind Evolocumab
    Reporting group description
    		 Double-blind evolocumab SC injection QM for 24 weeks.
    Reporting group title
    Double-Blind Placebo/Open-Label Evolocumab
    Reporting group description
    		 Participants originally randomized to placebo in the double-blind period then received open-label evolocumab 420 mg SC QM for 24 weeks.

    Reporting group title
    Double-Blind Evolocumab/Open-Label Evolocumab
    Reporting group description
    		 Participants originally randomized to evolocumab in the double-blind period then received open-label evolocumab 420 mg SC QM for 24 weeks.

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

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    End point title
    		 Percent Change From Baseline in LDL-C at Week 24
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Double-Blind Placebo Double-Blind Evolocumab
    Number of subjects analysed
    151
    295
    Units: percent change
        least squares mean (standard error)
    1.68 ± 2.03
    -55.23 ± 1.52
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-Blind Placebo v Double-Blind Evolocumab
    Number of subjects included in analysis
    446
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 repeated measures linear effects model
    Parameter type
    		 treatment difference
    Point estimate
    -56.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -61.55
         upper limit
    		 -52.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.36
    Notes
    [1] - Multiplicity adjustment was based on the combination of sequential testing, the fallback procedure, and the Hochberg procedure.

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

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    End point title
    		 Change From Baseline in LDL-C at Week 24
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Double-Blind Placebo Double-Blind Evolocumab
    Number of subjects analysed
    151
    295
    Units: mg/dL
        least squares mean (standard error)
    -2.3 ± 3.1
    -77.5 ± 2.3
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-Blind Placebo v Double-Blind Evolocumab
    Number of subjects included in analysis
    446
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 repeated measures linear effects model
    Parameter type
    		 treatment difference
    Point estimate
    -75.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -82.1
         upper limit
    		 -68.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.5
    Notes
    [2] - Multiplicity adjustment was based on the combination of sequential testing, the fallback procedure, and the Hochberg procedure.

    Secondary: Percentage of Participants Acheiving LDL-C < 70 mg/dL (1.8 mmol/L) at Week 24

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    End point title
    		 Percentage of Participants Acheiving LDL-C < 70 mg/dL (1.8 mmol/L) at Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Double-Blind Placebo Double-Blind Evolocumab
    Number of subjects analysed
    151
    296
    Units: percentage of participants
        number (confidence interval 95%)
    7.9 (4.6 to 13.4)
    73.3 (68.0 to 78.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Multiplicity adjustment was based on the combination of sequential testing, the fallback procedure, and the Hochberg procedure.
    Comparison groups
    Double-Blind Placebo v Double-Blind Evolocumab
    Number of subjects included in analysis
    447
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 treatment difference
    Point estimate
    65.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 57.8
         upper limit
    		 71.1
    Notes
    [3] - Based on Cochran-Mantel-Haenszel test stratified by statin use stratification factor. For testing, nonachievement was imputed for participants with a missing value.

    Secondary: Percentage of Participants With an LDL-C Response (50% Reduction of LDL-C From Baseline) at Week 24

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    End point title
    		 Percentage of Participants With an LDL-C Response (50% Reduction of LDL-C From Baseline) at Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Double-Blind Placebo Double-Blind Evolocumab
    Number of subjects analysed
    151
    295
    Units: percentage of participants
        number (confidence interval 95%)
    0.7 (0.1 to 3.7)
    72.5 (67.2 to 77.3)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Multiplicity adjustment was based on the combination of sequential testing, the fallback procedure, and the Hochberg procedure.
    Comparison groups
    Double-Blind Placebo v Double-Blind Evolocumab
    Number of subjects included in analysis
    446
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 treatment difference
    Point estimate
    71.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 65.7
         upper limit
    		 76.7
    Notes
    [4] - Based on Cochran-Mantel-Haenszel test stratified by statin use stratification factor. For testing, nonachievement was imputed for participants with a missing value.

    Secondary: Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (HDL-C) at Week 24

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    End point title
    		 Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (HDL-C) at Week 24
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Double-Blind Placebo Double-Blind Evolocumab
    Number of subjects analysed
    152
    296
    Units: percent change
        least squares mean (standard error)
    2.86 ± 1.74
    -48.07 ± 1.31
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-Blind Placebo v Double-Blind Evolocumab
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 repeated measures linear effects model
    Parameter type
    		 treatment difference
    Point estimate
    -50.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.88
         upper limit
    		 -46.99
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.01
    Notes
    [5] - Multiplicity adjustment was based on the combination of sequential testing, the fallback procedure, and the Hochberg procedure.

    Secondary: Percent Change From Baseline in Apolipoprotein B (ApoB) at Week 24

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B (ApoB) at Week 24
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Double-Blind Placebo Double-Blind Evolocumab
    Number of subjects analysed
    153
    302
    Units: percent change
        least squares mean (standard error)
    2.59 ± 1.50
    -45.14 ± 1.13
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-Blind Placebo v Double-Blind Evolocumab
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 repeated measures linear effects model
    Parameter type
    		 treatment difference
    Point estimate
    -47.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.11
         upper limit
    		 -44.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.72
    Notes
    [6] - Multiplicity adjustment was based on the combination of sequential testing, the fallback procedure, and the Hochberg procedure.

    Secondary: Percent Change From Baseline in Total Cholesterol (TC) at Week 24

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    End point title
    		 Percent Change From Baseline in Total Cholesterol (TC) at Week 24
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Double-Blind Placebo Double-Blind Evolocumab
    Number of subjects analysed
    152
    296
    Units: percent change
        least squares mean (standard error)
    2.34 ± 1.40
    -35.78 ± 1.06
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-Blind Placebo v Double-Blind Evolocumab
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 repeated measures linear effects model
    Parameter type
    		 treatment difference
    Point estimate
    -38.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.3
         upper limit
    		 -34.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.62
    Notes
    [7] - Multiplicity adjustment was based on the combination of sequential testing, the fallback procedure, and the Hochberg procedure.

    Secondary: Percent Change From Baseline in Lipoprotein(a) (Lp[a]) at Week 24

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    End point title
    		 Percent Change From Baseline in Lipoprotein(a) (Lp[a]) at Week 24
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Double-Blind Placebo Double-Blind Evolocumab
    Number of subjects analysed
    153
    302
    Units: percent change
        least squares mean (standard error)
    10.35 ± 3.34
    -16.44 ± 2.57
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-Blind Placebo v Double-Blind Evolocumab
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 repeated measures linear effects model
    Parameter type
    		 treatment difference
    Point estimate
    -26.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.17
         upper limit
    		 -19.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.76
    Notes
    [8] - Multiplicity adjustment was based on the combination of sequential testing, the fallback procedure, and the Hochberg procedure.

    Secondary: Percent Change From Baseline in Triglycerides at Week 24

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    End point title
    		 Percent Change From Baseline in Triglycerides at Week 24
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Double-Blind Placebo Double-Blind Evolocumab
    Number of subjects analysed
    152
    296
    Units: percent change
        least squares mean (standard error)
    13.21 ± 3.80
    -9.25 ± 2.89
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-Blind Placebo v Double-Blind Evolocumab
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 repeated measures linear effects model
    Parameter type
    		 treatment difference
    Point estimate
    -22.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.03
         upper limit
    		 -13.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.36
    Notes
    [9] - Multiplicity adjustment was based on the combination of sequential testing, the fallback procedure, and the Hochberg procedure.

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

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    End point title
    		 Percent Change From Baseline in HDL-C at Week 24
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
    End point type
    Secondary
    End point timeframe
    Bseline, Week 24
    End point values
    		 Double-Blind Placebo Double-Blind Evolocumab
    Number of subjects analysed
    152
    296
    Units: percent change
        least squares mean (standard error)
    2.73 ± 1.57
    11.08 ± 1.20
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-Blind Placebo v Double-Blind Evolocumab
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [10]
    Method
    		 repeated measures linear effects model
    Parameter type
    		 treatment difference
    Point estimate
    8.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.83
         upper limit
    		 11.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.8
    Notes
    [10] - Multiplicity adjustment was based on the combination of sequential testing, the fallback procedure, and the Hochberg procedure.

    Secondary: Percent Change From Baseline in Very Low-Density Lipoprotein Cholesterol (VLDL-C) at Week 24

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    End point title
    		 Percent Change From Baseline in Very Low-Density Lipoprotein Cholesterol (VLDL-C) at Week 24
    End point description
    Least squares mean is from the repeated measures model which includes treatment group, statin stratification factor, scheduled visit and the interaction of treatment with scheduled visit as covariates. (Hepatitis C stratification factor is not included in the model due to low participant numbers.)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Double-Blind Placebo Double-Blind Evolocumab
    Number of subjects analysed
    141
    284
    Units: percent change
        least squares mean (standard error)
    12.34 ± 3.54
    -9.81 ± 2.65
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-Blind Placebo v Double-Blind Evolocumab
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [11]
    Method
    		 repeated measures linear effects model
    Parameter type
    		 treatment difference
    Point estimate
    -22.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.04
         upper limit
    		 -14.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.01
    Notes
    [11] - Multiplicity adjustment was based on the combination of sequential testing, the fallback procedure, and the Hochberg procedure.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Double-blind Treatment Period: From first dose of study drug to up to week 24. Open-label Extension Period: From first dose of study drug in the OLE up to 30 days after last dose, or end of study, whichever was earlier.
    Adverse event reporting additional description
    Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Double-Blind Placebo
    Reporting group description
    		 Double-blind placebo SC injection QM for 24 weeks.

    Reporting group title
    Double-Blind Evolocumab
    Reporting group description
    		 Double-blind evolocumab SC injection QM for 24 weeks.

    Reporting group title
    Double-Blind Placebo/Open-Label Evolocumab
    Reporting group description
    		 Participants originally randomized to placebo in the double-blind period then received open-label evolocumab 420 mg SC QM for 24 weeks.

    Reporting group title
    Double-Blind Evolocumab/Open-Label Evolocumab
    Reporting group description
    		 Participants originally randomized to evolocumab in the double-blind period then received open-label evolocumab 420 mg SC QM for 24 weeks.

    Serious adverse events
    		 Double-Blind Placebo Double-Blind Evolocumab Double-Blind Placebo/Open-Label Evolocumab Double-Blind Evolocumab/Open-Label Evolocumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 157 (5.10%)
    10 / 307 (3.26%)
    8 / 152 (5.26%)
    14 / 299 (4.68%)
         number of deaths (all causes)
    0
    0
    0
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 307 (0.33%)
    1 / 152 (0.66%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    1 / 152 (0.66%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basosquamous carcinoma of skin
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    1 / 152 (0.66%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer stage 0, with cancer in situ
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hair follicle tumour benign
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    1 / 152 (0.66%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    1 / 152 (0.66%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma stage II
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    1 / 152 (0.66%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sarcomatoid carcinoma
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive emergency
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 307 (0.33%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 307 (0.33%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 307 (0.33%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    1 / 152 (0.66%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 307 (0.33%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 307 (0.33%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 307 (0.00%)
    1 / 152 (0.66%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 307 (0.33%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 307 (0.33%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis constrictive
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 307 (0.33%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 307 (0.33%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral artery thrombosis
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    1 / 152 (0.66%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    1 / 152 (0.66%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood loss anaemia
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    1 / 152 (0.66%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal fistula
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    1 / 152 (0.66%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    1 / 152 (0.66%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Lipohypertrophy
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    1 / 152 (0.66%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 307 (0.33%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 307 (0.33%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Staphylococcal infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 307 (0.33%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis bacterial
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Helicobacter gastritis
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    1 / 152 (0.66%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 307 (0.00%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Double-Blind Placebo Double-Blind Evolocumab Double-Blind Placebo/Open-Label Evolocumab Double-Blind Evolocumab/Open-Label Evolocumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 157 (26.11%)
    78 / 307 (25.41%)
    23 / 152 (15.13%)
    50 / 299 (16.72%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 157 (3.18%)
    0 / 307 (0.00%)
    3 / 152 (1.97%)
    4 / 299 (1.34%)
         occurrences all number
    5
    0
    3
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 157 (3.18%)
    6 / 307 (1.95%)
    3 / 152 (1.97%)
    1 / 299 (0.33%)
         occurrences all number
    6
    6
    4
    1
    Paraesthesia
         subjects affected / exposed
    0 / 157 (0.00%)
    7 / 307 (2.28%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    8
    0
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    5 / 157 (3.18%)
    2 / 307 (0.65%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    5
    2
    0
    1
    Influenza like illness
         subjects affected / exposed
    4 / 157 (2.55%)
    12 / 307 (3.91%)
    2 / 152 (1.32%)
    3 / 299 (1.00%)
         occurrences all number
    4
    15
    2
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 157 (2.55%)
    3 / 307 (0.98%)
    0 / 152 (0.00%)
    0 / 299 (0.00%)
         occurrences all number
    4
    3
    0
    0
    Diarrhoea
         subjects affected / exposed
    7 / 157 (4.46%)
    11 / 307 (3.58%)
    1 / 152 (0.66%)
    8 / 299 (2.68%)
         occurrences all number
    7
    12
    1
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 157 (1.91%)
    9 / 307 (2.93%)
    1 / 152 (0.66%)
    5 / 299 (1.67%)
         occurrences all number
    3
    10
    1
    5
    Back pain
         subjects affected / exposed
    4 / 157 (2.55%)
    12 / 307 (3.91%)
    4 / 152 (2.63%)
    2 / 299 (0.67%)
         occurrences all number
    4
    13
    4
    2
    Myalgia
         subjects affected / exposed
    6 / 157 (3.82%)
    6 / 307 (1.95%)
    0 / 152 (0.00%)
    3 / 299 (1.00%)
         occurrences all number
    6
    6
    0
    3
    Pain in extremity
         subjects affected / exposed
    3 / 157 (1.91%)
    7 / 307 (2.28%)
    0 / 152 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    3
    7
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 157 (1.27%)
    10 / 307 (3.26%)
    6 / 152 (3.95%)
    9 / 299 (3.01%)
         occurrences all number
    2
    10
    6
    9
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 157 (2.55%)
    7 / 307 (2.28%)
    1 / 152 (0.66%)
    5 / 299 (1.67%)
         occurrences all number
    4
    7
    1
    5
    Bronchitis
         subjects affected / exposed
    3 / 157 (1.91%)
    5 / 307 (1.63%)
    2 / 152 (1.32%)
    7 / 299 (2.34%)
         occurrences all number
    3
    5
    2
    7
    Sinusitis
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 307 (0.33%)
    1 / 152 (0.66%)
    8 / 299 (2.68%)
         occurrences all number
    1
    1
    1
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2017
    - To address regulatory concerns that subjects without clinical atherosclerotic cardiovascular disease (ASCVD) would be eligible, entry criteria were modified such that subjects without clinical ASCVD were required to have an LDL-C >/= 100 mg/dL. - Modified enrollment criteria such that a subpopulation of subjects not on statin background therapy could be included - Added a section to clarify that human immunodeficiency virus (HIV) worsening be recorded as an adverse event - The pregnancy test schedule was revised to address regulatory agency concerns, and details were provided to clarify when serum and urine pregnancy tests were performed.

    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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