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    Clinical Trial Results:
    A 2-part, Phase 2/3 Study to Assess the Safety, Tolerability and Efficacy of AMG 145 in Subjects With Homozygous Familial Hypercholesterolemia. Part A – Open-label, Single-arm, Multicenter Pilot Study to Evaluate Safety, Tolerability and Efficacy of AMG 145 in Subjects With Homozygous Familial Hypercholesterolemia. Part B – Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability and Efficacy of AMG 145 in Subjects With Homozygous Familial Hypercholesterolemia

    Summary
    EudraCT number
    		 2011-005399-40
    Trial protocol
    		 BE   CZ   ES   IT   NL   Outside EU/EEA  
    Global end of trial date
    31 Jan 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    20110233
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01588496
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to characterize the effect of 12 weeks of evolocumab on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in subjects with homozygous familial hypercholesterolemia (HoFH).
    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
    		 Subjects were permitted to remain on a stable dose of lipid-lowering medications throughout the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Apr 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    United States: 6
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Czech Republic: 3
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Lebanon: 1
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    South Africa: 33
    Worldwide total number of subjects
    58
    EEA total number of subjects
    16
    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)
    11
    Adults (18-64 years)
    47
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Male and female adults and adolescents ages ≥ 12 to ≤ 65 years (≥ 12 to ≤ 80 years in Part B) with a diagnosis of homozygous familial hypercholesterolemia (HoFH) were eligible for this study. The first participant enrolled on 05 April 2012and the last participant enrolled on 08 November 2013.

    Pre-assignment
    Screening details
    		 Part A was an open-label, single-arm, multicenter pilot study. Part B was a double-blind, randomized, placebo-controlled, multicenter study with expanded enrollment. In Part B participants were randomized in a 1:2 allocation stratified on the basis of screening low-density lipoprotein cholesterol (LDL-C) (< 420 mg/dL vs ≥ 420 mg/dL).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Part A was an open-label, single-arm, multicenter pilot study where all enrolled subjects received open-label evolocumab. Part B was a double-blind, randomized, placebo-controlled, multicenter study with expanded enrollment that was initiated after effective LDL-C reduction (defined as an average reduction in LDL-C of ≥ 15% at week 12) was demonstrated in Part A.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A: Evolocumab
    Arm description
    		 Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evolocumab
    Investigational medicinal product code
    AMG 145
    Other name
    Repatha
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection

    Arm title
    		 Part B: Evolocumab
    Arm description
    		 Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evolocumab
    Investigational medicinal product code
    AMG 145
    Other name
    Repatha
    Pharmaceutical forms
    Solution for injection, Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection

    Arm title
    		 Part B: Placebo
    Arm description
    		 Participants received double-blind placebo subcutaneously once a month for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection

    Number of subjects in period 1
    		Part A: Evolocumab Part B: Evolocumab Part B: Placebo
    Started
    8
    33
    17
    Received Treatment
    8
    33
    16
    Completed
    8
    33
    16
    Not completed
    0
    0
    1
         Consent withdrawn by subject
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: Evolocumab
    Reporting group description
    		 Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks.

    Reporting group title
    Part B: Placebo
    Reporting group description
    		 Participants received double-blind placebo subcutaneously once a month for 12 weeks.

    Reporting group title
    Part B: Evolocumab
    Reporting group description
    		 Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks.

    Reporting group values
    		 Part A: Evolocumab Part B: Placebo Part B: Evolocumab Total
    Number of subjects
    		 8 17 33 58
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.3 ± 12.4 32.8 ± 13.7 30.3 ± 12.4 -
    Gender, Male/Female
    Units: participants
        Female
    		 2 8 16 26
        Male
    		 6 9 17 32
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 1 1 2
        Black or African American
    		 0 0 0 0
         Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        White
    		 8 16 29 53
        Other
    		 0 0 3 3
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 0 0 1 1
        Not Hispanic or Latino
    		 8 17 32 57
    Stratification Factor: Low-Density Lipoprotein Cholesterol (LDL-C) Level
    Participants in Part A were not stratified based on LDL-C level.
    Units: Subjects
         < 420 mg/dL
    		 0 11 21 32
        ≥ 420 mg/dL
    		 0 6 12 18
        Missing
    		 8 0 0 8
    LDL-C Concentration
    LDL-C was quantified using the ultracentrifugation method. Data are provided for the full analysis set (all enrolled subjects who received at least 1 dose of evolocumab (Part A) or all randomized subjects who received at least 1 dose of investigational product (Part B).
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 441.7 ± 113.3 335.8 ± 146 356 ± 134.5 -
    Non-High-Density Lipoprotein Cholesterol (non-HDL-C) Concentration
    Data are provided for the full analysis set
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 470.6 ± 117.8 358.9 ± 149.1 374.9 ± 136.9 -
    Apolipoprotein B Concentration
    Data are provided for the full analysis set
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 269.1 ± 53 208.6 ± 79.5 208.3 ± 68.4 -
    Total Cholesterol/HDL-C Ratio
    Data are provided for the full analysis set
    Units: ratio
        arithmetic mean (standard deviation)
    		 15.988 ± 5.107 12.101 ± 6.619 11.972 ± 6.387 -
    Apolipoprotein B/Apolipoprotein A1 Ratio
    Data are provided for the full analysis set
    Units: ratio
        arithmetic mean (standard deviation)
    		 2.8 ± 0.729 2.053 ± 0.967 2.098 ± 1.046 -
    Lipoprotein(a) Concentration
    Data are provided for the full analysis set
    Units: nmol/L
        median (inter-quartile range (Q1-Q3))
    		 246.5 (61.5 to 276) 127.5 (79.5 to 200.5) 76 (25.5 to 145) -
    Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Concentration
    Data are provided for the full analysis set
    Units: ng/mL
        arithmetic mean (standard deviation)
    		 598.6 ± 121.1 640.3 ± 207.5 674.2 ± 180 -

    End points

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    End points reporting groups
    Reporting group title
    Part A: Evolocumab
    Reporting group description
    		 Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks.

    Reporting group title
    Part B: Evolocumab
    Reporting group description
    		 Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks.

    Reporting group title
    Part B: Placebo
    Reporting group description
    		 Participants received double-blind placebo subcutaneously once a month for 12 weeks.

    Primary: Part A: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12

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    End point title
    		 Part A: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 [1] [2]
    End point description
    LDL-C was quantified using the ultracentrifugation method. All endpoints are analyzed in the full analysis set.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Part A provided an estimate of the LDL-C reduction in this particular population and was used to guide the decision to initiate Part B; formal hypothesis testing was performed only in Part B.
    [2] - 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: This endpoint pertains to subjects in Part A only
    End point values
    		 Part A: Evolocumab
    Number of subjects analysed
    8
    Units: percent change
        arithmetic mean (standard error)
    -16.5 ± 6.7
    No statistical analyses for this end point

    Primary: Part B: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12

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    End point title
    		 Part B: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 [3]
    End point description
    LDL-C was quantified using the ultracentrifugation method.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    Notes
    [3] - 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: This endpoint pertains to subjects in Part B only
    End point values
    		 Part B: Placebo Part B: Evolocumab
    Number of subjects analysed
    16
    33
    Units: percent change
        least squares mean (standard error)
    7.88 ± 5.26
    -23.05 ± 3.78
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    LDL-C lowering was analyzed by comparing evolocumab and placebo. Statistical analysis was 2-sided with a significance level of 0.05.
    Comparison groups
    Part B: Placebo v Part B: Evolocumab
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [4]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -30.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -43.86
         upper limit
    		 -18
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.42
    Notes
    [4] - Model includes treatment group, baseline LDL-C level (< 420 mg/dL vs ≥ 420 mg/dL), scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

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

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    End point title
    		 Part A: Change From Baseline in LDL-C at Week 12 [5]
    End point description
    LDL-C was quantified using the ultracentrifugation method.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    Notes
    [5] - 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: This endpoint pertains to subjects in Part A only
    End point values
    		 Part A: Evolocumab
    Number of subjects analysed
    8
    Units: mg/dL
        arithmetic mean (standard error)
    -70.6 ± 32.3
    No statistical analyses for this end point

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

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    End point title
    		 Part A: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (non-HDL-C) at Week 12 [6]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    Notes
    [6] - 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: This endpoint pertains to subjects in Part A only
    End point values
    		 Part A: Evolocumab
    Number of subjects analysed
    8
    Units: percent change
        arithmetic mean (standard error)
    -16.6 ± 6.5
    No statistical analyses for this end point

    Secondary: Part A: Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12

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    End point title
    		 Part A: Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12 [7]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    Notes
    [7] - 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: This endpoint pertains to subjects in Part A only
    End point values
    		 Part A: Evolocumab
    Number of subjects analysed
    8
    Units: percent change
        arithmetic mean (standard error)
    -18.319 ± 6.058
    No statistical analyses for this end point

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

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    End point title
    		 Part A: Percent Change From Baseline in Apolipoprotein B at Week 12 [8]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    Notes
    [8] - 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: This endpoint pertains to subjects in Part A only
    End point values
    		 Part A: Evolocumab
    Number of subjects analysed
    8
    Units: percent change
        arithmetic mean (standard error)
    -14.9 ± 5
    No statistical analyses for this end point

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

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    End point title
    		 Part A: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 12 [9]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    Notes
    [9] - 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: This endpoint pertains to subjects in Part A only
    End point values
    		 Part A: Evolocumab
    Number of subjects analysed
    8
    Units: percent change
        arithmetic mean (standard error)
    -15.65 ± 4.69
    No statistical analyses for this end point

    Secondary: Part A: Percentage of Participants With 15% or Greater Reduction in LDL-C From Baseline at Week 12

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    End point title
    		 Part A: Percentage of Participants With 15% or Greater Reduction in LDL-C From Baseline at Week 12 [10]
    End point description
    LDL-C was quantified using the ultracentrifugation method.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    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: This endpoint pertains to subjects in Part A only
    End point values
    		 Part A: Evolocumab
    Number of subjects analysed
    8
    Units: percentage of participants
        number (not applicable)
    50
    No statistical analyses for this end point

    Secondary: Part A: Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) at Week 12

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    End point title
    		 Part A: Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) at Week 12 [11]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    Notes
    [11] - 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: This endpoint pertains to subjects in Part A only
    End point values
    		 Part A: Evolocumab
    Number of subjects analysed
    8
    Units: ng/mL
        arithmetic mean (standard error)
    -151.3 ± 81.7
    No statistical analyses for this end point

    Secondary: Part B: Mean Percent Change From Baseline in LDL-C at Weeks 6 and 12

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    End point title
    		 Part B: Mean Percent Change From Baseline in LDL-C at Weeks 6 and 12 [12]
    End point description
    LDL-C was quantified using the ultracentrifugation method.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 6 and 12
    Notes
    [12] - 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: This endpoint pertains to subjects in Part B only
    End point values
    		 Part B: Placebo Part B: Evolocumab
    Number of subjects analysed
    16
    33
    Units: percent change
        least squares mean (standard error)
    4.22 ± 4.56
    -25.56 ± 3.28
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Part B: Placebo v Part B: Evolocumab
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [13]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -29.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.94
         upper limit
    		 -18.62
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.54
    Notes
    [13] - Model includes treatment group, baseline LDL-C level (< 420 mg/dL vs ≥ 420 mg/dL), scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

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

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    End point title
    		 Part B: Percent Change From Baseline in Apolipoprotein B at Week 12 [14]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    Notes
    [14] - 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: This endpoint pertains to subjects in Part B only
    End point values
    		 Part B: Placebo Part B: Evolocumab
    Number of subjects analysed
    16
    33
    Units: percent change
        least squares mean (standard error)
    3.97 ± 4.74
    -19.17 ± 3.46
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Part B: Placebo v Part B: Evolocumab
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [15]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -23.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.83
         upper limit
    		 -11.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.81
    Notes
    [15] - Model includes treatment group, baseline LDL-C level (< 420 mg/dL vs ≥ 420 mg/dL), scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

    Secondary: Part B: Mean Percent Change From Baseline in Apolipoprotein B at Weeks 6 and 12

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    End point title
    		 Part B: Mean Percent Change From Baseline in Apolipoprotein B at Weeks 6 and 12 [16]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 6 and 12
    Notes
    [16] - 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: This endpoint pertains to subjects in Part B only
    End point values
    		 Part B: Placebo Part B: Evolocumab
    Number of subjects analysed
    16
    33
    Units: percent change
        least squares mean (standard error)
    2.65 ± 4.42
    -20.24 ± 3.18
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Part B: Placebo v Part B: Evolocumab
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [17]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -22.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.72
         upper limit
    		 -12.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.38
    Notes
    [17] - Model includes treatment group, baseline LDL-C level (< 420 mg/dL vs ≥ 420 mg/dL), scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

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

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    End point title
    		 Part B: Percent Change From Baseline in Lipoprotein (a) at Week 12 [18]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    Notes
    [18] - 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: This endpoint pertains to subjects in Part B only
    End point values
    		 Part B: Placebo Part B: Evolocumab
    Number of subjects analysed
    16
    33
    Units: percent change
        least squares mean (standard error)
    2.43 ± 5.49
    -9.4 ± 4.07
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Part B: Placebo v Part B: Evolocumab
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.088 [19]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -11.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.48
         upper limit
    		 1.82
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.77
    Notes
    [19] - Model includes treatment group, baseline LDL-C level (< 420 mg/dL vs ≥ 420 mg/dL), scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

    Secondary: Part B: Mean Percent Change From Baseline in Lipoprotein (a) at Weeks 6 and 12

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    End point title
    		 Part B: Mean Percent Change From Baseline in Lipoprotein (a) at Weeks 6 and 12 [20]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 6 and 12
    Notes
    [20] - 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: This endpoint pertains to subjects in Part B only
    End point values
    		 Part B: Placebo Part B: Evolocumab
    Number of subjects analysed
    16
    33
    Units: percent change
        least squares mean (standard error)
    -1.43 ± 4.78
    -12.71 ± 3.53
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Part B: Placebo v Part B: Evolocumab
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.088 [21]
    Method
    		 Repeated measures linear effects
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -11.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.11
         upper limit
    		 0.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.86
    Notes
    [21] - Model includes treatment group, baseline LDL-C level (< 420 mg/dL vs ≥ 420 mg/dL), scheduled visit, and the interaction of treatment with scheduled visit. Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug until 28 days after the last dose (12 weeks).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Part A: Evolocumab
    Reporting group description
    		 Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks.

    Reporting group title
    Part B: Evolocumab
    Reporting group description
    		 Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks.

    Reporting group title
    Part B: Placebo
    Reporting group description
    		 Participants received double-blind placebo subcutaneously once a month for 12 weeks.

    Serious adverse events
    		 Part A: Evolocumab Part B: Evolocumab Part B: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part A: Evolocumab Part B: Evolocumab Part B: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 8 (50.00%)
    11 / 33 (33.33%)
    10 / 16 (62.50%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 33 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 33 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 33 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 33 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 33 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 33 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 33 (3.03%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    1
    Fatigue
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 33 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    Injection site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 33 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    Medical device site reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 33 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 33 (3.03%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 33 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 33 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 33 (3.03%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 33 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 33 (6.06%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    Influenza
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 33 (9.09%)
    0 / 16 (0.00%)
         occurrences all number
    0
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 33 (6.06%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 33 (9.09%)
    1 / 16 (6.25%)
         occurrences all number
    0
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Apr 2012
    - added optional visits for weeks 2 and 10, since more frequent visits would help mitigate against the risk of missing a detectable therapeutic effect - clarified that only phase 3 was blinded - added additional information about the analysis between the phases of the study - changed the sample size in phase 2 - updated safety reporting language
    24 May 2013
    - clarified that phase 2 was successfully completed and updated the primary, secondary and tertiary endpoints for phase 3 based on phase 2 data - added co-primary and co-secondary efficacy endpoints to include changes from baseline at the mean of weeks 6 and 12 and at the mean of weeks 8 and 12 for the lipid parameters (see Amendment 3 below for subsequent changes to these endpoints) - added treatment response (≥ 15% reduction in LDL-C at week 12) as an exploratory endpoint in phase 3 - added the LDLR Defective Analysis Set in phase 3 - added multiplicity adjustment methods - updated safety reporting language - allowed additional flexibility for specific visits - expanded age limit to include ≥ 12 to ≤ 80 years - added an exclusion criterion for lomitapide use - updated the list of participating countries - added new evolocumab formulation and autoinjector/pen (AI/pen) language - introduced the simplified terminology of monthly dosing (QM) - implemented minor editorial clarifications and corrections
    12 Nov 2013
    - removed the use of co-primary and co-secondary endpoints - made percent change in LDL-C from baseline to week 12 the primary endpoint - removed changes from baseline at the mean of weeks 8 and 12 from all endpoints, but kept changes from baseline to the mean of weeks 6 and 12 as secondary and exploratory endpoints

    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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