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    Clinical Trial Results:
    A RaNdomized Double-blInd Placebo ConTrolled Study Characterizing THe Effects of PCSK9 Inhibition On Arterial Wall Inflammation in Patients with Elevated Lp(a) (ANITSCHKOW)

    Summary
    EudraCT number
    		 2015-003731-35
    Trial protocol
    		 NL  
    Global end of trial date
    05 Apr 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Apr 2019
    First version publication date
    14 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20130293
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02729025
    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
    05 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the effect of evolocumab on arterial wall inflammation, as measured by percent change from baseline in target-to-background ratio (TBR) of an index vessel by fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) at week 16 in subjects with baseline lipoprotein(a) (Lp[a]) ≥ 50 mg/dL and low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL.
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines, and Food and Drug Administration (FDA) regulations and guidelines set forth in 21 Code of Federal Regulations parts 11, 50, 54, 56, and 312. The study and all amendments were reviewed by an independent ethics committee (IEC) or institutional review board (IRB). 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
    14 Apr 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 90
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    United States: 18
    Worldwide total number of subjects
    129
    EEA total number of subjects
    90
    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)
    89
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 14 centers in Canada, the Netherlands, and the United States. Participants were enrolled from 14 April 2016 to 07 December 2017.

    Pre-assignment
    Screening details
    		 Eligible participants were randomized in a 1:1 ratio to receive either evolocumab or placebo. Randomization was stratified by baseline background statin therapy (on statin versus not on statin) and by screening lipoprotein(a) (Lp(a)) (< 175 mg/dL or ≥ 175 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
    		 Investigator, Data analyst, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo to evolocumab by subcutaneous injection once a month (QM) for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously once a month using an autoinjector/pen.

    Arm title
    		 Evolocumab 420 mg QM
    Arm description
    		 Participants received 420 mg evolocumab by subcutaneous injection 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 in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously once a month using an autoinjector/pen.

    Number of subjects in period 1
    		Placebo Evolocumab 420 mg QM
    Started
    64
    65
    Completed
    64
    64
    Not completed
    0
    1
         Sponsor Decision
    -
    1

    Baseline characteristics

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

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

    Reporting group values
    		 Placebo Evolocumab 420 mg QM Total
    Number of subjects
    		 64 65 129
    Age, Customized
    Units: Subjects
        18 - 64 years
    		 41 48 89
        ≥ 65 years
    		 23 17 40
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.7 ( 7.6 ) 60.0 ( 6.8 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 30 39 69
        Male
    		 34 26 60
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 3 2 5
        Black or African American
    		 2 4 6
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        White
    		 58 58 116
        Other
    		 0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 1 1
        Not Hispanic or Latino
    		 64 64 128
        Unknown or Not Reported
    		 0 0 0
    Location of the Index Vessel Used for Calculation of Maximum Target-to-background Ratio
    The index vessel used to calculate the mean of the maximum target-to-background ratio in the most diseased segment at baseline. Using quantitative fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) image analysis, the artery (right carotid, left carotid, or thoracic aorta) with the highest FDG uptake (highest mean of the maximum target-to-background ratio at baseline) was identified as the index vessel.
    Units: Subjects
        Ascending thoracic aorta
    		 54 49 103
        Left common carotid
    		 1 3 4
        Right common carotid
    		 8 11 19
        Missing
    		 1 2 3
    Stratification Factor: Baseline Statin Therapy
    Units: Subjects
        Yes
    		 33 34 67
        No
    		 31 31 62
    Stratification Factor: Screening Lipoprotein(a) (Lp[a]) Level
    Units: Subjects
        < 175 mg/dL
    		 60 61 121
        ≥ 175 mg/dL
    		 4 4 8
    Maximum Target-to-background Ratio (TBR) in the Most Diseased Section in the Index Vessel
    Arterial inflammation was assessed using 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography (FDG PET/CT). Maximum standardized uptake was calculated as time- and dose- corrected tissue radioactivity divided by body weight in the index vessel. TBR was calculated from the ratio of the standardized uptake value of the artery compared to mean background venous activity. Maximum TBR in the most diseased segment was from 3 contiguous slices (approx. 1.5 cm), centered on the slice with the highest maximum TBR in the index vessel. Data were available for 63 subjects in each arm.
    Units: ratio
        arithmetic mean (standard deviation)
    		 2.28765 ( 0.41284 ) 2.29667 ( 0.46063 ) -
    Lipoprotein(a) Concentration
    Units: nmol/L
        median (inter-quartile range (Q1-Q3))
    		 198.0 (151.3 to 300.0) 203.0 (162.5 to 301.5) -
    Low-density Lipoprotein Cholesterol (LDL-C) Concentration
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 141.7 ( 35.7 ) 146.2 ( 43.5 ) -
    Apolipoprotein B Concentration
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 108.0 ( 22.9 ) 109.9 ( 23.7 ) -

    End points

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

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

    Primary: Percent Change from Baseline in Maximum Target-to-background Ratio in the Most Diseased Segment of the Index Vessel at Week 16

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    End point title
    		 Percent Change from Baseline in Maximum Target-to-background Ratio in the Most Diseased Segment of the Index Vessel at Week 16
    End point description
    Arterial inflammation was assessed using 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT). Arterial 18F-FDG uptake is correlated with arterial macrophage content and predicts cardiovascular events. Images were analyzed by an experienced radiologist blinded to all patient characteristics. The maximum standardized uptake value was calculated as a time- and dose- corrected tissue radioactivity divided by body weight in the index and the target-to-background ratio (TBR) was calculated from the ratio of the standardized uptake value of the artery compared to mean background venous activity. The average maximum TBR for the most diseased segment (MDS) was calculated from a group of 3 contiguous slices (approximately 1.5 cm), centered on the slice with the highest maximum TBR in the index vessel. The index vessel was defined as the vessel (either the right or left carotid or aorta) with the highest mean TBR at baseline.
    End point type
    Primary
    End point timeframe
    Baseline and week 16
    End point values
    		 Placebo Evolocumab 420 mg QM
    Number of subjects analysed
    63
    63
    Units: percent change
        least squares mean (standard error)
    -5.31 ( 1.67 )
    -8.31 ( 1.67 )
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    A multivariate regression was modelled on the primary endpoint as well as three other response variables (percent change in Lp[a] at Weeks 8 and 16, baseline MDS TBR, and baseline Lp[a]). The primary endpoint was regressed on the treatment group and statin stratification factor; baseline MDS TBR and Lp(a) were regressed on the statin stratification factor, and percent changes in Lp(a) were regressed on the treatment group, statin stratification factor, visit, and treatment group by visit.
    Comparison groups
    Placebo v Evolocumab 420 mg QM
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 Multivariate regression model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.4
         upper limit
    		 1.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.24

    Secondary: Percent Change from Baseline in Lipoprotein(a) Concentration at Week 16

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    End point title
    		 Percent Change from Baseline in Lipoprotein(a) Concentration at Week 16
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 16
    End point values
    		 Placebo Evolocumab 420 mg QM
    Number of subjects analysed
    61
    63
    Units: percent change
        least squares mean (standard error)
    1.06 ( 1.94 )
    -12.83 ( 1.92 )
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab 420 mg QM
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -13.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.29
         upper limit
    		 -8.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.73
    Notes
    [1] - The model included treatment group, statin stratification, scheduled visit, and the interaction of treatment with scheduled visit.

    Secondary: Percent Change from Baseline in Low-density Lipoprotein Cholesterol (LDL-C) Concentration at Week 16

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    End point title
    		 Percent Change from Baseline in Low-density Lipoprotein Cholesterol (LDL-C) Concentration at Week 16
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 16
    End point values
    		 Placebo Evolocumab 420 mg QM
    Number of subjects analysed
    59
    62
    Units: percent change
        least squares mean (standard error)
    1.64 ( 1.86 )
    -59.02 ( 1.82 )
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab 420 mg QM
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -60.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -65.81
         upper limit
    		 -55.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.6
    Notes
    [2] - The model included treatment group, statin stratification, scheduled visit, and the interaction of treatment with scheduled visit.

    Secondary: Percent Change from Baseline in Apolipoprotein B Concentration at Week 16

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    End point title
    		 Percent Change from Baseline in Apolipoprotein B Concentration at Week 16
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 16
    End point values
    		 Placebo Evolocumab 420 mg QM
    Number of subjects analysed
    61
    63
    Units: percent change
        least squares mean (standard error)
    3.29 ( 1.53 )
    -48.30 ( 1.51 )
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Placebo v Evolocumab 420 mg QM
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Repeated measures linear effects model
    Parameter type
    		 LS Mean Treatment Difference
    Point estimate
    -51.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -55.85
         upper limit
    		 -47.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.15
    Notes
    [3] - The model included treatment group, statin stratification, scheduled visit, and the interaction of treatment with scheduled visit.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug up to 30 days after the last dose or until the end of study date, whichever was earlier; the maximum duration of treatment was 3.9 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Evolocumab 420 mg QM
    Reporting group description
    		 Participants received 420 mg evolocumab by subcutaneous injection once a month (QM) for 12 weeks.

    Reporting group title
    Placebo QM
    Reporting group description
    		 Participants received placebo to evolocumab by subcutaneous injection once a month (QM) for 12 weeks.

    Serious adverse events
    		 Evolocumab 420 mg QM Placebo QM
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 64 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Evolocumab 420 mg QM Placebo QM
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 65 (75.38%)
    47 / 64 (73.44%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Dysplastic naevus
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Hot flush
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    3 / 65 (4.62%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    Peripheral coldness
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Bunion operation
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 65 (0.00%)
    3 / 64 (4.69%)
         occurrences all number
    0
    5
    Chills
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Drug intolerance
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    2
    Fatigue
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 64 (1.56%)
         occurrences all number
    2
    2
    Influenza like illness
         subjects affected / exposed
    4 / 65 (6.15%)
    4 / 64 (6.25%)
         occurrences all number
    5
    4
    Injection site hypersensitivity
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Injection site pain
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Injection site rash
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Nodule
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Hypersensitivity
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Seasonal allergy
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Reproductive system and breast disorders
    Menopausal symptoms
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 64 (3.13%)
         occurrences all number
    1
    2
    Epistaxis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Pharyngeal inflammation
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 64 (1.56%)
         occurrences all number
    1
    2
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 64 (0.00%)
         occurrences all number
    4
    0
    Irritability
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Weight increased
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Bone contusion
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Epicondylitis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Ligament sprain
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Post-traumatic pain
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Procedural pain
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Vaccination complication
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Congenital, familial and genetic disorders
    Dermoid cyst
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Muscular dystrophy
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Cervical radiculopathy
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    3 / 65 (4.62%)
    1 / 64 (1.56%)
         occurrences all number
    4
    1
    Headache
         subjects affected / exposed
    4 / 65 (6.15%)
    7 / 64 (10.94%)
         occurrences all number
    5
    8
    Hypoaesthesia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Lethargy
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Memory impairment
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Migraine
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Paraesthesia
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 64 (3.13%)
         occurrences all number
    1
    2
    Retinal migraine
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Speech disorder
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Excessive cerumen production
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Eye disorders
    Keratitis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Visual impairment
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Abdominal pain
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain lower
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Dental caries
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 65 (1.54%)
    5 / 64 (7.81%)
         occurrences all number
    1
    6
    Dyspepsia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Food poisoning
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    1 / 65 (1.54%)
    5 / 64 (7.81%)
         occurrences all number
    1
    5
    Oesophageal pain
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Peptic ulcer
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Dry skin
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Eczema
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Erythema
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Hyperkeratosis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Psoriasis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Rash erythematous
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Rosacea
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Arthritis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    1 / 65 (1.54%)
    3 / 64 (4.69%)
         occurrences all number
    1
    3
    Bursitis
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 64 (3.13%)
         occurrences all number
    1
    2
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    3 / 65 (4.62%)
    0 / 64 (0.00%)
         occurrences all number
    4
    0
    Muscle twitching
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    3 / 65 (4.62%)
    2 / 64 (3.13%)
         occurrences all number
    3
    2
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    5 / 65 (7.69%)
    1 / 64 (1.56%)
         occurrences all number
    5
    2
    Osteoarthritis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 64 (1.56%)
         occurrences all number
    2
    1
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Tendonitis
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Cellulitis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Erysipelas
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Eye infection
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Folliculitis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    H1N1 influenza
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Herpes zoster
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Heterophyiasis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    7 / 65 (10.77%)
    3 / 64 (4.69%)
         occurrences all number
    7
    3
    Nail infection
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    6 / 65 (9.23%)
    13 / 64 (20.31%)
         occurrences all number
    6
    14
    Otitis externa
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Root canal infection
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 65 (3.08%)
    2 / 64 (3.13%)
         occurrences all number
    2
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 65 (1.54%)
    3 / 64 (4.69%)
         occurrences all number
    1
    3
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jan 2016
    - The age of the patients included in the study was amended from ≥ 45 to ≥ 50 years to meet the radiation dose limit required by the Dutch ethics committee. - The study schema was updated for clarity. - The primary and exploratory endpoints were reworded for clarity and the methods of analysis for the primary endpoint further detailed.
    25 Aug 2016
    - Clarification was provided to minimize the risk of confounding the primary endpoint with prior therapies targeting Lp(a); an exclusion criterion was added to exclude subjects with exposure to therapies targeting Lp(a) within the 12 months prior to screening. - The timing and method of pregnancy testing was clarified. - Additional details regarding the volume of blood drawn to satisfy the existing protocol-specified laboratory testing was included.
    08 Feb 2017
    - Blinding of central laboratory test results during the double-blind treatment period was clarified. - Guidance in obtaining local lipid panels was provided.

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

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