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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effect of Praluent on Neurocognitive Function in Patients with Heterozygous Familial Hypercholesterolemia or with Non-Familial Hypercholesterolemia at High and Very High Cardiovascular Risk

    Summary
    EudraCT number
    2016-003189-16
    Trial protocol
    EE   BG   SK  
    Global end of trial date
    05 Mar 2020

    Results information
    Results version number
    v2(current)
    This version publication date
    02 Jul 2021
    First version publication date
    20 Mar 2021
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    R727-CL-1532
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03694197
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc
    Sponsor organisation address
    777 Old Saw Mill River Rd., Tarrytown, NY, United States, 10591
    Public contact
    Clinical Trial Management, Regeneron Pharmaceuticals, Inc, 001 844-734-6643, clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trial Management, Regeneron Pharmaceuticals, Inc, 001 844-734-6643, clinicaltrials@regeneron.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 Mar 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study was to evaluate the effect on mental state (known as "neurocognitive function") with use of Praluent.
    Protection of trial subjects
    This clinical study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory requirements.
    Background therapy
    Background treatment with lipid modifying therapies (LMT) was allowed for all subjects (those who are using concomitant statins and for those who are not). The background LMT dose remained stable throughout the entire study, from screening to the end of study visit.
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Nov 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
    Chile: 67
    Country: Number of subjects enrolled
    Japan: 35
    Country: Number of subjects enrolled
    Mexico: 157
    Country: Number of subjects enrolled
    Russian Federation: 284
    Country: Number of subjects enrolled
    South Africa: 386
    Country: Number of subjects enrolled
    Ukraine: 358
    Country: Number of subjects enrolled
    United States: 690
    Country: Number of subjects enrolled
    Bulgaria: 157
    Country: Number of subjects enrolled
    Estonia: 42
    Worldwide total number of subjects
    2176
    EEA total number of subjects
    199
    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)
    1229
    From 65 to 84 years
    945
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 2176 subjects were randomized across 169 sites in Bulgaria, Chile, Estonia, Japan, Mexico, Russian Federation, South Africa, Ukraine, and the United States.

    Pre-assignment
    Screening details
    Subjects who met the eligibility criteria were randomized in 1:1 ratio into 2 treatment groups: placebo and alirocumab. Randomization was stratified by age (less than [<] 65 or greater than or equal to [>=] 65) and by statin use (no statin, low lipophilicity of the concomitant statin, or high lipophilicity of the concomitant statin).

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received subcutaneous (SC) injections of placebo matched to alirocumab every 2 weeks (Q2W) up to 94 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
    Placebo-matching alirocumab

    Arm title
    Alirocumab 75 Q2W/Up150 Q2W
    Arm description
    Subjects received SC injections of alirocumab at a dose of 75 milligrams (mg) Q2W and up-titrated to 150 mg Q2W at Week 12 in a blinded fashion (if LDL-C ≥ 50 mg/dL at Week 8) up to 94 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    SUB74847
    Other name
    Praluent
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    75mg Q2W up to 150mg Q2W

    Number of subjects in period 1
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Started
    1088
    1088
    Randomized and treated
    1085
    1086
    Completed
    890
    919
    Not completed
    198
    169
         Study Terminated by Sponsor
    4
    3
         Related to IMP Administration
    3
    6
         Poor Compliance to Protocol
    30
    26
         Physician decision
    4
    4
         Discont’d After Randomization, Prior to Treatment
    3
    2
         Subject Moved
    10
    16
         Adverse event, non-fatal
    64
    67
         Non-disclosed
    16
    12
         Consent withdrawn by subject
    64
    33

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received subcutaneous (SC) injections of placebo matched to alirocumab every 2 weeks (Q2W) up to 94 weeks.

    Reporting group title
    Alirocumab 75 Q2W/Up150 Q2W
    Reporting group description
    Subjects received SC injections of alirocumab at a dose of 75 milligrams (mg) Q2W and up-titrated to 150 mg Q2W at Week 12 in a blinded fashion (if LDL-C ≥ 50 mg/dL at Week 8) up to 94 weeks.

    Reporting group values
    Placebo Alirocumab 75 Q2W/Up150 Q2W Total
    Number of subjects
    1088 1088 2176
    Age categorical
    Safety population (SAF) included all subjects randomized and exposed to at least one dose of study drug, regardless of the amount of treatment administered (SAF population of subjects: Placebo=1084; Alirocumab=1087)
    Units: Subjects
        <45 years
    26 23 49
        >=45 to <65 years
    587 589 1176
        >=65 to <75 years
    374 369 743
        >=75
    97 106 203
        Subjects not included in SAF
    4 1 5
    Age Continuous
    Safety population (SAF) included all subjects randomized and exposed to at least one dose of study drug, regardless of the amount of treatment administered (SAF population of subjects: Placebo=1084; Alirocumab=1087)
    Units: years
        arithmetic mean (standard deviation)
    62.7 ± 9.02 62.6 ± 8.88 -
    Sex: Female, Male
    Safety population (SAF) included all subjects randomized and exposed to at least one dose of study drug, regardless of the amount of treatment administered (SAF population of subjects: Placebo=1084; Alirocumab=1087)
    Units: Subjects
        Female
    459 448 907
        Male
    625 639 1264
        Subjects not included in SAF
    4 1 5
    Ethnicity (NIH/OMB)
    Safety population (SAF) included all subjects randomized and exposed to at least one dose of study drug, regardless of the amount of treatment administered (SAF population of subjects: Placebo=1084; Alirocumab=1087)
    Units: Subjects
        Hispanic or Latino
    137 142 279
        Not Hispanic or Latino
    945 943 1888
        Unknown or Not Reported
    2 2 4
        Subjects not included in SAF
    4 1 5
    Race/Ethnicity, Customized
    Race; Safety population (SAF) included all subjects randomized and exposed to at least one dose of study drug, regardless of the amount of treatment administered (SAF population of subjects: Placebo=1084; Alirocumab=1087)
    Units: Subjects
        White
    888 886 1774
        Black or African American
    86 77 163
        Asian
    19 28 47
        American Indian or Alaska Native
    11 16 27
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Other
    80 80 160
        Subjects not included in SAF
    4 1 5
    CANTAB Cognitive Domain Spatial Working Memory (SWM) Strategy Raw Score
    Cambridge Neuropsychological Test Automated Battery (CANTAB) SWM task assessed cognitive domain of executive function. Colored boxes were shown on a screen. A token was hidden in a box. Subjects touched boxes to search for token until #of tokens found = #of boxes. SWM strategy index is #of times search began w/ a different box. Baseline score = last score before 1st dose. Raw score ranges from 4 to 28; high score = inefficient strategy. Primary safety population (subjects w/ SWM score at baseline and at least 1 score during treatment period (Placebo=1035; Alirocumab=1051))
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    15.9 ± 5.03 16.0 ± 5.11 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received subcutaneous (SC) injections of placebo matched to alirocumab every 2 weeks (Q2W) up to 94 weeks.

    Reporting group title
    Alirocumab 75 Q2W/Up150 Q2W
    Reporting group description
    Subjects received SC injections of alirocumab at a dose of 75 milligrams (mg) Q2W and up-titrated to 150 mg Q2W at Week 12 in a blinded fashion (if LDL-C ≥ 50 mg/dL at Week 8) up to 94 weeks.

    Primary: Change From Baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Cognitive Domain Spatial Working Memory (SWM) Strategy Z-Score at Week 96

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    End point title
    Change From Baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Cognitive Domain Spatial Working Memory (SWM) Strategy Z-Score at Week 96
    End point description
    CANTAB SWM task assessed cognitive domain of executive function. Colored boxes were shown on a computer screen. One at a time, a token was hidden in a box (never same box twice). Instructions were to touch boxes to search for token. Search continued until # of tokens found was = to # of boxes. SWM strategy index represents # of times a subject began a search with a different box. Z-score represents standardized measure of how far an individual deviated from study cohort average at baseline. A higher Z-score reflects better performance. Primary safety population (subjects from safety population who had an SWM strategy score at baseline & at least 1 score measured during treatment-emergent adverse event (TEAE) period (first double-blind treatment dose to last dose of double-blind treatment + 70 days). Subjects analyzed according to treatment actually received.
    End point type
    Primary
    End point timeframe
    Week 96
    End point values
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Number of subjects analysed
    1035
    1051
    Units: Z-score
        least squares mean (standard error)
    -0.180 ± 0.027
    -0.200 ± 0.027
    Statistical analysis title
    Alirocumab 75 Q2W/Up150 Q2W, Placebo
    Statistical analysis description
    Change at Week 96
    Comparison groups
    Alirocumab 75 Q2W/Up150 Q2W v Placebo
    Number of subjects included in analysis
    2086
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    = 0.6055 [2]
    Method
    Mixed-effect Model Repeated Measures
    Parameter type
    Least Square (LS) Mean Difference
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.094
         upper limit
    0.055
    Notes
    [1] - Upper confidence interval (CI) limit was compared to the noninferiority margin, which was 0.2%, and noninferiority was declared if the upper CI limit was below the noninferiority margin.
    [2] - P-value was taken from mixed-effect model with repeated measures (MMRM) analysis.

    Secondary: Change From Baseline in CANTAB Cognitive Domain SWM Strategy Raw Score at Week 96

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    End point title
    Change From Baseline in CANTAB Cognitive Domain SWM Strategy Raw Score at Week 96
    End point description
    CANTAB SWM task assessed cognitive domain of executive function. Colored boxes were shown on a screen. A token was hidden in one of the boxes (never same box twice). Instructions were to touch boxes to search for token until number of tokens found equaled number of boxes. SWM strategy index represents number of times a search began with a different box. Lower change from baseline raw scores reflect better SWM performance (i.e. less impairment). Primary safety population included subjects from the safety population who had an assessment of the SWM strategy score at baseline, and at least 1 score measured during the treatment-emergent adverse event (TEAE) period. The TEAE period is defined as the first double-blind treatment dose to last dose of double-blind treatment + 70 days (10 weeks). Subjects were analyzed according to the treatment actually received.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Number of subjects analysed
    868
    901
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    -0.9 ± 4.49
    -1.0 ± 4.31
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Calculated Low-density Lipoprotein Cholesterol (LDL-C) at Week 12, 24, 48, 72, and 96

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    End point title
    Percent Change From Baseline in Calculated Low-density Lipoprotein Cholesterol (LDL-C) at Week 12, 24, 48, 72, and 96
    End point description
    Percent change from baseline in calculated LDL-C at Week 12, 24, 48, 72, and 96 was reported. LDL-C was measured using conventional units milligram per deciliter (mg/dL). Intent-to-treat (ITT) population included all subjects with availability of at least 1 measurement value for calculated LDL-C before first dose of study drug (i.e. baseline) and within 1 of the analysis windows during the main efficacy period; the main efficacy period is defined as the time from the first double-blind study treatment injection up to the upper limit of the week 96 analysis window. ITT population analyzed according to treatment group allocated by randomization (as-randomized).
    End point type
    Secondary
    End point timeframe
    Week 12, 24, 48, 72, and 96
    End point values
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Number of subjects analysed
    1051
    1058
    Units: Percent Change
    least squares mean (standard error)
        Percent change at Week 12
    0.6 ± 1.0
    -49.6 ± 0.9
        Percent change at Week 24
    3.0 ± 1.0
    -54.2 ± 1.0
        Percent change at Week 48
    2.8 ± 1.1
    -51.4 ± 1.1
        Percent change at Week 72
    2.4 ± 1.2
    -50.4 ± 1.2
        Percent change at Week 96
    4.0 ± 1.3
    -46.2 ± 1.3
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Apolipoprotein (Apo) B at Week 12, 24, 48, 72, and 96

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    End point title
    Percent Change From Baseline in Apolipoprotein (Apo) B at Week 12, 24, 48, 72, and 96
    End point description
    Percent change from baseline in Apo B at Week 12, 24, 48, 72, and 96 was reported. Apo B was measured using conventional units mg/dL. ITT population included all subjects with availability of at least 1 measurement value for calculated LDL-C before first dose of study drug (i.e. baseline) and within 1 of the analysis windows during the main efficacy period; the main efficacy period is defined as the time from the first double-blind study treatment injection up to the upper limit of the week 96 analysis window. ITT population analyzed according to treatment group allocated by randomization (as-randomized).
    End point type
    Secondary
    End point timeframe
    Week 12, 24, 48, 72, and 96
    End point values
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Number of subjects analysed
    1051
    1058
    Units: Percent Change
    least squares mean (standard error)
        Percent change at Week 12
    0.8 ± 0.7
    -36.7 ± 0.7
        Percent change at Week 24
    2.1 ± 0.8
    -40.9 ± 0.8
        Percent change at Week 48
    1.1 ± 0.8
    -39.0 ± 0.8
        Percent change at Week 72
    0.2 ± 0.9
    -39.1 ± 0.8
        Percent change at Week 96
    1.4 ± 0.9
    -36.4 ± 0.9
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (non-HDL-C) at Week 12, 24, 48, 72, and 96

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    End point title
    Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (non-HDL-C) at Week 12, 24, 48, 72, and 96
    End point description
    Percent change from baseline in non-HDL-C at Week 12, 24, 48, 72, and 96 was reported. Non-HDL-C was measured using conventional units mg/dL. ITT population included all subjects with availability of at least 1 measurement value for calculated LDL-C before first dose of study drug (i.e. baseline) and within 1 of the analysis windows during the main efficacy period; the main efficacy period is defined as the time from the first double-blind study treatment injection up to the upper limit of the week 96 analysis window. ITT population analyzed according to treatment group allocated by randomization (as-randomized).
    End point type
    Secondary
    End point timeframe
    Week 12, 24, 48, 72, and 96
    End point values
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Number of subjects analysed
    1051
    1058
    Units: Percent Change
    least squares mean (standard error)
        Percent change at Week 12
    0.7 ± 0.8
    -40.4 ± 0.8
        Percent change at Week 24
    2.2 ± 0.9
    -44.0 ± 0.9
        Percent change at Week 48
    1.7 ± 0.9
    -41.1 ± 0.9
        Percent change at Week 72
    1.7 ± 1.0
    -40.6 ± 1.0
        Percent change at Week 96
    2.5 ± 1.1
    -37.0 ± 1.1
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Total Cholesterol (Total-C) at Week 12, 24, 48, 72, and 96

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    End point title
    Percent Change From Baseline in Total Cholesterol (Total-C) at Week 12, 24, 48, 72, and 96
    End point description
    Percent change from baseline in calculated Total-C at Week 12, 24, 48, 72, and 96 was reported. Total-C was measured using conventional units mg/dL. ITT population included all subjects with availability of at least 1 measurement value for calculated LDL-C before first dose of study drug (i.e. baseline) and within 1 of the analysis windows during the main efficacy period; the main efficacy period is defined as the time from the first double-blind study treatment injection up to the upper limit of the week 96 analysis window. ITT population analyzed according to treatment group allocated by randomization (as-randomized).
    End point type
    Secondary
    End point timeframe
    Week 12, 24, 48, 72, and 96
    End point values
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Number of subjects analysed
    1051
    1058
    Units: Percent Change
    least squares mean (standard error)
        Percent change at Week 12
    -0.3 ± 0.6
    -29.6 ± 0.6
        Percent change at Week 24
    1.5 ± 0.6
    -31.8 ± 0.6
        Percent change at Week 48
    1.1 ± 0.7
    -29.6 ± 0.7
        Percent change at Week 72
    1.1 ± 0.7
    -29.0 ± 0.7
        Percent change at Week 96
    1.8 ± 0.7
    -26.5 ± 0.7
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Lipoprotein a [Lp(a)] at Week 12, 24, 48, 72, and 96

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    End point title
    Percent Change From Baseline in Lipoprotein a [Lp(a)] at Week 12, 24, 48, 72, and 96
    End point description
    Percent change from baseline in Lp(a) at Week 12, 24, 48, 72, and 96 was reported. Lp(a) was measured using conventional units mg/dL. ITT Population was used. The two-step multiple imputation procedure is used to address missing values in the randomized population. In the first step, the monotone missing pattern is induced in the multiply-imputed data. In the second step, the missing data at subsequent visits are imputed using the regression method for continuous variables.
    End point type
    Secondary
    End point timeframe
    Week 12, 24, 48, 72, and 96
    End point values
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Number of subjects analysed
    1051
    1058
    Units: Percent Change
    least squares mean (standard error)
        Percent change at Week 12
    -3.3 ± 0.8
    -22.4 ± 0.8
        Percent change at Week 24
    -0.5 ± 0.9
    -24.7 ± 0.9
        Percent change at Week 48
    -1.4 ± 1.0
    -24.3 ± 1.0
        Percent change at Week 72
    -1.7 ± 1.0
    -25.1 ± 1.0
        Percent change at Week 96
    4.8 ± 1.1
    -17.7 ± 1.1
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 12, 24, 48, 72, and 96

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    End point title
    Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 12, 24, 48, 72, and 96
    End point description
    Percent change from baseline in HDL-C at Week 12, 24, 48, 72, and 96 was reported. HDL-C was measured using conventional units mg/dL. ITT population included all subjects with availability of at least 1 measurement value for calculated LDL-C before first dose of study drug (i.e. baseline) and within 1 of the analysis windows during the main efficacy period; the main efficacy period is defined as the time from the first double-blind study treatment injection up to the upper limit of the week 96 analysis window. ITT population analyzed according to treatment group allocated by randomization (as-randomized).
    End point type
    Secondary
    End point timeframe
    Week 12, 24, 48, 72, and 96
    End point values
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Number of subjects analysed
    1051
    1058
    Units: Percent Change
    least squares mean (standard error)
        Percent change at Week 12
    0.6 ± 0.5
    5.9 ± 0.5
        Percent change at Week 24
    3.8 ± 0.6
    9.0 ± 0.6
        Percent change at Week 48
    3.8 ± 0.6
    9.2 ± 0.6
        Percent change at Week 72
    4.4 ± 0.7
    10.3 ± 0.6
        Percent change at Week 96
    5.5 ± 0.7
    10.8 ± 0.7
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Triglycerides (TG) at Week 12, 24, 48, 72, and 96

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    End point title
    Percent Change From Baseline in Triglycerides (TG) at Week 12, 24, 48, 72, and 96
    End point description
    Percent change from baseline in TG at Week 12, 24, 48, 72, and 96 was reported. TG was measured using conventional units mg/dL. ITT population was used. The two-step multiple imputation procedure is used to address missing values in the randomized population. In the first step, the monotone missing pattern is induced in the multiply-imputed data. In the second step, the missing data at subsequent visits are imputed using the regression method for continuous variables.
    End point type
    Secondary
    End point timeframe
    Week 12, 24, 48, 72, and 96
    End point values
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Number of subjects analysed
    1051
    1058
    Units: Percent Change
    least squares mean (standard error)
        Percent change at Week 12
    0.7 ± 1.0
    -11.0 ± 1.0
        Percent change at Week 24
    -1.8 ± 1.0
    -12.9 ± 1.0
        Percent change at Week 48
    -1.8 ± 1.1
    -11.3 ± 1.1
        Percent change at Week 72
    -2.1 ± 1.1
    -12.3 ± 1.1
        Percent change at Week 96
    -2.7 ± 1.1
    -11.9 ± 1.1
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Apolipoprotein (Apo) A-1 at Week 12, 24, 48, 72, and 96

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    End point title
    Percent Change From Baseline in Apolipoprotein (Apo) A-1 at Week 12, 24, 48, 72, and 96
    End point description
    Percent change from baseline in Apo A-1 at Week 12, 24, 48, 72, and 96 was reported. Apo A-1 was measured using conventional units mg/dL. ITT population included all subjects with availability of at least 1 measurement value for calculated LDL-C before first dose of study drug (i.e. baseline) and within 1 of the analysis windows during the main efficacy period; the main efficacy period is defined as the time from the first double-blind study treatment injection up to the upper limit of the week 96 analysis window. ITT population analyzed according to treatment group allocated by randomization (as-randomized).
    End point type
    Secondary
    End point timeframe
    Week 12, 24, 48, 72, and 96
    End point values
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Number of subjects analysed
    1051
    1058
    Units: Percent Change
    least squares mean (standard error)
        Percent change at Week 12
    -1.3 ± 0.4
    1.7 ± 0.4
        Percent change at Week 24
    2.9 ± 0.4
    6.1 ± 0.4
        Percent change at Week 48
    4.7 ± 0.4
    7.7 ± 0.4
        Percent change at Week 72
    4.4 ± 0.4
    7.8 ± 0.4
        Percent change at Week 96
    4.2 ± 0.4
    7.5 ± 0.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Reached Low-Density Lipoprotein Cholesterol (LDL-C) Level Less Than (<) 70 mg/dL (1.81 Millimoles per Liter [mmol/L]) at Week 12, 24, 48, 72, and 96

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    End point title
    Percentage of Subjects Who Reached Low-Density Lipoprotein Cholesterol (LDL-C) Level Less Than (<) 70 mg/dL (1.81 Millimoles per Liter [mmol/L]) at Week 12, 24, 48, 72, and 96
    End point description
    Percentage of subjects who reached LDL-C level < 70 mg/dL (1.81 mmol/L) at Week 12, 24, 48, 72, and 96 were reported. ITT population was used. The two-step multiple imputation procedure is used to address missing values in the randomized population. In the first step, the monotone missing pattern is induced in the multiply-imputed data. In the second step, the missing data at subsequent visits are imputed using the regression method for continuous variables.
    End point type
    Secondary
    End point timeframe
    Week 12, 24, 48, 72, and 96
    End point values
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Number of subjects analysed
    1051
    1058
    Units: Percentage of Subjects
    number (not applicable)
        Week 12
    10.3
    69.4
        Week 24
    8.4
    74.7
        Week 48
    10.7
    71.4
        Week 72
    11.3
    69.7
        Week 96
    10.7
    64.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Reached Low-Density Lipoprotein Cholesterol (LDL-C) Level Less Than (<) 50 mg/dL (1.29 mmol/L) at Week 12, 24, 48, 72, and 96

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    End point title
    Percentage of Subjects Who Reached Low-Density Lipoprotein Cholesterol (LDL-C) Level Less Than (<) 50 mg/dL (1.29 mmol/L) at Week 12, 24, 48, 72, and 96
    End point description
    Percentage of subjects who reached LDL-C level < 50 mg/dL (1.29 mmol/L) at Week 12, 24, 48, 72, and 96 were reported. ITT population was used. The two-step multiple imputation procedure is used to address missing values in the randomized population. In the first step, the monotone missing pattern is induced in the multiply-imputed data. In the second step, the missing data at subsequent visits are imputed using the regression method for continuous variables.
    End point type
    Secondary
    End point timeframe
    Week 12, 24, 48, 72, and 96
    End point values
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Number of subjects analysed
    1051
    1058
    Units: Percentage of Subjects
    number (not applicable)
        Week 12
    1.7
    45.6
        Week 24
    2.0
    56.9
        Week 48
    2.1
    51.3
        Week 72
    2.5
    52.1
        Week 96
    2.4
    46.4
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
    End point description
    An Adverse Event (AE) was any untoward medical occurrence in a subject administered a study drug which may or may not have a causal relationship with the study drug. TEAE was defined as AEs that developed or worsened/became serious during on-treatment period (time from the first double-blind study treatment injection up to 70 days after the last double-blind study treatment injection). A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-subject hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included subjects with both serious and non-serious AEs. Safety analysis set (SAF) (included all subjects randomized and exposed to at least 1 dose of study drug, regardless of the amount of treatment administered)
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Number of subjects analysed
    1084
    1087
    Units: Subjects
        Subjects with any TEAEs
    857
    866
        Subjects with any Serious TEAEs
    216
    189
        Subjects with any TEAE leading to death
    17
    13
        TEAE leading to treatment discontinuation
    59
    64
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to the end of study (Week 96) regardless of seriousness or relationship to investigational product (IP).
    Adverse event reporting additional description
    Safety population included all subjects randomized and exposed to at least one dose of study drug, regardless of the amount of treatment administered. Subjects were analyzed according to the treatment received (placebo or Praluent 75 mg Q2W/up-titrate 150 mg Q2W).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received subcutaneous (SC) injections of placebo matched to alirocumab every 2 weeks (Q2W) up to 94 weeks.

    Reporting group title
    Alirocumab 75 Q2W/Up150 Q2W
    Reporting group description
    Subjects received SC injections of alirocumab at a dose of 75 milligrams (mg) Q2W and up-titrated to 150 mg Q2W at Week 12 in a blinded fashion (if LDL-C ≥ 50 mg/dL at Week 8) up to 94 weeks.

    Serious adverse events
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    216 / 1084 (19.93%)
    189 / 1087 (17.39%)
         number of deaths (all causes)
    24
    17
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 1084 (0.65%)
    6 / 1087 (0.55%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    3 / 1084 (0.28%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    3 / 1084 (0.28%)
    3 / 1087 (0.28%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    3 / 1084 (0.28%)
    4 / 1087 (0.37%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 1084 (0.18%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    2 / 1084 (0.18%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dry gangrene
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paget-Schroetter syndrome
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cardiac pacemaker replacement
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hospitalisation
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    3 / 1084 (0.28%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Breast cancer stage III
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acinic cell carcinoma of salivary gland
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign neoplasm of epididymis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer recurrent
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cancer stage II
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma stage IV
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant melanoma
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 1084 (0.09%)
    3 / 1087 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer stage I
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal cancer metastatic
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bladder neoplasm
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer stage IV
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Homicide
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 1084 (0.28%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 1084 (0.18%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 1084 (0.18%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Fatigue
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device site haematoma
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 1084 (0.09%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Vascular stent occlusion
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stent-graft endoleak
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Somatic symptom disorder
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    3 / 1084 (0.28%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterovaginal prolapse
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Female genital tract fistula
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix haemorrhage uterine
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erectile dysfunction
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic obstruction
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    2 / 1084 (0.18%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal injury
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery restenosis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary bypass thrombosis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Strangulated incisional hernia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary bypass stenosis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    16 / 1084 (1.48%)
    14 / 1087 (1.29%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    13 / 1084 (1.20%)
    5 / 1087 (0.46%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    10 / 1084 (0.92%)
    11 / 1087 (1.01%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    8 / 1084 (0.74%)
    6 / 1087 (0.55%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    7 / 1084 (0.65%)
    5 / 1087 (0.46%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    4 / 1084 (0.37%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    4 / 1084 (0.37%)
    4 / 1087 (0.37%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    4 / 1084 (0.37%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    3 / 1084 (0.28%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    3 / 1084 (0.28%)
    4 / 1087 (0.37%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 1084 (0.18%)
    3 / 1087 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conduction disorder
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frederick's syndrome
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia paroxysmal
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Vestibulocerebellar syndrome
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood loss anaemia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microcytic anaemia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic haematoma
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoclonal B-cell lymphocytosis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenic purpura
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    4 / 1084 (0.37%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    4 / 1084 (0.37%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 1084 (0.37%)
    3 / 1087 (0.28%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    3 / 1084 (0.28%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal stenosis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    5 / 1084 (0.46%)
    4 / 1087 (0.37%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    4 / 1084 (0.37%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 1084 (0.28%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Transient ischaemic attack
         subjects affected / exposed
    3 / 1084 (0.28%)
    3 / 1087 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    2 / 1084 (0.18%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar stroke
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 1084 (0.09%)
    3 / 1087 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular encephalopathy
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental impairment
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multifocal motor neuropathy
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo CNS origin
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Amaurosis fugax
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 1084 (0.00%)
    4 / 1087 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic retinopathy
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 1084 (0.18%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal adhesions
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal incarcerated hernia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyclic vomiting syndrome
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal vascular malformation haemorrhagic
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingival bleeding
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoperitoneum
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal mass
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oroantral fistula
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 1084 (0.37%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    3 / 1084 (0.28%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder tamponade
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 1084 (0.18%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic skin ulcer
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    2 / 1084 (0.18%)
    6 / 1087 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back disorder
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis reactive
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoriatic arthropathy
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    2 / 1084 (0.18%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic syndrome
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    5 / 1084 (0.46%)
    4 / 1087 (0.37%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 1084 (0.37%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 1084 (0.28%)
    4 / 1087 (0.37%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 1084 (0.28%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue haemorrhagic fever
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysentery
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1087 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 1084 (0.09%)
    3 / 1087 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic fever with renal syndrome
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1087 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1087 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Alirocumab 75 Q2W/Up150 Q2W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    387 / 1084 (35.70%)
    366 / 1087 (33.67%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    73 / 1084 (6.73%)
    64 / 1087 (5.89%)
         occurrences all number
    93
    81
    Nervous system disorders
    Headache
         subjects affected / exposed
    85 / 1084 (7.84%)
    71 / 1087 (6.53%)
         occurrences all number
    123
    83
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    71 / 1084 (6.55%)
    60 / 1087 (5.52%)
         occurrences all number
    82
    66
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    65 / 1084 (6.00%)
    60 / 1087 (5.52%)
         occurrences all number
    72
    78
    Influenza
         subjects affected / exposed
    69 / 1084 (6.37%)
    63 / 1087 (5.80%)
         occurrences all number
    77
    69
    Nasopharyngitis
         subjects affected / exposed
    89 / 1084 (8.21%)
    82 / 1087 (7.54%)
         occurrences all number
    117
    98
    Urinary tract infection
         subjects affected / exposed
    46 / 1084 (4.24%)
    61 / 1087 (5.61%)
         occurrences all number
    65
    78

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Apr 2016
    The purpose of this amendment was to incorporate changes made based on feedback received from the FDA and to address inconsistencies in the original version.
    08 Aug 2016
    The overall purpose of this amendment was to address inconsistencies, provide clarifications and correct errors as follows: To correct and replace EudraCT number - To clarify that the last study drug administration is week 94 and not week 96 - To revise the total number of site locations from up to 600 to up to 300 - To add study milestones - To add the proportion of patients reaching LDL-C <50 (1.29 mmol/L) mg/dL as a secondary efficacy endpoint because it is the criterion for dose adjustment - To clarify gonadal hormone levels for female and male patients - To add GDS-S and MoCA to the Schedule of Events table - To add that limited clinical data are available on the impact of very low circulating LDL on neurocognitive function - To allow study drug administration prior to performing study assessments at visit 4 - To allow unscheduled neurocognitive testing during visits when a neurocognitive AE is reported and the CANTAB test is not planned or in the case of early treatment discontinuation - To modify reasons for permanent discontinuation of study drug - Add new onset of diabetes as an AE of interest - To revise the list of AE causality evaluation factors for the “not related” category - To more precisely define Neurocognitive Events of Special Interest - To add electronic systems used to process and/or collect data - To clarify that the sponsor may not implement a change in the design or operation of the protocol/ICF without a heath authority and/or IRB/EC approved amendment
    10 Jan 2017
    The main purpose of this amendment was to incorporate the following changes requested during the regulatory review via the Voluntary Harmonization Procedure (VHP): Added a history of serious allergic reactions and severe hepatic impairment as exclusion criteria - Provide the list of highly effective contraception methods in accordance with recommendations of the Clinical Trial Facilitation Group (CTFG) - Describe the procedure to be followed if emergency unblinding of a patient by the investigator is required during the study - Indicate that any patient with 2 consecutive LDL-C levels that are increased >25% compared to the randomization visit LDL-C level may receive rescue treatment if no reason for LDL-C levels above the threshold value can be determined - Add mild cognitive impairment and dementia as reasons for potential permanent discontinuation of study drug - Define what constitutes the end of the study
    17 May 2017
    The following changes were made to the protocol: Added coronary calcium scan as a clarification of possible diagnostic methods to document history of coronary heart disease - Revised exclusion criteria to enhance enrollment (#5), to provide a definition for “as needed” (pro re nata [PRN]) use (#6), to provide comprehensive list of exclusionary medications (#6), to clarify “hyperthyroidism/or hypothyroidism” (#8), and to remove history of serious allergic reactions (such as anaphylaxis) as this is not included in the approved drug labeling (#11) - Clarified procedures to follow if emergency unblinding is required - Added collection of menstrual cycle data in the study to facilitate meaningful analysis of reproductive hormone data - Clarified the visits (days on which blood samples are not collected) when study drug may be administered prior to study assessments to provide more flexibility in drug administration - Added collection of a laboratory sample for hepatitis B surface antigen and hepatitis C antibody at the end-of-study visit - Removed the requirement that patients be identified by their initials on case report forms (CRFs) and other documents submitted to the sponsor to preserve patient confidentiality - Removed gabapentin from the list of exclusionary medications since use of gabapentin won’t impact interpretation of study endpoints - Provided a more comprehensive list of medications for calculating the anticholinergic burden (ACB)
    17 Jul 2018
    The main purpose of this amendment was to correct that optional laboratory evaluations are mandatory. Other minor edits and corrections were also made: Corrected that certain laboratory evaluations should be performed at the end of study visit even in the absence of clinically relevant abnormal values in these parameters at previous visits - Clarified that medication history to be collected is limited to medication history related to lipid-modifying therapy - Clarified definition of non-high density lipoprotein - Specified that research samples should be serum and plasma - Specified that adverse events of special interest (AESI) should be reported

    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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