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    Clinical Trial Results:
    An Open-Label Extension Study to Assess the Long-Term Safety and Efficacy of ISIS 301012 in Patients with Familial Hypercholesterolemia or Severe-Hypercholesterolemia

    Summary
    EudraCT number
    		 2005-003450-10
    Trial protocol
    		 GB  
    Global end of trial date
    15 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Apr 2016
    First version publication date
    06 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    301012-CS6
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00694109
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Genzyme Corporation
    Sponsor organisation address
    500 Kendall Street, Cambridge, MA, United States, 02142
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    21 Nov 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and efficacy of extended dosing with ISIS 301012 (mipomersen) in subjects with familial hypercholesterolemia or severe hypercholesterolemia on concomitant lipid-lowering therapy.
    Protection of trial subjects
    Pediatric Subjects: The study was conducted by investigators experienced in the treatment of pediatric subjects. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Adult Subjects: Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2008
    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
    Brazil: 5
    Country: Number of subjects enrolled
    Canada: 34
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    South Africa: 22
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 75
    Worldwide total number of subjects
    142
    EEA total number of subjects
    2
    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)
    7
    Adults (18-64 years)
    114
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 33 centers in 7 countries. A total of 144 subjects were enrolled in the study. 1 subject never received study drug. 2 of the enrolled subjects came from a phase 2 study and its extension and consequently had very different treatment from the other treated subjects, and thus were excluded from all summary tables.

    Pre-assignment
    Screening details
    		 Subjects who successfully completed ISIS 301012­-CS5 (NCT00607373), ISIS 301012- CS7 (NCT00706849), ISIS 301012-CS17 (NCT00694109) or MIPO3500108 (NCT00794664) with an acceptable safety profile were eligible for study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Mipomersen
    Arm description
    		 Mipomersen for up to 4 years (depending on subject's consent). Subjects were followed for additional 24 week post-treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mipomersen sodium
    Investigational medicinal product code
    ISIS 301012
    Other name
    Kynamro®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Mipomersen sodium 200 mg (for subjects weighed ≥ 50 kg) or 160 mg (for subjects weighed <50 kg) once a week.

    Number of subjects in period 1
    		Mipomersen
    Started
    142
    Treated
    141
    Consented 2 years additional treatment
    42
    Completed consented length of treatment
    60
    Completed
    25
    Not completed
    117
         Consented but did not receive additional treatment
    3
         Not consented for additional 2 years of treatment
    18
         Physician decision
    3
         Pregnancy
    1
         Adverse event
    74
         Unspecified
    2
         Enrolled but not treated
    1
         Withdrawal by subject
    13
         Lack of efficacy
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Mipomersen
    Reporting group description
    		 Mipomersen for up to 4 years (depending on subject's consent). Subjects were followed for additional 24 week post-treatment.

    Reporting group values
    		 Mipomersen Total
    Number of subjects
    		 142 142
    Age categorical
    Units: Subjects
    Age continuous
    Number of subjects analysed for this parameter are 141.
    Units: years
        arithmetic mean (standard deviation)
    		 49.3 ± 15.3 -
    Gender categorical
    Units: Subjects
        Female
    		 57 57
        Male
    		 84 84
        Not Available
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Mipomersen
    Reporting group description
    		 Mipomersen for up to 4 years (depending on subject's consent). Subjects were followed for additional 24 week post-treatment.

    Primary: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C)

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    End point title
    		 Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) [1]
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned to be performed .
    End point values
    		 Mipomersen
    Number of subjects analysed
    141
    Units: percent change
    arithmetic mean (confidence interval 95%)
        week 26 (n = 130)
    -28.5 (-31.9 to -25.1)
        week 52 (n = 111)
    -27 (-31.2 to -22.8)
        week 76 (n = 66)
    -27.3 (-33 to -21.6)
        week 104 (n = 57)
    -27.9 (-33.9 to -21.8)
        week 130 (n = 42)
    -21.9 (-31.1 to -12.7)
        week 156 (n = 30)
    -21.4 (-31.2 to -11.7)
        week 182 (n = 26)
    -23.6 (-36.6 to -10.6)
        week 208 (n = 27)
    -26.3 (-36.4 to -16.2)
        week 234 (n = 17)
    -22.5 (-34.3 to -10.6)
        24 weeks post last dose (n=117)
    1.6 (-2.6 to 5.9)
    No statistical analyses for this end point

    Primary: Percent Change From Baseline in Apolipoprotein B (Apo B)

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B (Apo B) [2]
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned to be performed .
    End point values
    		 Mipomersen
    Number of subjects analysed
    141
    Units: percent change
    arithmetic mean (confidence interval 95%)
        week 26 (n = 130)
    -28.9 (-32 to -25.8)
        week 52 (n = 111)
    -28.1 (-32 to -24.2)
        week 76 (n = 66)
    -30.3 (-34.7 to -26)
        week 104 (n = 57)
    -31.2 (-36.5 to -25.9)
        week 130 (n = 43)
    -29.1 (-35.7 to -22.5)
        week 156 (n = 30)
    -30.2 (-38.1 to -22.2)
        week 182 (n = 26)
    -31.1 (-39.9 to -22.2)
        week 208 (n = 27)
    -33.3 (-40.8 to -25.9)
        week 234 (n = 17)
    -31.4 (-38.7 to -24.1)
        24 weeks post last dose (n=117)
    -3.46 (-6.9 to 0)
    No statistical analyses for this end point

    Primary: Percent Change From Baseline in Total Cholesterol

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    End point title
    		 Percent Change From Baseline in Total Cholesterol [3]
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned to be performed .
    End point values
    		 Mipomersen
    Number of subjects analysed
    141
    Units: percent change
    arithmetic mean (confidence interval 95%)
        week 26 (n = 130)
    -21.7 (-24.4 to -18.9)
        week 52 (n = 111)
    -20.4 (-23.9 to -16.8)
        week 76 (n = 66)
    -20.1 (-24.6 to -15.5)
        week 104 (n = 57)
    -19.8 (-24.8 to -14.7)
        week 130 (n = 43)
    -14.9 (-22.1 to -7.8)
        week 156 (n = 30)
    -14.4 (-22.3 to -6.6)
        week 182 (n = 26)
    -14.3 (-25 to -3.5)
        week 208 (n = 27)
    -16.5 (-24.2 to -8.8)
        week 234 (n = 17)
    -12.5 (-21.5 to -3.4)
        24 weeks post last dose (n=117)
    1.94 (-1.5 to 5.4)
    No statistical analyses for this end point

    Primary: Percent Change From Baseline in Non High-Density Lipoprotein Cholesterol (Non-HDL-C)

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    End point title
    		 Percent Change From Baseline in Non High-Density Lipoprotein Cholesterol (Non-HDL-C) [4]
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned to be performed .
    End point values
    		 Mipomersen
    Number of subjects analysed
    141
    Units: percent change
    arithmetic mean (confidence interval 95%)
        week 26 (n = 130)
    -27.2 (-30.4 to -24.1)
        week 52 (n = 111)
    -25.4 (-29.5 to -21.3)
        week 76 (n = 66)
    -25 (-30.4 to -19.7)
        week 104 (n = 57)
    -26.2 (-32 to -20.4)
        week 130 (n = 43)
    -20.7 (-29.1 to -12.3)
        week 156 (n = 30)
    -20 (-29.6 to -10.3)
        week 182 (n = 26)
    -21.7 (-34.7 to -8.7)
        week 208 (n = 27)
    -23.9 (-33.7 to -14.1)
        week 234 (n = 17)
    -19.9 (-31.5 to -8.2)
        24 weeks post last dose (n=117)
    2.5 (-1.8 to 6.7)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Triglycerides

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    End point title
    		 Percent Change From Baseline in Triglycerides
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    141
    Units: percent change
    arithmetic mean (confidence interval 95%)
        week 26 (n = 130)
    -20.1 (-33.1 to -1.2)
        week 52 (n = 111)
    -7.9 (-31.5 to 16.9)
        week 76 (n = 66)
    -10.2 (-27.7 to 13.8)
        week 104 (n = 57)
    -12.5 (-37.1 to 7.2)
        week 130 (n = 43)
    -10.9 (-36 to 10)
        week 156 (n = 30)
    -10.4 (-23.8 to 12.7)
        week 182 (n = 26)
    -12.9 (-27.4 to -1.6)
        week 208 (n = 27)
    -13.9 (-40 to 33)
        week 234 (n = 17)
    1.3 (-15.4 to 15.7)
        24 weeks post last dose (n=117)
    2.1 (-17.2 to 27.7)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in lipoprotein (a)

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    End point title
    		 Percent Change From Baseline in lipoprotein (a)
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    141
    Units: percent change
    arithmetic mean (confidence interval 95%)
        week 26 (n = 130)
    -20.5 (-39.3 to -3.6)
        week 52 (n = 111)
    -19 (-33.3 to 0)
        week 76 (n = 66)
    -17.9 (-33.3 to -0.5)
        week 104 (n = 57)
    -16.6 (-36.1 to 0)
        week 130 (n = 43)
    -15.8 (-31.3 to 0)
        week 156 (n = 30)
    -9.1 (-33.8 to 7.3)
        week 182 (n = 26)
    -9 (-27.2 to 7.6)
        week 208 (n = 27)
    -9.9 (-32.5 to 4.1)
        week 234 (n = 17)
    -18.3 (-31.6 to -4.8)
        24 weeks post last dose (n=117)
    0 (-6 to 5)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in LDL Particles' Size (Total)

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    End point title
    		 Percent Change From Baseline in LDL Particles' Size (Total)
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    140
    Units: percent change
    arithmetic mean (confidence interval 95%)
        week 52 (n=91)
    -26.77 (-32.7 to -20.8)
        week 104 (n=47)
    -27.77 (-35.3 to -20.3)
        week 156 (n=20)
    -25.1 (-40.3 to -9.9)
        week 208 (n=19)
    -32.65 (-44.9 to -20.4)
        End of treatment (n=139)
    -22.63 (-27 to -18.3)
        24 weeks post last dose (n=115)
    6.11 (0.8 to 11.5)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in LDL Particles' Size (Large)

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    End point title
    		 Percent Change From Baseline in LDL Particles' Size (Large)
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    140
    Units: percent change
    arithmetic mean (confidence interval 95%)
        week 52 (n=91)
    -5.01 (-16.8 to 6.8)
        week 104 (n=47)
    -14.32 (-27 to -1.6)
        week 156 (n=20)
    -27.04 (-40.6 to -13.4)
        week 208 (n=19)
    -22.67 (-41.6 to -3.8)
        End of treatment (n=139)
    -2.94 (-13.2 to 7.3)
        24 weeks post last dose (n=115)
    6.19 (-6.1 to 18.5)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in LDL Particles' Size (Medium)

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    End point title
    		 Percent Change From Baseline in LDL Particles' Size (Medium)
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    140
    Units: percent change
    arithmetic mean (confidence interval 95%)
        week 52 (n=91)
    -9.5 (-31.8 to 12.8)
        week 104 (n=47)
    11.09 (-42.2 to 64.4)
        week 156 (n=20)
    -19.62 (-57.3 to 18)
        week 208 (n=19)
    -15.82 (-62 to 30.4)
        End of treatment (n=139)
    -5.65 (-30.3 to 19)
        24 weeks post last dose (n=115)
    46.92 (5.6 to 88.2)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in LDL Particles' Size (Small)

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    End point title
    		 Percent Change From Baseline in LDL Particles' Size (Small)
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    140
    Units: percent change
    arithmetic mean (confidence interval 95%)
        week 52 (n=91)
    -8.79 (-33.7 to 16.2)
        week 104 (n=47)
    1.72 (-43.9 to 47.4)
        week 156 (n=20)
    -18.95 (-58.8 to 20.9)
        week 208 (n=19)
    -27.95 (-67.9 to 12)
        End of treatment (n=139)
    -5.17 (-29.2 to 18.8)
        24 weeks post last dose (n=115)
    51.94 (7.7 to 96.2)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in LDL Particles' Size (Very Small)

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    End point title
    		 Percent Change From Baseline in LDL Particles' Size (Very Small)
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    140
    Units: percent change
    arithmetic mean (confidence interval 95%)
        week 52 (n=91)
    -5.05 (-32.2 to 22.2)
        week 104 (n=47)
    -0.11 (-44.4 to 44.2)
        week 156 (n=20)
    -18.7 (-59.2 to 21.8)
        week 208 (n=19)
    -30.77 (-69.3 to 7.8)
        End of treatment (n=139)
    0.75 (-28 to 29.5)
        24 weeks post last dose (n=115)
    60.22 (7.5 to 112.9)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in HDL Particles' Size (Large)

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    End point title
    		 Percent Change From Baseline in HDL Particles' Size (Large)
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    140
    Units: percent change
    arithmetic mean (confidence interval 95%)
        week 52 (n=89)
    160.8 (-38.3 to 359.9)
        week 104 (n=47)
    43.23 (-12.2 to 98.7)
        week 156 (n=20)
    58.26 (-38 to 154.6)
        week 208 (n=19)
    61.76 (-41.6 to 165.2)
        End of treatment (n=134)
    121.16 (-17.3 to 259.6)
        24 weeks post last dose (n=110)
    85.93 (-7.3 to 179.1)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in HDL Particles' Size (Medium)

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    End point title
    		 Percent Change From Baseline in HDL Particles' Size (Medium)
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    140
    Units: Percent Change
    arithmetic mean (confidence interval 95%)
        week 52 (n=44)
    154.77 (2.8 to 306.8)
        week 104 (n=28)
    176.14 (-68.6 to 420.9)
        week 156 (n=9)
    21.24 (-65.1 to 107.6)
        week 208 (n=8)
    838.32 (-1109.3 to 2785.9)
        End of treatment (n=68)
    388.16 (94.5 to 681.8)
        24 weeks post last dose (n=56)
    233.78 (7.9 to 459.7)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in HDL Particles' Size (Small)

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    End point title
    		 Percent Change From Baseline in HDL Particles' Size (Small)
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    140
    Units: Percent Change
    arithmetic mean (confidence interval 95%)
        week 52 (n=91)
    1.83 (-7.3 to 10.9)
        week 104 (n=47)
    -9.81 (-17.7 to -2)
        week 156 (n=20)
    -14.18 (-25.1 to -3.2)
        week 208 (n=19)
    -11.47 (-20 to -2.9)
        End of treatment (n=139)
    0.44 (-6.9 to 7.7)
        24 weeks post last dose (n=115)
    8.31 (0.6 to 16)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Intermediate Density Lipoprotein Particles' Size

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    End point title
    		 Percent Change From Baseline in Intermediate Density Lipoprotein Particles' Size
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    140
    Units: Percent Change
    arithmetic mean (confidence interval 95%)
        week 52 (n=79)
    -9.9 (-45.6 to 25.8)
        week 104 (n=40)
    -27.35 (-66.5 to 11.8)
        week 156 (n=16)
    155.42 (-90.1 to 401)
        week 208 (n=15)
    32.88 (-104 to 169.8)
        End of treatment (n=122)
    24.66 (-28.4 to 77.8)
        24 weeks post last dose (n=101)
    57.46 (15.2 to 99.8)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Very Low Density Lipoprotein (VLDL) Particles' Size (Large) and Chylomicron Particles' Size

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    End point title
    		 Percent Change From Baseline in Very Low Density Lipoprotein (VLDL) Particles' Size (Large) and Chylomicron Particles' Size
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    140
    Units: Percent Change
    arithmetic mean (confidence interval 95%)
        week 52 (n=86)
    109.23 (33.7 to 184.8)
        week 104 (n=46)
    107.5 (-10.2 to 225.2)
        week 156 (n=19)
    123.42 (-113 to 359.8)
        week 208 (n=18)
    241.76 (-241.5 to 725.1)
        End of treatment (n=132)
    86.75 (28.4 to 145.1)
        24 weeks post last dose (n=110)
    90.82 (21.8 to 159.9)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in VLDL Particles' Size (Medium)

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    End point title
    		 Percent Change From Baseline in VLDL Particles' Size (Medium)
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    140
    Units: Percent Change
    arithmetic mean (confidence interval 95%)
        week 52 (n=88)
    70.81 (2.1 to 139.5)
        week 104 (n=47)
    97.74 (-21 to 216.5)
        week 156 (n=20)
    172.46 (5.3 to 339.7)
        week 208 (n=19)
    98.7 (-71.3 to 268.7)
        End of treatment (n=136)
    63.25 (12.1 to 114.4)
        24 weeks post last dose (n=113)
    99.57 (16.8 to 182.3)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in VLDL Particles' Size (Small)

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    End point title
    		 Percent Change From Baseline in VLDL Particles' Size (Small)
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    140
    Units: Percent Change
    arithmetic mean (confidence interval 95%)
        week 52 (n=91)
    49.51 (-41.1 to 140.4)
        week 104 (n=47)
    30.48 (-75.1 to 136.1)
        week 156 (n=20)
    9.34 (-48.3 to 67)
        week 208 (n=19)
    -30.36 (-49.8 to -10.9)
        End of treatment (n=139)
    31.27 (-27.3 to 89.8)
        24 weeks post last dose (n=115)
    32.14 (-5.3 to 69.6)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Total VLDL Particles' Size and Chylomicron Particles' Size

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    End point title
    		 Percent Change From Baseline in Total VLDL Particles' Size and Chylomicron Particles' Size
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    140
    Units: Percent Change
    arithmetic mean (confidence interval 95%)
        week 52 (n=91)
    19.94 (-36.7 to 74.6)
        week 104 (n=47)
    -14.25 (-36.4 to 7.9)
        week 156 (n=20)
    3.48 (-27.5 to 34.5)
        week 208 (n=19)
    -18.66 (-43.6 to 6.3)
        End of treatment (n=139)
    12.82 (-25.5 to 51.2)
        24 weeks post last dose (n=115)
    19.69 (3.2 to 36.1)
    No statistical analyses for this end point

    Secondary: Change From Baseline in C-Reactive Protein

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    End point title
    		 Change From Baseline in C-Reactive Protein
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with c-reactive protein assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    141
    Units: mg/L
    arithmetic mean (confidence interval 95%)
        week 26 (n=130)
    0.67 (-0.8 to 2.1)
        week 52 (n=111)
    -0.37 (-1.4 to 0.6)
        week 76 (n=84)
    -1.05 (-2 to -0.1)
        week 104 (n=58)
    0.12 (-0.8 to 1)
        week 130 (n=42)
    -0.18 (-1.1 to 0.8)
        week 156 (n=30)
    0.02 (-0.5 to 2.1)
        week 182 (n=31)
    0.73 (0.1 to 1.4)
        week 208 (n=27)
    0.2 (-0.5 to 0.9)
        week 234 (n=18)
    0.53 (-0.5 to 1.5)
        End of treatment (n=140)
    0.41 (-0.6 to 1.4)
        24 weeks post last dose (n=116)
    0.09 (-0.9 to 1.1)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Apolipoprotein A-1

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    End point title
    		 Percent Change From Baseline in Apolipoprotein A-1
    End point description
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for subjects randomized to placebo in their index study and for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for subjects randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study). Safety set: all enrolled subjects who received at least 1 injection of study drug. Here n=subjects with lipid parameter assessment at specified time.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
    End point values
    		 Mipomersen
    Number of subjects analysed
    141
    Units: percent change
    arithmetic mean (confidence interval 95%)
        week 26 (n=130)
    -1.01 (-3.8 to 1.7)
        week 52 (n=111)
    -1.59 (-4.7 to 1.6)
        week 76 (n=66)
    -3.73 (-7.9 to 0.5)
        week 104 (n=57)
    -4.33 (-9.1 to 0.4)
        week 130 (n=43)
    -1.37 (-6.1 to 3.4)
        week 156 (n=30)
    -5.55 (-11.2 to 0)
        week 182 (n=26)
    -3.17 (-9.4 to 3.1)
        week 208 (n=27)
    -2.19 (-7.2 to 2.8)
        week 234 (n=17)
    3.68 (-3 to 10.3)
        24 weeks post last dose (n = 117)
    -0.67 (-3.5 to 2.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (59.7 months) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported adverse events and death are treatment-emergent that is AEs that developed/worsened and death that occurred during the ‘on treatment period’ (from the start of study drug in this study up to 24 weeks post-treatment)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Mipomersen
    Reporting group description
    		 Mipomersen for up to 4 years (depending on subject's consent). Subjects were followed for additional 24 week post-treatment.

    Serious adverse events
    		 Mipomersen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 141 (25.53%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast Cancer
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal Cancer
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous Cell Carcinoma
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Aortic Aneurysm
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Aortic Stenosis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Femoral Artery Occlusion
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral Artery Dissection
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Ileostomy
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device Malfunction
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Contrast Media Allergy
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Hypertension
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Alcoholism
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal Anastomotic Leak
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary Artery Restenosis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Extradural Haematoma
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Aortic Valve Stenosis
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Angina Unstable
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Supraventricular Tachycardia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dementia Alzheimer's Type
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Amnesia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Arachnoid Cyst
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Partial Seizures
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Splenic Haemorrhage
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diverticulum Intestinal
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Biliary Colic
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Glomerulonephritis Membranous
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Neck Pain
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Mipomersen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    141 / 141 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Benign Breast Neoplasm
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Lipoma
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Seborrhoeic Keratosis
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Melanocytic Naevus
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Skin Papilloma
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Thyroid Neoplasm
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Vascular disorders
    Aortic Arteriosclerosis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Aortic Aneurysm
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Aortic Dilatation
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Aortic Stenosis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Aortic Calcification
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    8 / 141 (5.67%)
         occurrences all number
    9
    Hot Flush
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Haematoma
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Flushing
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    4
    Infarction
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Hypertensive Crisis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Intermittent Claudication
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Hypotension
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Peripheral Coldness
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Orthostatic Hypotension
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Pallor
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Subclavian Artery Stenosis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Phlebitis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Peripheral Vascular Disorder
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 141 (4.26%)
         occurrences all number
    10
    Chest Discomfort
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Chest Pain
         subjects affected / exposed
    9 / 141 (6.38%)
         occurrences all number
    9
    Chills
         subjects affected / exposed
    27 / 141 (19.15%)
         occurrences all number
    103
    Cyst
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Device Breakage
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Exercise Tolerance Decreased
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Facial Pain
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Device Failure
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Feeling Cold
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Discomfort
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Gait Disturbance
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Influenza Like Illness
         subjects affected / exposed
    70 / 141 (49.65%)
         occurrences all number
    282
    Fatigue
         subjects affected / exposed
    38 / 141 (26.95%)
         occurrences all number
    93
    Injection Site Discolouration
         subjects affected / exposed
    55 / 141 (39.01%)
         occurrences all number
    144
    Injection Site Bruising
         subjects affected / exposed
    72 / 141 (51.06%)
         occurrences all number
    316
    Injection Site Discomfort
         subjects affected / exposed
    14 / 141 (9.93%)
         occurrences all number
    55
    Injection Site Atrophy
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Injection Site Erythema
         subjects affected / exposed
    117 / 141 (82.98%)
         occurrences all number
    822
    Injection Site Eczema
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Injection Site Exfoliation
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Injection Site Extravasation
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    3
    Injection Site Haematoma
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Injection Site Haemorrhage
         subjects affected / exposed
    17 / 141 (12.06%)
         occurrences all number
    35
    Injection Site Hypertrophy
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    5
    Injection Site Hypoaesthesia
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    4
    Injection Site Induration
         subjects affected / exposed
    31 / 141 (21.99%)
         occurrences all number
    62
    Injection Site Hypersensitivity
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    5
    Injection Site Macule
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    21
    Injection Site Lymphadenopathy
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Injection Site Inflammation
         subjects affected / exposed
    12 / 141 (8.51%)
         occurrences all number
    25
    Injection Site Nodule
         subjects affected / exposed
    9 / 141 (6.38%)
         occurrences all number
    22
    Injection Site Oedema
         subjects affected / exposed
    19 / 141 (13.48%)
         occurrences all number
    84
    Injection Site Pain
         subjects affected / exposed
    102 / 141 (72.34%)
         occurrences all number
    807
    Injection Site Mass
         subjects affected / exposed
    14 / 141 (9.93%)
         occurrences all number
    88
    Injection Site Pallor
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    15
    Injection Site Papule
         subjects affected / exposed
    7 / 141 (4.96%)
         occurrences all number
    34
    Injection Site Paraesthesia
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Injection Site Pruritus
         subjects affected / exposed
    46 / 141 (32.62%)
         occurrences all number
    206
    Injection Site Swelling
         subjects affected / exposed
    31 / 141 (21.99%)
         occurrences all number
    157
    Injection Site Recall Reaction
         subjects affected / exposed
    10 / 141 (7.09%)
         occurrences all number
    15
    Injection Site Reaction
         subjects affected / exposed
    12 / 141 (8.51%)
         occurrences all number
    48
    Injection Site Rash
         subjects affected / exposed
    16 / 141 (11.35%)
         occurrences all number
    54
    Injection Site Warmth
         subjects affected / exposed
    19 / 141 (13.48%)
         occurrences all number
    47
    Injection Site Vesicles
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Injection Site Urticaria
         subjects affected / exposed
    10 / 141 (7.09%)
         occurrences all number
    28
    Non-Cardiac Chest Pain
         subjects affected / exposed
    5 / 141 (3.55%)
         occurrences all number
    5
    Malaise
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Localised Oedema
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Local Swelling
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Oedema Peripheral
         subjects affected / exposed
    10 / 141 (7.09%)
         occurrences all number
    10
    Pain
         subjects affected / exposed
    13 / 141 (9.22%)
         occurrences all number
    41
    Pyrexia
         subjects affected / exposed
    25 / 141 (17.73%)
         occurrences all number
    38
    Temperature Intolerance
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Vaccination Site Pain
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Swelling
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Tenderness
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Xerosis
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Vessel Puncture Site Bruise
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Seasonal Allergy
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    4
    Serum Sickness
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    3
    Reproductive system and breast disorders
    Erectile Dysfunction
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Dyspareunia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Breast Mass
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Amenorrhoea
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    3
    Menopausal Symptoms
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Ovarian Cyst
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Menstruation Delayed
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Menorrhagia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Pelvic Pain
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Pruritus Genital
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Prostatitis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Testicular Cyst
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Uterine Prolapse
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Uterine Haemorrhage
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Vaginal Discharge
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Vaginal Haemorrhage
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Vulvovaginal Burning Sensation
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Vulvovaginal Dryness
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchial Hyperreactivity
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Dysphonia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    15 / 141 (10.64%)
         occurrences all number
    22
    Dyspnoea
         subjects affected / exposed
    12 / 141 (8.51%)
         occurrences all number
    14
    Dyspnoea Exertional
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    5
    Epistaxis
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    16
    Hypoxia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Paranasal Sinus Hypersecretion
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Hiccups
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Nasal Congestion
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    4
    Painful Respiration
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Oropharyngeal Pain
         subjects affected / exposed
    13 / 141 (9.22%)
         occurrences all number
    18
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Rhinitis Allergic
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    3
    Productive Cough
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    4
    Sinus Disorder
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Respiratory Tract Congestion
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Sinus Congestion
         subjects affected / exposed
    6 / 141 (4.26%)
         occurrences all number
    8
    Rhinorrhoea
         subjects affected / exposed
    8 / 141 (5.67%)
         occurrences all number
    9
    Upper Respiratory Tract Congestion
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Sleep Apnoea Syndrome
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Wheezing
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Psychiatric disorders
    Abnormal Sleep-Related Event
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Confusional State
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Anxiety
         subjects affected / exposed
    6 / 141 (4.26%)
         occurrences all number
    8
    Attention Deficit/Hyperactivity Disorder
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Depression
         subjects affected / exposed
    8 / 141 (5.67%)
         occurrences all number
    8
    Libido Decreased
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Panic Attack
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    9 / 141 (6.38%)
         occurrences all number
    9
    Stress
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    5
    Investigations
    Albumin Urine Present
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    21 / 141 (14.89%)
         occurrences all number
    23
    Alanine Aminotransferase Increased
         subjects affected / exposed
    26 / 141 (18.44%)
         occurrences all number
    33
    Beta 2 Microglobulin Urine Increased
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Blood Bicarbonate Decreased
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    4
    Blood Potassium Increased
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Blood Creatinine Increased
         subjects affected / exposed
    5 / 141 (3.55%)
         occurrences all number
    6
    Blood Uric Acid Increased
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Blood Phosphorus Decreased
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Body Temperature Increased
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Blood Testosterone Decreased
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Blood Pressure Increased
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Carotid Bruit
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Cardiac Murmur
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    4
    C-Reactive Protein Increased
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Electrocardiogram T Wave Inversion
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Electrocardiogram T Wave Abnormal
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Electrocardiogram St Segment Depression
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Heart Rate Increased
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Electrocardiogram Abnormal
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Haematocrit Decreased
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    4
    Haemoglobin Decreased
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    International Normalised Ratio Increased
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Liver Function Test Abnormal
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Hepatic Enzyme Increased
         subjects affected / exposed
    6 / 141 (4.26%)
         occurrences all number
    7
    Multiple Gated Acquisition Scan Abnormal
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Lymph Node Palpable
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Liver Scan Abnormal
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Platelet Count Decreased
         subjects affected / exposed
    5 / 141 (3.55%)
         occurrences all number
    9
    Lymphocyte Count Decreased
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Mycobacterium Tuberculosis Complex Test Positive
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Peripheral Pulse Decreased
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Nuclear Magnetic Resonance Imaging Abnormal
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Red Blood Cell Count Decreased
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Prothrombin Time Prolonged
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Red Blood Cell Acanthocytes Present
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Protein Urine Present
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Red Blood Cells Urine Positive
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Scan Myocardial Perfusion Abnormal
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Red Blood Cell Schistocytes Present
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Weight Increased
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Urine Analysis Abnormal
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Transaminases Increased
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Weight Decreased
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    White Blood Cell Count Decreased
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Animal Scratch
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Ankle Fracture
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Back Injury
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Arthropod Sting
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Brain Contusion
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Arthropod Bite
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    5
    Contusion
         subjects affected / exposed
    9 / 141 (6.38%)
         occurrences all number
    15
    Concussion
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Epicondylitis
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Fractured Coccyx
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Excoriation
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    3
    Jaw Fracture
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Fall
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    3
    Incisional Hernia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Gastrointestinal Anastomotic Leak
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Injury
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Kidney Contusion
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Laceration
         subjects affected / exposed
    7 / 141 (4.96%)
         occurrences all number
    7
    Ligament Sprain
         subjects affected / exposed
    8 / 141 (5.67%)
         occurrences all number
    8
    Post Procedural Contusion
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Muscle Strain
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    4
    Limb Injury
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Meniscus Injury
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Procedural Vomiting
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Radius Fracture
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Procedural Pain
         subjects affected / exposed
    9 / 141 (6.38%)
         occurrences all number
    10
    Post-Traumatic Pain
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Repetitive Strain Injury
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Road Traffic Accident
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Scratch
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Spinal Compression Fracture
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    3
    Splenic Haematoma
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Sunburn
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Suture Related Complication
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Thermal Burn
         subjects affected / exposed
    5 / 141 (3.55%)
         occurrences all number
    6
    Tibia Fracture
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Tooth Fracture
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Vaccination Complication
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Wound
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    14 / 141 (9.93%)
         occurrences all number
    19
    Atrial Fibrillation
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Aortic Valve Disease
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Aortic Valve Incompetence
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Bradycardia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Coronary Artery Disease
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Extrasystoles
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Atrioventricular Block Second Degree
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Myocardial Ischaemia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Palpitations
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    7
    Supraventricular Extrasystoles
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Tachycardia
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Ventricular Extrasystoles
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Ventricular Dysfunction
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Nervous system disorders
    Burning Sensation
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    3
    Carotid Artery Stenosis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Carpal Tunnel Syndrome
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Cluster Headache
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Cognitive Disorder
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    10 / 141 (7.09%)
         occurrences all number
    11
    Dizziness Postural
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    3
    Dysgeusia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    35 / 141 (24.82%)
         occurrences all number
    81
    Hypoaesthesia
         subjects affected / exposed
    7 / 141 (4.96%)
         occurrences all number
    8
    Lethargy
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    11
    Loss Of Consciousness
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Morton's Neuralgia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Migraine With Aura
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Migraine
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    6
    Nerve Compression
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Orthostatic Intolerance
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Neuropathy Peripheral
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Post Herpetic Neuralgia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Neuralgia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Restless Legs Syndrome
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Presyncope
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Sciatica
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Syncope
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Sinus Headache
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    6
    Somnolence
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Transient Ischaemic Attack
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Viith Nerve Paralysis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    8 / 141 (5.67%)
         occurrences all number
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 141 (6.38%)
         occurrences all number
    11
    Thrombocytopenia
         subjects affected / exposed
    5 / 141 (3.55%)
         occurrences all number
    5
    Leukopenia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Lymphadenopathy
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    4
    Ear and labyrinth disorders
    Ear Discomfort
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Ear Pain
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Eustachian Tube Dysfunction
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Hypoacusis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Tinnitus
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Vertigo
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Eye disorders
    Cataract
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    6
    Arcus Lipoides
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Dry Eye
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Diplopia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Eye Irritation
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Eye Swelling
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Eye Pain
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Eyelid Cyst
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Halo Vision
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Vitreous Floaters
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Vision Blurred
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Presbyopia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Ocular Hyperaemia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal Hernia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Abdominal Distension
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Abdominal Discomfort
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    3
    Anal Haemorrhage
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Abdominal Pain
         subjects affected / exposed
    14 / 141 (9.93%)
         occurrences all number
    24
    Abdominal Pain Upper
         subjects affected / exposed
    7 / 141 (4.96%)
         occurrences all number
    9
    Dental Caries
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Abdominal Pain Lower
         subjects affected / exposed
    5 / 141 (3.55%)
         occurrences all number
    5
    Colitis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Bezoar
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    6 / 141 (4.26%)
         occurrences all number
    7
    Diverticulum
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Diverticulum Intestinal
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    21 / 141 (14.89%)
         occurrences all number
    37
    Dyspepsia
         subjects affected / exposed
    5 / 141 (3.55%)
         occurrences all number
    7
    Faeces Soft
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Faecal Incontinence
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Dysphagia
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Gastric Ulcer
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Food Poisoning
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Gastritis
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Flatulence
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Gastritis Erosive
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Gingival Recession
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Hiatus Hernia
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Haematochezia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Haemorrhoids
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Hypoaesthesia Oral
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Intestinal Obstruction
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Lip Blister
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Lip Swelling
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Inguinal Hernia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Oesophageal Dilatation
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Mouth Ulceration
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    37 / 141 (26.24%)
         occurrences all number
    105
    Odynophagia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Oesophagitis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Oesophageal Spasm
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Rectal Haemorrhage
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Pancreatic Duct Dilatation
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Proctitis Ulcerative
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Periodontal Disease
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Retching
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    13 / 141 (9.22%)
         occurrences all number
    21
    Umbilical Hernia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    5 / 141 (3.55%)
         occurrences all number
    5
    Tooth Impacted
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Vomiting Projectile
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Hepatobiliary disorders
    Cholecystitis Chronic
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Biliary Cyst
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Cholelithiasis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Cholecystitis Acute
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Hepatic Cyst
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Hepatic Fibrosis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Hepatomegaly
         subjects affected / exposed
    9 / 141 (6.38%)
         occurrences all number
    9
    Hepatic Steatosis
         subjects affected / exposed
    17 / 141 (12.06%)
         occurrences all number
    19
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Cold Sweat
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Dermatitis Acneiform
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Dermatitis Contact
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    3
    Blister
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Dermatitis
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Ecchymosis
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    10
    Dry Skin
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Dermatitis Allergic
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    4
    Hair Growth Abnormal
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    5
    Eczema
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Erythema
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Lipodystrophy Acquired
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Ingrowing Nail
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Ingrown Hair
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Intertrigo
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Macule
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Petechiae
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Onychoclasis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Pain Of Skin
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    6 / 141 (4.26%)
         occurrences all number
    18
    Pruritus Generalised
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Pigmentation Disorder
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Rash Papular
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Rash Maculo-Papular
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    6 / 141 (4.26%)
         occurrences all number
    11
    Rash Erythematous
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    3
    Scab
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Rash Vesicular
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Rash Pruritic
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Skin Lesion
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Skin Hyperpigmentation
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    6 / 141 (4.26%)
         occurrences all number
    8
    Skin Plaque
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Xanthoma
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Xanthelasma
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Renal and urinary disorders
    Bladder Discomfort
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Albuminuria
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    4
    Haematuria
         subjects affected / exposed
    6 / 141 (4.26%)
         occurrences all number
    6
    Dysuria
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Nephrolithiasis
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Micturition Urgency
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Nephropathy
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Proteinuria
         subjects affected / exposed
    6 / 141 (4.26%)
         occurrences all number
    8
    Pollakiuria
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Pyelocaliectasis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Pyuria
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Renal Cyst
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Renal Failure
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Stress Urinary Incontinence
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Urinary Tract Disorder
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Urge Incontinence
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    19 / 141 (13.48%)
         occurrences all number
    26
    Arthritis
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    5
    Back Pain
         subjects affected / exposed
    24 / 141 (17.02%)
         occurrences all number
    34
    Bunion
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Bone Pain
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Bursitis
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Chondrocalcinosis Pyrophosphate
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Cervical Spinal Stenosis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Coccydynia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Costochondritis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Exostosis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Fibromyalgia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Dupuytren's Contracture
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Flank Pain
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Intervertebral Disc Degeneration
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Fracture Pain
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Muscle Atrophy
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Haemarthrosis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Joint Effusion
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Joint Swelling
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Muscular Weakness
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    5
    Muscle Spasms
         subjects affected / exposed
    8 / 141 (5.67%)
         occurrences all number
    13
    Muscle Tightness
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Muscle Twitching
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Musculoskeletal Discomfort
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Musculoskeletal Chest Pain
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Musculoskeletal Pain
         subjects affected / exposed
    7 / 141 (4.96%)
         occurrences all number
    8
    Myalgia
         subjects affected / exposed
    33 / 141 (23.40%)
         occurrences all number
    53
    Osteoarthritis
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Neck Pain
         subjects affected / exposed
    6 / 141 (4.26%)
         occurrences all number
    8
    Musculoskeletal Stiffness
         subjects affected / exposed
    5 / 141 (3.55%)
         occurrences all number
    5
    Osteopenia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Pain In Jaw
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Pain In Extremity
         subjects affected / exposed
    14 / 141 (9.93%)
         occurrences all number
    19
    Plantar Fasciitis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Spinal Osteoarthritis
         subjects affected / exposed
    5 / 141 (3.55%)
         occurrences all number
    8
    Soft Tissue Atrophy
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Rotator Cuff Syndrome
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    7
    Temporomandibular Joint Syndrome
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Tendon Pain
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Tendonitis
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Infections and infestations
    Abscess Limb
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Asymptomatic Bacteriuria
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Acarodermatitis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Acute Sinusitis
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    3
    Anal Abscess
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Bronchitis
         subjects affected / exposed
    10 / 141 (7.09%)
         occurrences all number
    16
    Conjunctivitis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Bronchopneumonia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Cellulitis
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Ear Infection
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    5
    Cystitis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Eye Infection
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Gastroenteritis
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    5
    Diverticulitis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Folliculitis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Furuncle
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Genital Herpes Simplex
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Gastrointestinal Infection
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Gastrointestinal Viral Infection
         subjects affected / exposed
    5 / 141 (3.55%)
         occurrences all number
    9
    Helicobacter Gastritis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Gastroenteritis Viral
         subjects affected / exposed
    5 / 141 (3.55%)
         occurrences all number
    5
    H1n1 Influenza
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Giardiasis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Herpes Zoster
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Kidney Infection
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Influenza
         subjects affected / exposed
    17 / 141 (12.06%)
         occurrences all number
    23
    Laryngitis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Lower Respiratory Tract Infection
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    3
    Localised Infection
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    28 / 141 (19.86%)
         occurrences all number
    54
    Otitis Externa
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Oral Herpes
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Otitis Media Acute
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Onychomycosis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Paronychia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Pharyngitis Streptococcal
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    3
    Post Procedural Infection
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Respiratory Tract Infection
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Rhinitis
         subjects affected / exposed
    4 / 141 (2.84%)
         occurrences all number
    4
    Pneumonia
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Sinusitis
         subjects affected / exposed
    20 / 141 (14.18%)
         occurrences all number
    35
    Skin Bacterial Infection
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Tinea Cruris
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Sinobronchitis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Tooth Abscess
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Tinea Versicolour
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Tooth Infection
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Urinary Tract Infection
         subjects affected / exposed
    23 / 141 (16.31%)
         occurrences all number
    37
    Upper Respiratory Tract Infection
         subjects affected / exposed
    27 / 141 (19.15%)
         occurrences all number
    34
    Viral Infection
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Vaginal Infection
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Wound Infection
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Wound Sepsis
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Fluid Retention
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Decreased Appetite
         subjects affected / exposed
    3 / 141 (2.13%)
         occurrences all number
    5
    Dehydration
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    3
    Glucose Tolerance Impaired
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    2
    Gout
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    2
    Hyperkalaemia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Iron Deficiency
         subjects affected / exposed
    2 / 141 (1.42%)
         occurrences all number
    3
    Vitamin B12 Deficiency
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Type 2 Diabetes Mellitus
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1
    Vitamin D Deficiency
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences all number
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Aug 2007
    It included the following changes: - The dose regimen was changed from 200 mg every other week with dose-titration to effect to 200 mg once a week without the option to dose-titrate to effect. - In addition, it reduced the treatment period from 2 years to 6 months in accordance with the extension of the treatment period in the studies that were to roll into this open-label extension study. - It also modified the protocol to include subjects who completed study ISIS 301012-CS7. - Other modifications were made to maintain consistency between this study and other ongoing mipomersen clinical trials. The background information for the drug was updated to reflect the status of the mipomersen development program and to be consistent with the Investigator’s Brochure. - Minor changes were also made to improve the overall clarity of the original protocol.
    17 Jul 2008
    It included the following changes: - This amendment indicated that sponsorship was transferred from Isis Pharmaceuticals, Inc. to the Genzyme Corporation. - The safety reporting information was updated to provide contact information for the Genzyme Pharmacovigilance Department. - Modifications were made to extend dosing of mipomersen from 26 weeks to 52 weeks for the purpose of obtaining additional long-term safety and efficacy data. - Minor changes were also made to improve the overall clarity of the protocol and to align the text with the Investigator’s Brochure.
    24 Aug 2009
    It included the following changes: Dosing of mipomersen was extended from 52 weeks to 104 weeks for the purpose of obtaining additional long-term safety and efficacy data. - Included subjects who completed study MIPO3500108, which expanded the population to include subjects with severe hypercholesterolemia. The title of the study was updated to reflect this change. - Safety monitoring and stopping rules were revised to reflect information from the larger safety database. - This amendment also allowed for temporary dose adjustment for liver chemistry elevations, as well as for injection site reactions and constitutional symptoms leading the subject to consider discontinuation from the study. - Added a new section to the protocol recommending magnetic resonance imaging (MRI) or computed tomography (CT) scanning if clinically indicated. - This amendment noted that additional pharmacokinetic (PK) samples were to be drawn (not just for trough levels), in order to determine peak mipomersen levels after dosing. - Minor changes were also made to improve the overall clarity of the protocol and to align the text with the Investigator’s Brochure.
    17 Feb 2010
    It included the following changes: - Included MRI assessments of liver fat fraction at approximately 6-month intervals during the study. These MRI assessments were added to provide further characterization of potential changes in liver fat with long-term treatment with mipomersen. - In addition, it included a metabolomics analysis, which was added to help in understanding the cellular mechanisms underlying any imaging findings observed. - Other changes included minor changes to safety monitoring rules and clarifications made to study conduct and corrections to minor inconsistencies.
    18 May 2011
    It included the following changes: - Extended dosing from 2 years to 4 years or until mipomersen was commercially available (whichever came first) for the purpose of obtaining additional long-term safety and efficacy data. - Included that subjects must establish sufficient sustained efficacy throughout the treatment period per Investigator judgment, such as ≥15% LDL-C reduction from the subject's primary study baseline value, regardless of dosing regimen. - Dose adjustment instructions were modified to align with current development plans for mipomersen, specifically, to offer an alternative dosing regimen (70 mg thrice per week) for subjects with intolerable injection site reactions or flu-like symptoms with the 200 mg per week injections and to extend the dose interval for subjects with liver enzyme elevations (200 mg every other week). - Included additional post-dose serial PK blood samples for the purpose of further exploring the PK profile after mipomersen administration.
    12 Sep 2011
    It included following changes:- Biopsy data collected in order to evaluate whether hepatic abnormalities were present in subjects who had already completed, or were expected to complete, more than 2 years of treatment. - Blood samples collected at the visits specified on the schedule of events and stored specifically for hepatic biomarker testing.

    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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