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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study followed by an Open-Label continuation Period to Assess the Safety and Efficacy of Two Different Regimens of Mipomersen in Patients with Familial Hypercholesterolemia and Inadequately Controlled Low-Density-Lipoprotein Cholesterol

    Summary
    EudraCT number
    		 2011-001480-42
    Trial protocol
    		 ES   SE   BE   GB   FR   HU   DE   CZ   GR   IT   PL   SK   NL   DK  
    Global end of trial date
    16 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jul 2019
    First version publication date
    18 Jul 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MIPO3801011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01475825
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Sanofi: EFC12875
    Sponsors
    Sponsor organisation name
    Genzyme Corporation
    Sponsor organisation address
    500 Kendall Street, Cambridge, MA, United States, 02142
    Public contact
    Sanofi aventis recherche & développement, Trial Transparency Team, Contact-US@sanofi.com
    Scientific contact
    Sanofi aventis recherche & développement, Trial Transparency Team, 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 Apr 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether mipomersen (ISIS 301012) significantly reduces atherogenic lipid levels in subjects with severe heterozygous familial hypercholesterolemia (severe HeFH), defined as low-density lipoprotein cholesterol (LDL-C) levels ≥200 mg/dL plus the presence of coronary heart disease (CHD)/risk equivalents or LDL-C levels ≥300 mg/dL regardless of the presence of CHD/risk equivalents (referred to as Cohort 1) compared to placebo. Two different mipomersen dosing regimens will be studied: subcutaneous (SC) mipomersen 200 mg once weekly versus placebo, and SC mipomersen 70 mg thrice weekly versus placebo.
    Protection of trial 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
    15 Dec 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 18
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Poland: 23
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Croatia: 4
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    India: 8
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Malaysia: 5
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Russian Federation: 62
    Country: Number of subjects enrolled
    South Africa: 11
    Country: Number of subjects enrolled
    Korea, Republic of: 2
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    Ukraine: 28
    Country: Number of subjects enrolled
    United States: 36
    Worldwide total number of subjects
    310
    EEA total number of subjects
    117
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    260
    From 65 to 84 years
    50
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Study was conducted from 15 Dec 2011 to 16 Feb 2016. Out of 310 randomized subjects, 201 were in Cohort 1 and 109 in Cohort 2. One subject in the Cohort 1/Regimen B/Placebo group was randomized but not treated, hence not considered in safety population.

    Pre-assignment
    Screening details
    		 During the 4-week Screening period, subjects were evaluated for inclusion in the study, and assigned to 1 of 2 cohorts. One subject in Cohort 1/Regimen B/ placebo group was randomized and completed some of the screening procedures (laboratory tests and imaging evaluations) into the study but withdrew prior to receiving treatment.

    Period 1
    Period 1 title
    BTP/BTP Follow up & OLC, except OLC FU (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Regimen A: Mipomersen, 200 mg, Once Weekly
    Arm description
    		 Subjects received once weekly subcutaneous (SC) injections of mipomersen sodium 200 milligrams (mg) during the 60-week Blinded Treatment Period (BTP). Subjects who chose to participate in the open label continuation (OLC) received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety Follow-up (FU) Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post-treatment safety FU Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mipomersen Sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Mipomersen Sodium 200 mg injection once weekly during the double-blind treatment period followed by same treatment in open label period in Regimen A.

    Arm title
    		 Regimen A: Placebo, Once Weekly
    Arm description
    		 Subjects received once weekly SC injections of Placebo during the 60-week BTP. Subjects who chose to participate in the OLC received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety FU Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post-treatment safety FU Period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo injection once weekly during the double blind treatment period in Regimen A.

    Investigational medicinal product name
    Mipomersen Sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Mipomersen Sodium 200 mg injection once weekly during the open label period in Regimen A.

    Arm title
    		 Regimen B: Mipomersen, 70 mg, Thrice Weekly
    Arm description
    		 Subjects received thrice weekly SC injections of mipomersen sodium 70 mg during the 60-week BTP. Subjects who chose to participate in the OLC received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety FU Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post-treatment safety FU Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mipomersen Sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Mipomersen Sodium 70 mg injections thrice weekly during the double blind treatment period followed by same treatment in open label period in Regimen B.

    Arm title
    		 Regimen B: Placebo, Thrice Weekly
    Arm description
    		 Subjects received thrice weekly SC injections of placebo during the 60-week BTP. Subjects who chose to participate in the OLC received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety FU Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post-treatment safety FU Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo injection thrice weekly during the double blind treatment period in Regimen B.

    Investigational medicinal product name
    Mipomersen Sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Mipomersen Sodium 70 mg injections thrice weekly during the open label period in Regimen B.

    Number of subjects in period 1 [1]
    		Regimen A: Mipomersen, 200 mg, Once Weekly Regimen A: Placebo, Once Weekly Regimen B: Mipomersen, 70 mg, Thrice Weekly Regimen B: Placebo, Thrice Weekly
    Started
    104
    51
    102
    52
    Randomized and Treated
    104
    51
    102
    52
    Completed Blinded Treatment Period (BTP)
    60
    42
    59
    40
    Entered Open-Label Continuation (OLC)
    45
    31
    44
    29
    Completed BTP, BTP Follow up, OLC
    37
    19
    38
    22
    Completed
    37
    19
    38
    22
    Not completed
    67
    32
    64
    30
         Consent withdrawn by subject
    9
    3
    11
    8
         Non-compliance with Study Drug
    1
    2
    4
    -
         Physician decision
    -
    1
    -
    -
         Not Available
    -
    -
    2
    -
         Did not enter OLC
    13
    11
    15
    10
         Adverse Event
    41
    15
    27
    11
         Death
    1
    -
    1
    -
         Lost to follow-up
    1
    -
    3
    1
         Protocol deviation
    1
    -
    -
    -
         Lack of efficacy
    -
    -
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Subject disposition has been reported for the treated subjects.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Regimen A: Mipomersen, 200 mg, Once Weekly
    Reporting group description
    		 Subjects received once weekly subcutaneous (SC) injections of mipomersen sodium 200 milligrams (mg) during the 60-week Blinded Treatment Period (BTP). Subjects who chose to participate in the open label continuation (OLC) received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety Follow-up (FU) Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post-treatment safety FU Period.

    Reporting group title
    Regimen A: Placebo, Once Weekly
    Reporting group description
    		 Subjects received once weekly SC injections of Placebo during the 60-week BTP. Subjects who chose to participate in the OLC received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety FU Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post-treatment safety FU Period.

    Reporting group title
    Regimen B: Mipomersen, 70 mg, Thrice Weekly
    Reporting group description
    		 Subjects received thrice weekly SC injections of mipomersen sodium 70 mg during the 60-week BTP. Subjects who chose to participate in the OLC received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety FU Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post-treatment safety FU Period.

    Reporting group title
    Regimen B: Placebo, Thrice Weekly
    Reporting group description
    		 Subjects received thrice weekly SC injections of placebo during the 60-week BTP. Subjects who chose to participate in the OLC received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety FU Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post-treatment safety FU Period.

    Reporting group values
    		 Regimen A: Mipomersen, 200 mg, Once Weekly Regimen A: Placebo, Once Weekly Regimen B: Mipomersen, 70 mg, Thrice Weekly Regimen B: Placebo, Thrice Weekly Total
    Number of subjects
    		 104 51 102 52 309
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.36 ( 9.766 ) 55.49 ( 10.481 ) 53.15 ( 11.918 ) 54.38 ( 9.939 ) -
    Gender categorical
    Units: Subjects
        Female
    		 58 29 54 27 168
        Male
    		 46 22 48 25 141
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 4 4 4 6 18
        Not Hispanic or Latino
    		 99 45 95 46 285
        Unknown or Not Reported
    		 1 2 3 0 6
    LDL-C Baseline Values
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 232 ( 93.1 ) 229 ( 72.3 ) 240 ( 76.7 ) 229 ( 81.4 ) -
    Subject analysis sets

    Subject analysis set title
    Cohort 1: Regimen A: Mipomersen, 200 mg, Once Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 1, who received once weekly SC injections of mipomersen sodium 200 mg during the 60-week Blinded Treatment Period, continued the dosing regimen during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Subject analysis set title
    Cohort 1: Regimen A: Placebo, Once Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 1, who received once weekly SC injections of Placebo during the 60-week Blinded Treatment Period, received the same full dose regimen of mipomersen (per their assigned regimen during the BTP) during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Subject analysis set title
    Cohort 1: Regimen B: Mipomersen, 70 mg, Thrice Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 1, who received thrice weekly SC injections of mipomersen sodium 70 mg during the 60-week Blinded Treatment Period, continued the dosing regimen during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Subject analysis set title
    Cohort 1: Regimen B: Placebo, Thrice Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 1, who received thrice weekly SC injections of placebo during the 60-week BTP, received the same full dose regimen of mipomersen (per their assigned regimen during the BTP) during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Subject analysis set title
    Cohort 2: Regimen A: Mipomersen, 200 mg, Once Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 2, who received once weekly SC injections of mipomersen sodium 200 mg during the 60-week Blinded Treatment Period, continued the dosing regimen during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Subject analysis set title
    Cohort 2: Regimen A: Placebo, Once Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 2, who received once weekly SC injections of Placebo during the 60-week Blinded Treatment Period, received the same full dose regimen of mipomersen (per their assigned regimen during the BTP) during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Subject analysis set title
    Cohort 2: Regimen B: Mipomersen, 70 mg, Thrice Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 2, who received thrice weekly SC injections of mipomersen sodium 70 mg during the 60-week Blinded Treatment Period, continued the dosing regimen during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Subject analysis set title
    Cohort 2: Regimen B: Placebo, Thrice Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 2, who received thrice weekly SC injections of placebo during the 60-week Blinded Treatment Period, received the same full dose regimen of mipomersen (per their assigned regimen during the BTP) during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Subject analysis sets values
    		 Cohort 1: Regimen A: Mipomersen, 200 mg, Once Weekly Cohort 1: Regimen A: Placebo, Once Weekly Cohort 1: Regimen B: Mipomersen, 70 mg, Thrice Weekly Cohort 1: Regimen B: Placebo, Thrice Weekly Cohort 2: Regimen A: Mipomersen, 200 mg, Once Weekly Cohort 2: Regimen A: Placebo, Once Weekly Cohort 2: Regimen B: Mipomersen, 70 mg, Thrice Weekly Cohort 2: Regimen B: Placebo, Thrice Weekly
    Number of subjects
    67
    34
    66
    33
    37
    17
    36
    19
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.2 ( 10.05 )
    56.2 ( 10.77 )
    51.7 ( 12.75 )
    56.1 ( 8.93 )
    58.5 ( 8.97 )
    54.1 ( 10.04 )
    55.8 ( 9.83 )
    51.5 ( 11.14 )
    Gender categorical
    Units: Subjects
        Female
    42
    21
    39
    19
    16
    8
    15
    8
        Male
    25
    13
    27
    14
    21
    9
    21
    11
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    2
    2
    3
    2
    2
    2
    1
    4
        Not Hispanic or Latino
    64
    31
    60
    31
    35
    14
    35
    15
        Unknown or Not Reported
    1
    1
    3
    0
    0
    1
    0
    0
    LDL-C Baseline Values
    Units: mg/dL
        arithmetic mean (standard deviation)
    262 ( 103.1 )
    255 ( 75.0 )
    274 ( 75.1 )
    263 ( 82.9 )
    177 ( 20.8 )
    179 ( 25.6 )
    178 ( 17.6 )
    169 ( 26.6 )

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Regimen A: Mipomersen, 200 mg, Once Weekly
    Reporting group description
    		 Subjects received once weekly subcutaneous (SC) injections of mipomersen sodium 200 milligrams (mg) during the 60-week Blinded Treatment Period (BTP). Subjects who chose to participate in the open label continuation (OLC) received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety Follow-up (FU) Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post-treatment safety FU Period.

    Reporting group title
    Regimen A: Placebo, Once Weekly
    Reporting group description
    		 Subjects received once weekly SC injections of Placebo during the 60-week BTP. Subjects who chose to participate in the OLC received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety FU Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post-treatment safety FU Period.

    Reporting group title
    Regimen B: Mipomersen, 70 mg, Thrice Weekly
    Reporting group description
    		 Subjects received thrice weekly SC injections of mipomersen sodium 70 mg during the 60-week BTP. Subjects who chose to participate in the OLC received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety FU Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post-treatment safety FU Period.

    Reporting group title
    Regimen B: Placebo, Thrice Weekly
    Reporting group description
    		 Subjects received thrice weekly SC injections of placebo during the 60-week BTP. Subjects who chose to participate in the OLC received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety FU Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post-treatment safety FU Period.

    Subject analysis set title
    Cohort 1: Regimen A: Mipomersen, 200 mg, Once Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 1, who received once weekly SC injections of mipomersen sodium 200 mg during the 60-week Blinded Treatment Period, continued the dosing regimen during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Subject analysis set title
    Cohort 1: Regimen A: Placebo, Once Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 1, who received once weekly SC injections of Placebo during the 60-week Blinded Treatment Period, received the same full dose regimen of mipomersen (per their assigned regimen during the BTP) during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Subject analysis set title
    Cohort 1: Regimen B: Mipomersen, 70 mg, Thrice Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 1, who received thrice weekly SC injections of mipomersen sodium 70 mg during the 60-week Blinded Treatment Period, continued the dosing regimen during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Subject analysis set title
    Cohort 1: Regimen B: Placebo, Thrice Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 1, who received thrice weekly SC injections of placebo during the 60-week BTP, received the same full dose regimen of mipomersen (per their assigned regimen during the BTP) during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Subject analysis set title
    Cohort 2: Regimen A: Mipomersen, 200 mg, Once Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 2, who received once weekly SC injections of mipomersen sodium 200 mg during the 60-week Blinded Treatment Period, continued the dosing regimen during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Subject analysis set title
    Cohort 2: Regimen A: Placebo, Once Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 2, who received once weekly SC injections of Placebo during the 60-week Blinded Treatment Period, received the same full dose regimen of mipomersen (per their assigned regimen during the BTP) during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Subject analysis set title
    Cohort 2: Regimen B: Mipomersen, 70 mg, Thrice Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 2, who received thrice weekly SC injections of mipomersen sodium 70 mg during the 60-week Blinded Treatment Period, continued the dosing regimen during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Subject analysis set title
    Cohort 2: Regimen B: Placebo, Thrice Weekly
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in Cohort 2, who received thrice weekly SC injections of placebo during the 60-week Blinded Treatment Period, received the same full dose regimen of mipomersen (per their assigned regimen during the BTP) during the 26-week Open-Label Continuation Period, and then entered the 24-week post-treatment safety FU period.

    Primary: Percent Change From Baseline To Primary Efficacy Time Point (PET) In LDL-C In Cohort 1

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    End point title
    		 Percent Change From Baseline To Primary Efficacy Time Point (PET) In LDL-C In Cohort 1
    End point description
    The percent change from baseline to PET in LDL-C was measured in Cohort 1, which included subjects with severe heterozygous familial hypercholesterolemia (HeFH). Severe HeFH was defined as LDL-C levels ≥200 mg/deciliter (dL) plus the presence of coronary heart disease (CHD)/risk equivalents or LDL-C levels ≥300 mg/dL regardless of the presence of CHD/risk equivalents. The full analysis set for Cohort 1 included all randomized subjects who took at least 1 dose of study drug in Cohort 1 (mipomersen or placebo), had a valid baseline LDL-C measurement, and had at least 1 post-baseline LDL-C measurement.
    End point type
    Primary
    End point timeframe
    Baseline and Week 61
    End point values
    		 Cohort 1: Regimen A: Mipomersen, 200 mg, Once Weekly Cohort 1: Regimen A: Placebo, Once Weekly Cohort 1: Regimen B: Mipomersen, 70 mg, Thrice Weekly Cohort 1: Regimen B: Placebo, Thrice Weekly
    Number of subjects analysed
    67
    34
    66
    33
    Units: percent change
        least squares mean (standard error)
    -27.17 ( 5.653 )
    -6.77 ( 6.749 )
    -22.96 ( 5.362 )
    -10.62 ( 5.765 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The comparison of percent changes between active treatment and placebo is performed using a mixed model for repeated measured (MMRM) with terms for baseline LDL-C, geographic region, gender, and statin use, treatment group, study visit, and study visit by treatment group interaction. The visits used in the model include Weeks 5, 17, 30, 42, 55 and 61. An unstructured variance-covariance structure was used to model within-subject errors.
    Comparison groups
    Cohort 1: Regimen A: Mipomersen, 200 mg, Once Weekly v Cohort 1: Regimen A: Placebo, Once Weekly
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 MMRM
    Parameter type
    		 Least squares mean difference
    Point estimate
    -20.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.8
         upper limit
    		 -7
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.697
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The comparison of percent changes between active treatment and placebo is performed using a MMRM with terms for baseline LDL-C, geographic region, gender, and statin use, treatment group, study visit, and study visit by treatment group interaction. The visits used in the model include Weeks 5, 17, 30, 42, 55 and 61. An unstructured variance-covariance structure was used to model within-subject errors.
    Comparison groups
    Cohort 1: Regimen B: Placebo, Thrice Weekly v Cohort 1: Regimen B: Mipomersen, 70 mg, Thrice Weekly
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.058
    Method
    		 MMRM
    Parameter type
    		 Least squares mean difference
    Point estimate
    -12.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.09
         upper limit
    		 0.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.406

    Secondary: Percent Change From Baseline To Primary Efficacy Time Point (PET) In LDL-C In Cohort 2

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    End point title
    		 Percent Change From Baseline To Primary Efficacy Time Point (PET) In LDL-C In Cohort 2
    End point description
    The percent change from baseline to PET in LDL-C was measured in Cohort 2, which included participants with HeFH with LDL-C levels ≥160 mg/dL and <200 mg/dL, plus the presence of CHD/risk equivalents. The full analysis set included all randomized subjects who took at least 1 dose of study drug (mipomersen or placebo), had a valid baseline LDL-C measurement, and had at least 1 post-baseline LDL-C measurement.
    End point type
    Secondary
    End point timeframe
    Baseline, PET (up to 60 weeks)
    End point values
    		 Cohort 2: Regimen A: Mipomersen, 200 mg, Once Weekly Cohort 2: Regimen A: Placebo, Once Weekly Cohort 2: Regimen B: Mipomersen, 70 mg, Thrice Weekly Cohort 2: Regimen B: Placebo, Thrice Weekly
    Number of subjects analysed
    37
    17
    36
    19
    Units: percent change
        least squares mean (standard error)
    -31.20 ( 8.927 )
    -9.25 ( 10.621 )
    -43.60 ( 8.342 )
    -13.57 ( 9.066 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline To Primary Efficacy Time Point (PET) In Apolipoprotein B (Apo B) In Cohort 1

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    End point title
    		 Percent Change From Baseline To Primary Efficacy Time Point (PET) In Apolipoprotein B (Apo B) In Cohort 1
    End point description
    The percent change from baseline to PET in Apo B was measured in subjects in Cohort 1 with HeFH during the Blinded Treatment Period. The full analysis set included all randomized subjects who took at least 1 dose of study drug (mipomersen or placebo), had a valid baseline LDL-C measurement, and had at least 1 post-baseline LDL-C measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 61
    End point values
    		 Cohort 1: Regimen A: Mipomersen, 200 mg, Once Weekly Cohort 1: Regimen A: Placebo, Once Weekly Cohort 1: Regimen B: Mipomersen, 70 mg, Thrice Weekly Cohort 1: Regimen B: Placebo, Thrice Weekly
    Number of subjects analysed
    67
    34
    66
    33
    Units: percent change
        least squares mean (standard deviation)
    -24.14 ( 5.058 )
    -2.83 ( 6.115 )
    -21.43 ( 4.861 )
    -7.28 ( 5.309 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline To Primary Efficacy Time Point (PET) In Apolipoprotein B (Apo B) In Cohort 2

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    End point title
    		 Percent Change From Baseline To Primary Efficacy Time Point (PET) In Apolipoprotein B (Apo B) In Cohort 2
    End point description
    The percent change from baseline to PET in Apo B was measured in subjects in Cohort 2 with HeFH during the Blinded Treatment Period. The full analysis set included all randomized subjects who took at least 1 dose of study drug (mipomersen or placebo), had a valid baseline LDL-C measurement, and had at least 1 post-baseline LDL-C measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 61
    End point values
    		 Cohort 2: Regimen A: Mipomersen, 200 mg, Once Weekly Cohort 2: Regimen A: Placebo, Once Weekly Cohort 2: Regimen B: Mipomersen, 70 mg, Thrice Weekly Cohort 2: Regimen B: Placebo, Thrice Weekly
    Number of subjects analysed
    37
    17
    36
    19
    Units: percent change
        least squares mean (standard error)
    -30.76 ( 7.309 )
    -6.67 ( 8.758 )
    -36.34 ( 7.039 )
    -3.77 ( 8.109 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline To Primary Efficacy Time Point (PET) in Lipoprotein (a) In Cohort 1

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    End point title
    		 Percent Change From Baseline To Primary Efficacy Time Point (PET) in Lipoprotein (a) In Cohort 1
    End point description
    The percent change from baseline to PET in Lipoprotein A1 was measured in subjects in Cohort 1 with HeFH during the Blinded Treatment Period. The full analysis set included all randomized subjects who took at least 1 dose of study drug (mipomersen or placebo), had a valid baseline LDL-C measurement, and had at least 1 post-baseline LDL-C measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 61
    End point values
    		 Cohort 1: Regimen A: Mipomersen, 200 mg, Once Weekly Cohort 1: Regimen A: Placebo, Once Weekly Cohort 1: Regimen B: Mipomersen, 70 mg, Thrice Weekly Cohort 1: Regimen B: Placebo, Thrice Weekly
    Number of subjects analysed
    67
    34
    66
    33
    Units: Percent change
        least squares mean (standard error)
    -18.84 ( 7.870 )
    -16.85 ( 9.959 )
    -27.18 ( 5.497 )
    -10.08 ( 5.992 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline To Primary Efficacy Time Point (PET) in Lipoprotein (a) In Cohort 2

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    End point title
    		 Percent Change From Baseline To Primary Efficacy Time Point (PET) in Lipoprotein (a) In Cohort 2
    End point description
    The percent change from baseline to PET in Lipoprotein A1 was measured in subjects in Cohort 2 with HeFH during the Blinded Treatment Period. The full analysis set included all randomized subjects who took at least 1 dose of study drug (mipomersen or placebo), had a valid baseline LDL-C measurement, and had at least 1 post-baseline LDL-C measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 61
    End point values
    		 Cohort 2: Regimen A: Mipomersen, 200 mg, Once Weekly Cohort 2: Regimen A: Placebo, Once Weekly Cohort 2: Regimen B: Mipomersen, 70 mg, Thrice Weekly Cohort 2: Regimen B: Placebo, Thrice Weekly
    Number of subjects analysed
    37
    17
    36
    19
    Units: percent change
        least squares mean (standard error)
    -23.41 ( 10.002 )
    -11.86 ( 11.871 )
    -35.56 ( 11.846 )
    18.79 ( 15.271 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were monitored from the time of the administration of the subject's first dose of study drug (mipomersen or placebo) through the subject's last visit of the Post-Treatment Period, up to Week 110.
    Adverse event reporting additional description
    Adverse events were collected for all randomized subjects who received at least 1 dose of study drug (mipomersen or placebo). There were 4 deaths occurred during the study of which one death occurred during OLC follow up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Regimen A: Placebo, Once Weekly
    Reporting group description
    		 Subjects received once weekly SC injections of Placebo during the 60-week BTP. Subjects who chose to participate in the OLC received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety FU Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post-treatment safety FU Period. One death occurred during BTP follow up.

    Reporting group title
    Regimen A: Mipomersen, 200 mg, Once Weekly
    Reporting group description
    		 Subjects received once weekly SC injections of mipomersen sodium 200 mg during the 60-week BTP. Subjects who chose to participate in the OLC received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety FU Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post-treatment safety FU Period. One death occurred during BTP and the other one occurred during OLC follow up period.

    Reporting group title
    Regimen B: Placebo, Thrice Weekly
    Reporting group description
    		 Subjects received thrice weekly SC injections of placebo during the 60-week BTP. Subjects who chose to participate in the OLC received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety FU Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post- treatment safety FU Period.

    Reporting group title
    Regimen B: Mipomersen, 70 mg, Thrice Weekly
    Reporting group description
    		 Subjects received thrice weekly SC injections of mipomersen sodium 70 mg during the 60-week BTP. Subjects who chose to participate in the OLC received during 26 weeks the same full dose regimen of mipomersen per their assigned regimen during the BTP. A 24-week post-treatment safety FU Period was conducted during which subjects, including those who discontinued prematurely and received ≥1 dose of investigational product, were asked to complete 2 post-treatment visits. Subjects who chose not to participate in the OLC continued directly into the post-treatment safety FU Period. One death occurred during BTP follow up.

    Serious adverse events
    		 Regimen A: Placebo, Once Weekly Regimen A: Mipomersen, 200 mg, Once Weekly Regimen B: Placebo, Thrice Weekly Regimen B: Mipomersen, 70 mg, Thrice Weekly
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 51 (25.49%)
    17 / 104 (16.35%)
    11 / 52 (21.15%)
    23 / 102 (22.55%)
         number of deaths (all causes)
    1
    2
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphoma
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism Venous
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    1 / 52 (1.92%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Artery Stenosis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 104 (1.92%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Drug Intolerance
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    1 / 52 (1.92%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza Like Illness
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 104 (0.96%)
    1 / 52 (1.92%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical Polyp
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    1 / 52 (1.92%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibrocystic Breast Disease
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian Cyst Torsion
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea Exertional
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuritic Pain
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    1 / 52 (1.92%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    1 / 52 (1.92%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Major Depression
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    1 / 52 (1.92%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    1 / 52 (1.92%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Helicobacter Test Negative
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    1 / 52 (1.92%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Low Density Lipoprotein Increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Coronary Artery Restenosis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post Procedural Haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    1 / 52 (1.92%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    2 / 52 (3.85%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    4 / 51 (7.84%)
    7 / 104 (6.73%)
    4 / 52 (7.69%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 104 (0.96%)
    3 / 52 (5.77%)
    4 / 102 (3.92%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 104 (2.88%)
    1 / 52 (1.92%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Stenosis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    1 / 52 (1.92%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    3 / 102 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid Artery Stenosis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral Infarction
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hemiparesis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    1 / 52 (1.92%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Eye Haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Hernia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    1 / 52 (1.92%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis Erosive
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large Intestine Perforation
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    1 / 52 (1.92%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction Gastric
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic Cyst
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Cyst
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint Contracture
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Osteoarthritis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    1 / 52 (1.92%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia Pyelonephritis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 104 (0.96%)
    0 / 52 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Regimen A: Placebo, Once Weekly Regimen A: Mipomersen, 200 mg, Once Weekly Regimen B: Placebo, Thrice Weekly Regimen B: Mipomersen, 70 mg, Thrice Weekly
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 51 (70.59%)
    87 / 104 (83.65%)
    37 / 52 (71.15%)
    82 / 102 (80.39%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 51 (11.76%)
    7 / 104 (6.73%)
    6 / 52 (11.54%)
    6 / 102 (5.88%)
         occurrences all number
    6
    14
    6
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 51 (1.96%)
    7 / 104 (6.73%)
    3 / 52 (5.77%)
    2 / 102 (1.96%)
         occurrences all number
    1
    9
    3
    2
    Influenza Like Illness
         subjects affected / exposed
    15 / 51 (29.41%)
    46 / 104 (44.23%)
    14 / 52 (26.92%)
    29 / 102 (28.43%)
         occurrences all number
    55
    160
    32
    109
    Injection Site Discolouration
         subjects affected / exposed
    3 / 51 (5.88%)
    6 / 104 (5.77%)
    3 / 52 (5.77%)
    5 / 102 (4.90%)
         occurrences all number
    3
    7
    3
    5
    Injection Site Erythema
         subjects affected / exposed
    5 / 51 (9.80%)
    8 / 104 (7.69%)
    5 / 52 (9.62%)
    14 / 102 (13.73%)
         occurrences all number
    5
    13
    6
    17
    Injection Site Induration
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 104 (0.96%)
    4 / 52 (7.69%)
    4 / 102 (3.92%)
         occurrences all number
    2
    1
    5
    4
    Injection Site Pain
         subjects affected / exposed
    3 / 51 (5.88%)
    14 / 104 (13.46%)
    3 / 52 (5.77%)
    8 / 102 (7.84%)
         occurrences all number
    3
    27
    4
    10
    Injection Site Pruritus
         subjects affected / exposed
    5 / 51 (9.80%)
    3 / 104 (2.88%)
    3 / 52 (5.77%)
    7 / 102 (6.86%)
         occurrences all number
    5
    4
    4
    7
    Injection Site Swelling
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 104 (3.85%)
    2 / 52 (3.85%)
    8 / 102 (7.84%)
         occurrences all number
    2
    8
    9
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 51 (1.96%)
    5 / 104 (4.81%)
    3 / 52 (5.77%)
    6 / 102 (5.88%)
         occurrences all number
    1
    6
    3
    6
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    8 / 51 (15.69%)
    22 / 104 (21.15%)
    1 / 52 (1.92%)
    20 / 102 (19.61%)
         occurrences all number
    10
    29
    1
    30
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    7 / 51 (13.73%)
    18 / 104 (17.31%)
    2 / 52 (3.85%)
    13 / 102 (12.75%)
         occurrences all number
    10
    24
    2
    16
    Bacterial Test Positive
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 104 (0.96%)
    1 / 52 (1.92%)
    3 / 102 (2.94%)
         occurrences all number
    4
    1
    1
    3
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 104 (0.96%)
    3 / 52 (5.77%)
    6 / 102 (5.88%)
         occurrences all number
    2
    1
    3
    6
    C-Reactive Protein Increased
         subjects affected / exposed
    3 / 51 (5.88%)
    4 / 104 (3.85%)
    3 / 52 (5.77%)
    7 / 102 (6.86%)
         occurrences all number
    4
    4
    3
    7
    Hepatic Enzyme Increased
         subjects affected / exposed
    0 / 51 (0.00%)
    9 / 104 (8.65%)
    0 / 52 (0.00%)
    4 / 102 (3.92%)
         occurrences all number
    0
    9
    0
    4
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 104 (0.00%)
    0 / 52 (0.00%)
    1 / 102 (0.98%)
         occurrences all number
    4
    0
    0
    1
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    5 / 51 (9.80%)
    10 / 104 (9.62%)
    7 / 52 (13.46%)
    5 / 102 (4.90%)
         occurrences all number
    6
    15
    8
    5
    Palpitations
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 104 (1.92%)
    3 / 52 (5.77%)
    3 / 102 (2.94%)
         occurrences all number
    0
    2
    5
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 51 (1.96%)
    9 / 104 (8.65%)
    1 / 52 (1.92%)
    5 / 102 (4.90%)
         occurrences all number
    2
    14
    1
    5
    Headache
         subjects affected / exposed
    4 / 51 (7.84%)
    8 / 104 (7.69%)
    5 / 52 (9.62%)
    10 / 102 (9.80%)
         occurrences all number
    6
    17
    9
    11
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 104 (1.92%)
    3 / 52 (5.77%)
    2 / 102 (1.96%)
         occurrences all number
    2
    2
    3
    2
    Gastrointestinal disorders
    Abdominal Pain Lower
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 104 (0.00%)
    1 / 52 (1.92%)
    0 / 102 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 51 (3.92%)
    7 / 104 (6.73%)
    1 / 52 (1.92%)
    8 / 102 (7.84%)
         occurrences all number
    2
    7
    1
    11
    Nausea
         subjects affected / exposed
    3 / 51 (5.88%)
    9 / 104 (8.65%)
    2 / 52 (3.85%)
    8 / 102 (7.84%)
         occurrences all number
    3
    13
    4
    10
    Hepatobiliary disorders
    Hepatic Steatosis
         subjects affected / exposed
    3 / 51 (5.88%)
    11 / 104 (10.58%)
    1 / 52 (1.92%)
    11 / 102 (10.78%)
         occurrences all number
    3
    11
    1
    11
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 104 (0.00%)
    3 / 52 (5.77%)
    2 / 102 (1.96%)
         occurrences all number
    0
    0
    3
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 51 (7.84%)
    3 / 104 (2.88%)
    3 / 52 (5.77%)
    2 / 102 (1.96%)
         occurrences all number
    6
    5
    3
    4
    Back Pain
         subjects affected / exposed
    2 / 51 (3.92%)
    6 / 104 (5.77%)
    4 / 52 (7.69%)
    4 / 102 (3.92%)
         occurrences all number
    2
    6
    4
    4
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 51 (1.96%)
    5 / 104 (4.81%)
    3 / 52 (5.77%)
    4 / 102 (3.92%)
         occurrences all number
    1
    5
    3
    4
    Myalgia
         subjects affected / exposed
    0 / 51 (0.00%)
    9 / 104 (8.65%)
    4 / 52 (7.69%)
    7 / 102 (6.86%)
         occurrences all number
    0
    9
    4
    9
    Pain In Extremity
         subjects affected / exposed
    3 / 51 (5.88%)
    5 / 104 (4.81%)
    0 / 52 (0.00%)
    5 / 102 (4.90%)
         occurrences all number
    3
    6
    0
    6
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 51 (9.80%)
    7 / 104 (6.73%)
    4 / 52 (7.69%)
    3 / 102 (2.94%)
         occurrences all number
    8
    10
    4
    3
    Influenza
         subjects affected / exposed
    4 / 51 (7.84%)
    5 / 104 (4.81%)
    6 / 52 (11.54%)
    10 / 102 (9.80%)
         occurrences all number
    6
    7
    8
    11
    Nasopharyngitis
         subjects affected / exposed
    5 / 51 (9.80%)
    7 / 104 (6.73%)
    7 / 52 (13.46%)
    12 / 102 (11.76%)
         occurrences all number
    6
    10
    9
    13
    Respiratory Tract Infection Viral
         subjects affected / exposed
    1 / 51 (1.96%)
    6 / 104 (5.77%)
    0 / 52 (0.00%)
    3 / 102 (2.94%)
         occurrences all number
    1
    15
    0
    6
    Upper Respiratory Tract Infection
         subjects affected / exposed
    5 / 51 (9.80%)
    5 / 104 (4.81%)
    3 / 52 (5.77%)
    9 / 102 (8.82%)
         occurrences all number
    5
    5
    3
    12
    Urinary Tract Infection
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 104 (3.85%)
    1 / 52 (1.92%)
    10 / 102 (9.80%)
         occurrences all number
    1
    4
    1
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jan 2016
    Following amendments were made: 1) OLC period was introduced. Subjects who completed BTP prior to implementation of amendment 2 and had been followed <=8 weeks during the safety follow-up period were allowed to restart dosing immediately. Subjects who had completed the BTP and had been followed for >=8 weeks during the safety follow up period were allowed to restart dosing after a 1-week evaluation period if the results were acceptable. 2) An Independent Cardiovascular Adjudication Committee was established to apply uniform criteria for the evaluation of prospectively defined major adverse cardiac events.

    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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