Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   42869   clinical trials with a EudraCT protocol, of which   7063   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .

    Clinical Trials marked as "Trial now transitioned" were transitioned to the Clinical Trial Regulation 536/2014 and can be further followed in the Clinical Trial Information System  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, with an Open Label Extension, Phase 2/3 Study of ISIS 304801 Administered Subcutaneously to Subjects with Familial Partial Lipodystrophy

    Summary
    EudraCT number
    2015-000493-35
    Trial protocol
    DE   BE   PT   ES   NL   GR   IT  
    Global end of trial date
    13 Nov 2019

    Results information
    Results version number
    v2(current)
    This version publication date
    07 Nov 2021
    First version publication date
    19 Aug 2021
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Sections such as subject disposition, baseline characteristics and endpoints were updated.

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    ISIS-304801-CS17
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02527343
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Ionis Pharmaceuticals, Inc.
    Sponsor organisation address
    2855 Gazelle Ct., Carlsbad, CA, United States, 92010
    Public contact
    Joseph Tami, Ionis Pharmaceuticals, Inc., +1 760603-2430, jtami@ionisph.com
    Scientific contact
    Joseph Tami, Ionis Pharmaceuticals, Inc., +1 760603-2430, jtami@ionisph.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
    13 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Nov 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate the efficacy of volanesorsen for reduction in severity of metabolic derangement in subjects with familial partial lipodystrophy (FPL) with hypertriglyceridemia and uncontrolled diabetes.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Dec 2015
    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: 2
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Russian Federation: 4
    Country: Number of subjects enrolled
    United States: 29
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Netherlands: 1
    Worldwide total number of subjects
    40
    EEA total number of subjects
    4
    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)
    37
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    The study was conducted at 12 study centers in the United States, Russia, Brazil, Germany, Belgium, Canada, and Netherlands from 28 December 2015 to 13 November 2019.

    Pre-assignment
    Screening details
    A total of 40 subjects were randomized into this study.

    Period 1
    Period 1 title
    RT Period: Weeks 1 to 52
    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
    No

    Arm title
    Randomized Treatment Period: Placebo
    Arm description
    Subjects received volanesorsen-matching placebo as a subcutaneous (SC) injection once-weekly from Weeks 1 to 52 of the randomized treatment (RT) period. Subjects were allowed dose adjustment based on monitoring rules.
    Arm type
    Placebo

    Investigational medicinal product name
    Volanesorsen-matching Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Volanesorsen-matching placebo administered as a SC injection.

    Arm title
    Randomized Treatment Period: Volanesorsen
    Arm description
    Subjects received 300 mg of volanesorsen as a SC injection once-weekly from Weeks 1 to 52 of the randomized treatment period. Subjects were allowed dose adjustment based on monitoring rules.
    Arm type
    Experimental

    Investigational medicinal product name
    Volanesorsen
    Investigational medicinal product code
    Other name
    ISIS 304801, IONIS-APOCIIIRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Volanesorsen 300 mg administered as a SC injection.

    Number of subjects in period 1
    Randomized Treatment Period: Placebo Randomized Treatment Period: Volanesorsen
    Started
    19
    21
    Completed
    13
    14
    Not completed
    6
    7
         Adverse Event (AE) or Serious-Adverse Event (SAE)
    -
    4
         Investigator's Judgement
    1
    -
         Voluntary withdrawal
    1
    -
         Unspecified
    4
    3
    Period 2
    Period 2 title
    RT Post Treatment Follow-up: Weeks 54-65
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Assessor, Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Randomized Post-Treatment Follow-up Period: Placebo
    Arm description
    Following the randomized treatment period, subjects who received volanesorsen-matching placebo in randomized treatment period and did not enter the open label extension (OLE) period went straight to the 13-week post-treatment (PT) follow-up period.
    Arm type
    Placebo

    Investigational medicinal product name
    Volanesorsen-matching Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Volanesorsen-matching placebo administered as a SC injection.

    Arm title
    Randomized Post-Treatment Follow-up Period: Volanesorsen
    Arm description
    Following the randomized treatment period, subjects who received 300 mg of volanesorsen in randomized treatment period and did not enter in the OLE period went straight to the 13-week post-treatment follow-up period.
    Arm type
    Experimental

    Investigational medicinal product name
    Volanesorsen
    Investigational medicinal product code
    Other name
    ISIS 304801, IONIS-APOCIIIRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Volanesorsen 300 mg administered as a SC injection.

    Number of subjects in period 2
    Randomized Post-Treatment Follow-up Period: Placebo Randomized Post-Treatment Follow-up Period: Volanesorsen
    Started
    7
    9
    Completed
    6
    7
    Not completed
    1
    2
         AE or SAE
    1
    -
         Unspecified
    -
    2
    Period 3
    Period 3 title
    OLE Period-Year 1: Week 53 to 104
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Open-Label Extension Period: Placebo/Volanesorsen
    Arm description
    Subjects in the Randomized Treatment Period: Placebo arm group who completed the randomized treatment period, were to receive 300 mg of volanesorsen as a SC injection once-weekly for 52 weeks (from Weeks 53 to 104) in the OLE period. Subjects were allowed dose adjustment based on monitoring rules.
    Arm type
    Experimental

    Investigational medicinal product name
    Volanesorsen
    Investigational medicinal product code
    Other name
    ISIS 304801, IONIS-APOCIIIRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Volanesorsen 300 mg administered as a SC injection.

    Arm title
    Open-Label Extension Period: Volanesorsen/Volanesorsen
    Arm description
    Subjects in the Randomized Treatment Period: Volanesorsen arm group who completed the randomized treatment period, received 300 mg of volanesorsen as a SC injection once-weekly for 52 weeks (from Weeks 53 to 104) in the OLE period. Subjects were allowed dose adjustment based on monitoring rules.
    Arm type
    Experimental

    Investigational medicinal product name
    Volanesorsen
    Investigational medicinal product code
    Other name
    ISIS 304801, IONIS-APOCIIIRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Volanesorsen 300 mg administered as a SC injection.

    Number of subjects in period 3
    Open-Label Extension Period: Placebo/Volanesorsen Open-Label Extension Period: Volanesorsen/Volanesorsen
    Started
    12
    12
    Completed
    1
    3
    Not completed
    11
    9
         Investigator's Judgement
    1
    -
         AE or SAE
    2
    1
         Voluntary withdrawal
    3
    1
         Unspecified
    5
    7
    Period 4
    Period 4 title
    OLE Period-Year 2: Week 105 to 156
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Open-Label Extension Period: Placebo/Volanesorsen
    Arm description
    Subjects in the Randomized Treatment Period: Placebo arm group who completed the randomized treatment period, after Week 104 of the OLE period, subjects had the option of continuing treatment with 300 mg of volanesorsen as a SC injection once-weekly for up to an additional 52 weeks (from Week 105 to 156). Subjects were allowed dose adjustment based on monitoring rules.
    Arm type
    Placebo

    Investigational medicinal product name
    Volanesorsen
    Investigational medicinal product code
    Other name
    ISIS 304801, IONIS-APOCIIIRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Volanesorsen 300 mg administered as a SC injection.

    Arm title
    Open-Label Extension Period: Volanesorsen/Volanesorsen
    Arm description
    Subjects in the Randomized Treatment Period: Volanesorsen arm group who completed the randomized treatment period, after Week 104 of the OLE period, subjects had the option of continuing treatment with 300 mg of volanesorsen as a SC injection once-weekly for up to an additional 52 weeks (from Week 105 to 156). Subjects were allowed dose adjustment based on monitoring rules.
    Arm type
    Experimental

    Investigational medicinal product name
    Volanesorsen
    Investigational medicinal product code
    Other name
    ISIS 304801, IONIS-APOCIIIRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Volanesorsen 300 mg administered as a SC injection.

    Number of subjects in period 4
    Open-Label Extension Period: Placebo/Volanesorsen Open-Label Extension Period: Volanesorsen/Volanesorsen
    Started
    1
    2
    Completed
    0
    0
    Not completed
    1
    2
         Unspecified
    1
    2
    Period 5
    Period 5 title
    PT Follow-up: Weeks 104 to 169
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    OLE Post-Treatment Follow up Period: Placebo/Volanesorsen
    Arm description
    Subjects in the Randomized Treatment Period: Placebo arm group who completed the randomized treatment period and were not entered in the option for an additional 52 weeks of dosing in the OLE post-treatment period went straight to a 13-week post-treatment follow-up period after completion of the first 52 weeks (from Weeks 53 to 104) of the OLE. Subjects were allowed dose adjustment based on monitoring rules. Subjects who were entered in the OLE post-treatment period went straight to a 13-week post-treatment follow-up period after completion of Week 156 of the OLE.
    Arm type
    Placebo

    Investigational medicinal product name
    Volanesorsen
    Investigational medicinal product code
    Other name
    ISIS 304801, IONIS-APOCIIIRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Volanesorsen 300 mg administered as a SC injection.

    Arm title
    OLE Post-Treatment Follow up Period: Volanesorsen/Volanesorsen
    Arm description
    Subjects in the Randomized Treatment Period: Volanesorsen arm group who completed the randomized treatment period and were not entered in the option for an additional 52 weeks of dosing in the OLE post-treatment period went straight to a 13-week post-treatment follow-up period after completion of the first 52 weeks (from Weeks 53 to 104) of the OLE. Subjects were allowed dose adjustment based on monitoring rules. Subjects who were entered in the OLE post-treatment period went straight to a 13-week post-treatment follow-up period after completion of Week 156 of the OLE.
    Arm type
    Experimental

    Investigational medicinal product name
    Volanesorsen
    Investigational medicinal product code
    Other name
    ISIS 304801, IONIS-APOCIIIRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Volanesorsen 300 mg administered as a SC injection.

    Number of subjects in period 5
    OLE Post-Treatment Follow up Period: Placebo/Volanesorsen OLE Post-Treatment Follow up Period: Volanesorsen/Volanesorsen
    Started
    12
    12
    Completed
    11
    11
    Not completed
    1
    1
         Voluntary withdrawal
    1
    -
         Unspecified
    -
    1

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Randomized Treatment Period: Placebo
    Reporting group description
    Subjects received volanesorsen-matching placebo as a subcutaneous (SC) injection once-weekly from Weeks 1 to 52 of the randomized treatment (RT) period. Subjects were allowed dose adjustment based on monitoring rules.

    Reporting group title
    Randomized Treatment Period: Volanesorsen
    Reporting group description
    Subjects received 300 mg of volanesorsen as a SC injection once-weekly from Weeks 1 to 52 of the randomized treatment period. Subjects were allowed dose adjustment based on monitoring rules.

    Reporting group values
    Randomized Treatment Period: Placebo Randomized Treatment Period: Volanesorsen Total
    Number of subjects
    19 21
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    48 ± 12 46 ± 10 -
    Gender categorical
    Units: Subjects
        Female
    14 15 29
        Male
    5 6 11
    Race
    Units: Subjects
        White
    17 20 37
        Asian
    1 1 2
        Other Race
    1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1 1 2
        Not Hispanic or Latino
    18 20 38
        Unknown or Not Reported
    0 0 0
    Fasting Triglycerides
    Units: milligrams per deciliter (mg/dL)
        arithmetic mean (standard deviation)
    1290.95 ± 1296.19 1241.31 ± 1090.83 -
    Hepatic Fat Fraction
    Number analyzed (“n”) (n= 16, 17) signifies the number of subjects with data available for hepatic fat fraction.
    Units: percentage (Hepatic Fat Fraction)
        arithmetic mean (standard deviation)
    17.00 ± 7.52 18.10 ± 8.41 -
    Hemoglobin A1c
    Units: percentage of HbA1c
        arithmetic mean (standard deviation)
    8.25 ± 1.13 7.84 ± 1.62 -
    Short Form (SF)-36 Weighted Sum of Scores
    The SF-36 Health Survey is a 36-item, subject-reported survey of subject health. SF-36 consists of 8 health dimensions,which are weighted sums of the questions in each section. SF-36 included 36 questions related to 8 health dimensions:physical functioning, physical role functioning, bodily pain, general health perceptions, vitality, social role functioning,emotional role functioning, and mental health. Each dimension was scored on a scale of 0 to 100 where, higher score = better quality of life. “n” (n= 16, 17)= number of subjects with data available.
    Units: score on a scale
        arithmetic mean (standard deviation)
    48.51 ± 12.83 46.31 ± 12.38 -
    EQ-5D Questionnaires: Index Scores
    EQ-5D-5L: standardized health-related quality of life (QoL) questionnaire. EQ-5D-5L consists of 2 components: health state profile and VAS. EQ-5D health state profile comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state. Number analyzed (n= 12, 17 ) = number of subjects with data available.
    Units: score on a scale
        arithmetic mean (standard deviation)
    0.83 ± 0.20 0.84 ± 0.18 -
    EQ-5D Questionnaires: Visual Analog Scale
    EQ-5D-5L is a standardized health-related QoL questionnaire EQ-5D-5L consists of two components: a health state profile and VAS. EQ-5D-5L- VAS is designed to rate the subject’s current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. Number analyzed (n= 12, 17) signifies the number of subjects with data available for EQ-5D Questionnaires: VAS.
    Units: score on a scale
        arithmetic mean (standard deviation)
    70 ± 18 71 ± 18 -

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Randomized Treatment Period: Placebo
    Reporting group description
    Subjects received volanesorsen-matching placebo as a subcutaneous (SC) injection once-weekly from Weeks 1 to 52 of the randomized treatment (RT) period. Subjects were allowed dose adjustment based on monitoring rules.

    Reporting group title
    Randomized Treatment Period: Volanesorsen
    Reporting group description
    Subjects received 300 mg of volanesorsen as a SC injection once-weekly from Weeks 1 to 52 of the randomized treatment period. Subjects were allowed dose adjustment based on monitoring rules.
    Reporting group title
    Randomized Post-Treatment Follow-up Period: Placebo
    Reporting group description
    Following the randomized treatment period, subjects who received volanesorsen-matching placebo in randomized treatment period and did not enter the open label extension (OLE) period went straight to the 13-week post-treatment (PT) follow-up period.

    Reporting group title
    Randomized Post-Treatment Follow-up Period: Volanesorsen
    Reporting group description
    Following the randomized treatment period, subjects who received 300 mg of volanesorsen in randomized treatment period and did not enter in the OLE period went straight to the 13-week post-treatment follow-up period.
    Reporting group title
    Open-Label Extension Period: Placebo/Volanesorsen
    Reporting group description
    Subjects in the Randomized Treatment Period: Placebo arm group who completed the randomized treatment period, were to receive 300 mg of volanesorsen as a SC injection once-weekly for 52 weeks (from Weeks 53 to 104) in the OLE period. Subjects were allowed dose adjustment based on monitoring rules.

    Reporting group title
    Open-Label Extension Period: Volanesorsen/Volanesorsen
    Reporting group description
    Subjects in the Randomized Treatment Period: Volanesorsen arm group who completed the randomized treatment period, received 300 mg of volanesorsen as a SC injection once-weekly for 52 weeks (from Weeks 53 to 104) in the OLE period. Subjects were allowed dose adjustment based on monitoring rules.
    Reporting group title
    Open-Label Extension Period: Placebo/Volanesorsen
    Reporting group description
    Subjects in the Randomized Treatment Period: Placebo arm group who completed the randomized treatment period, after Week 104 of the OLE period, subjects had the option of continuing treatment with 300 mg of volanesorsen as a SC injection once-weekly for up to an additional 52 weeks (from Week 105 to 156). Subjects were allowed dose adjustment based on monitoring rules.

    Reporting group title
    Open-Label Extension Period: Volanesorsen/Volanesorsen
    Reporting group description
    Subjects in the Randomized Treatment Period: Volanesorsen arm group who completed the randomized treatment period, after Week 104 of the OLE period, subjects had the option of continuing treatment with 300 mg of volanesorsen as a SC injection once-weekly for up to an additional 52 weeks (from Week 105 to 156). Subjects were allowed dose adjustment based on monitoring rules.
    Reporting group title
    OLE Post-Treatment Follow up Period: Placebo/Volanesorsen
    Reporting group description
    Subjects in the Randomized Treatment Period: Placebo arm group who completed the randomized treatment period and were not entered in the option for an additional 52 weeks of dosing in the OLE post-treatment period went straight to a 13-week post-treatment follow-up period after completion of the first 52 weeks (from Weeks 53 to 104) of the OLE. Subjects were allowed dose adjustment based on monitoring rules. Subjects who were entered in the OLE post-treatment period went straight to a 13-week post-treatment follow-up period after completion of Week 156 of the OLE.

    Reporting group title
    OLE Post-Treatment Follow up Period: Volanesorsen/Volanesorsen
    Reporting group description
    Subjects in the Randomized Treatment Period: Volanesorsen arm group who completed the randomized treatment period and were not entered in the option for an additional 52 weeks of dosing in the OLE post-treatment period went straight to a 13-week post-treatment follow-up period after completion of the first 52 weeks (from Weeks 53 to 104) of the OLE. Subjects were allowed dose adjustment based on monitoring rules. Subjects who were entered in the OLE post-treatment period went straight to a 13-week post-treatment follow-up period after completion of Week 156 of the OLE.

    Primary: Randomized Treatment Period: Percent Change From Baseline to Month 3 in Fasting Triglycerides (TG)

    Close Top of page
    End point title
    Randomized Treatment Period: Percent Change From Baseline to Month 3 in Fasting Triglycerides (TG)
    End point description
    Baseline was defined as the average of Day 1 predose fasting assessment and the last fasting measurement prior to Day 1 predose fasting assessment. Month 3 value was defined as the average of Week 12 and Week 13 fasting TG assessments of the randomized treatment period. The data was analyzed using an analysis of covariance (ANCOVA) model with the randomization stratification factor (diagnosis of disease with or without genetics and family history) and treatment group as factors and log-transformed baseline fasting TG as a covariate. Full analysis set (FAS) included all subjects who were randomized and received at least one dose of study drug in the randomized treatment period, and who had a baseline fasting TG assessment. This endpoint is reported here for the randomized treatment period only, as per the planned analysis.
    End point type
    Primary
    End point timeframe
    Baseline to Month 3
    End point values
    Randomized Treatment Period: Placebo Randomized Treatment Period: Volanesorsen
    Number of subjects analysed
    19
    21
    Units: percent change
        least squares mean (confidence interval 95%)
    -21.64 (-60.85 to 17.57)
    -88.47 (-133.56 to -43.38)
    Statistical analysis title
    RT Period: Placebo vs Volanesorsen
    Comparison groups
    Randomized Treatment Period: Placebo v Randomized Treatment Period: Volanesorsen
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0009
    Method
    ANCOVA
    Parameter type
    Difference in Least Square Mean
    Point estimate
    -66.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -104.17
         upper limit
    -29.48

    Secondary: Randomized Treatment Period: Percent Change From Baseline in Hepatic Steatosis as Assessed by Hepatic Fat Fraction Using Magnetic Resonance Imaging (MRI)

    Close Top of page
    End point title
    Randomized Treatment Period: Percent Change From Baseline in Hepatic Steatosis as Assessed by Hepatic Fat Fraction Using Magnetic Resonance Imaging (MRI)
    End point description
    Baseline was defined as the last non-missing assessment prior to the first dose of study drug in the randomized treatment period. Randomized treatment period: Month 6 value was defined as Week 25 or Week 26 for MRI assessment and Month 12 was defined as Week 50 or Week 52 for MRI assessment. Hepatic steatosis is a reversible condition in which large vacuoles of triglyceride fat accumulate in the liver cells, causing nonspecific inflammation. Hepatic Steatosis was assessed by hepatic fat fraction using MRI. FAS included all subjects who were randomized and received at least one dose of study drug in the randomized treatment period, and who had a baseline fasting TG assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6 and 12
    End point values
    Randomized Treatment Period: Placebo Randomized Treatment Period: Volanesorsen
    Number of subjects analysed
    19
    21
    Units: percent change
    least squares mean (confidence interval 95%)
        Percent Change at Month 6
    2.83 (-23.46 to 29.12)
    -22.86 (-52.07 to 6.34)
        Percent Change at Month 12
    1.46 (-30.49 to 33.42)
    -51.87 (-87.87 to -15.87)
    Statistical analysis title
    RT Period: Placebo vs Volanesorsen
    Statistical analysis description
    Month 6
    Comparison groups
    Randomized Treatment Period: Placebo v Randomized Treatment Period: Volanesorsen
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0736
    Method
    ANCOVA
    Parameter type
    Difference in Least Square Mean
    Point estimate
    -25.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -54.03
         upper limit
    2.65
    Statistical analysis title
    RT Period: Placebo vs Volanesorsen
    Statistical analysis description
    Month 12
    Comparison groups
    Randomized Treatment Period: Placebo v Randomized Treatment Period: Volanesorsen
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0039
    Method
    ANCOVA
    Parameter type
    Difference in Least Square Mean
    Point estimate
    -53.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -87.71
         upper limit
    -18.95

    Secondary: Open-Label Extension Period: Percent Change From Baseline in Hepatic Steatosis as Assessed by Hepatic Fat Fraction Using MRI

    Close Top of page
    End point title
    Open-Label Extension Period: Percent Change From Baseline in Hepatic Steatosis as Assessed by Hepatic Fat Fraction Using MRI
    End point description
    Baseline was defined as the last non-missing assessment prior to the first dose of study drug in the randomized treatment period. Open-label extension period: Month 6 value was defined as Week 77 or Week 78 for MRI assessment and Month 12 value was defined as Week 102 or Week 104 for MRI assessment . Hepatic steatosis is a reversible condition in which large vacuoles of triglyceride fat accumulate in the liver cells, causing nonspecific inflammation. Hepatic Steatosis was assessed by hepatic fat fraction using MRI. FAS included all subjects who were randomized and received at least one dose of study drug in the open-label extension period, and who had a baseline fasting TG assessment. Here, “number analysed” ( “n”) signifies subjects evaluable for this endpoint at specified time points and overall number of subjects (“N”) analyzed signifies subjects who were evaluable for OLE Period.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6 and 12
    End point values
    Open-Label Extension Period: Placebo/Volanesorsen Open-Label Extension Period: Volanesorsen/Volanesorsen
    Number of subjects analysed
    12
    12
    Units: percent change
    arithmetic mean (standard deviation)
        Percent Change at Month 6 (n=6, 5)
    -18.4 ± 54.7
    -60.2 ± 43.6
        Percent Change at Month 12 (n=2, 2)
    -93.5 ± 44.4
    -22.1 ± 47.5
    No statistical analyses for this end point

    Secondary: Randomized Treatment Period: Change From Baseline in Hemoglobin A1c (HbA1c)

    Close Top of page
    End point title
    Randomized Treatment Period: Change From Baseline in Hemoglobin A1c (HbA1c)
    End point description
    Baseline was defined as the last non-missing assessment prior to the first dose of study drug. Randomized treatment period: The Month 3 value was defined as Week 13, Month 6 value was defined as Week 26, Month 9 value was defined as Week 38 and Month 12 value was defined as Week 52. FAS included all subjects who were randomized and received at least one dose of study drug in the randomized treatment period, and who had a baseline fasting TG assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 3, 6, 9, and 12
    End point values
    Randomized Treatment Period: Placebo Randomized Treatment Period: Volanesorsen
    Number of subjects analysed
    19
    21
    Units: percentage of HbA1c
    least squares mean (confidence interval 95%)
        Change at Month 3
    -0.51 (-1.22 to 0.20)
    -0.21 (-1.00 to 0.58)
        Change at Month 6
    0.06 (-1.02 to 1.15)
    0.26 (-0.98 to 1.50)
        Change at Month 9
    0.68 (-0.49 to 1.85)
    0.48 (-0.84 to 1.80)
        Change at Month 12
    0.48 (-0.49 to 1.45)
    0.28 (-0.78 to 1.35)
    Statistical analysis title
    RT Period: Placebo vs Volanesorsen
    Statistical analysis description
    Month 3
    Comparison groups
    Randomized Treatment Period: Placebo v Randomized Treatment Period: Volanesorsen
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4108
    Method
    ANCOVA
    Parameter type
    Difference in Least Square Mean
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.43
         upper limit
    1.03
    Statistical analysis title
    RT Period: Placebo vs Volanesorsen
    Statistical analysis description
    Month 6
    Comparison groups
    Randomized Treatment Period: Placebo v Randomized Treatment Period: Volanesorsen
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7308
    Method
    ANCOVA
    Parameter type
    Difference in Least Square Mean
    Point estimate
    0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.95
         upper limit
    1.34
    Statistical analysis title
    RT Period: Placebo vs Volanesorsen
    Statistical analysis description
    Month 9
    Comparison groups
    Randomized Treatment Period: Placebo v Randomized Treatment Period: Volanesorsen
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7511
    Method
    ANCOVA
    Parameter type
    Difference in Least Square Mean
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.45
         upper limit
    1.06
    Statistical analysis title
    RT Period: Placebo vs Volanesorsen
    Statistical analysis description
    Month 12
    Comparison groups
    Randomized Treatment Period: Placebo v Randomized Treatment Period: Volanesorsen
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7659
    Method
    ANCOVA
    Parameter type
    Difference in Least Square Mean
    Point estimate
    -0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.52
         upper limit
    1.13

    Secondary: Open Label Extension Period: Change From Baseline in HbA1c

    Close Top of page
    End point title
    Open Label Extension Period: Change From Baseline in HbA1c
    End point description
    Baseline was defined as the last non-missing assessment prior to the first dose of study drug. Open-label extension period: Month 3 value was defined as Week 65, Month 6 value was defined as Week 78, Month 9 value was defined as Week 90 and Month 12 value was defined as Week 104. FAS included all subjects who were randomized and received at least one dose of study drug in the open-label extension period, and who had a baseline fasting TG assessment. Here, “n” signifies subjects evaluable for this endpoint at specified time points “N” analyzed signifies subjects who were evaluable for OLE Period.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 3, 6, 9, and 12
    End point values
    Open-Label Extension Period: Placebo/Volanesorsen Open-Label Extension Period: Volanesorsen/Volanesorsen
    Number of subjects analysed
    12
    12
    Units: Baseline, Months 3, 6, 9, and 12
    arithmetic mean (standard deviation)
        Change at Month 3 (n= 6, 8)
    0.42 ± 1.54
    0.91 ± 2.18
        Change at Month 6 (n= 6, 3)
    0.35 ± 1.54
    -0.75 ± 0.35
        Change at Month 9 (n= 2, 2)
    0.35 ± 1.06
    -0.05 ± 0.64
        Change at Month 12 (n= 2, 2)
    0.00 ± 0.71
    0.30 ± 0.99
    No statistical analyses for this end point

    Secondary: Randomized Treatment Period: Percentage of Participants Who Achieved Greater Than or Equal to (≥) 40% Reduction in Fasting Triglyceride and ≥ 30% Reduction of Hepatic Fat Fraction at Month 6

    Close Top of page
    End point title
    Randomized Treatment Period: Percentage of Participants Who Achieved Greater Than or Equal to (≥) 40% Reduction in Fasting Triglyceride and ≥ 30% Reduction of Hepatic Fat Fraction at Month 6
    End point description
    The baseline of TG is defined as the average of Day 1 pre-dose fasting assessment and the last fasting measurement prior to Day 1 pre-dose fasting assessment. The baseline of hepatic fat fraction is defined as the last non-missing assessment prior to the first dose of study drug. Randomized treatment period: Month 6 value was defined as the average of Week 25 and Week 26 for fasting TG assessment and Week 25 or Week 26 for hepatic fat fraction. FAS included all subjects who were randomized and received at least one dose of study drug in the randomized treatment period, and who had a baseline fasting TG assessment. This endpoint is reported here for the randomized treatment period only, as per the planned analysis.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    Randomized Treatment Period: Placebo Randomized Treatment Period: Volanesorsen
    Number of subjects analysed
    19
    21
    Units: percentage of subjects
        number (not applicable)
    5.3
    42.9
    No statistical analyses for this end point

    Secondary: Randomized Treatment Period: Change From Baseline in Disease Burden Score

    Close Top of page
    End point title
    Randomized Treatment Period: Change From Baseline in Disease Burden Score
    End point description
    The Disease Burden Score is a questionnaire that allows subjects to self-report their chronic conditions and then assess the degree to which each condition interferes with daily activities.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug to Week 52
    End point values
    Randomized Treatment Period: Placebo Randomized Treatment Period: Volanesorsen
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: score on scale
        number (not applicable)
    Notes
    [1] - Data for this endpoint was not collected due to the change in planned analysis.
    [2] - Data for this endpoint was not collected due to the change in planned analysis.
    No statistical analyses for this end point

    Secondary: Open-Label Extension Period: Change From Baseline in Disease Burden Score

    Close Top of page
    End point title
    Open-Label Extension Period: Change From Baseline in Disease Burden Score
    End point description
    The Disease Burden Score is a questionnaire that allows subjects to self-report their chronic conditions and then assess the degree to which each condition interferes with daily activities.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug in open label extension period to Week 117
    End point values
    Open-Label Extension Period: Placebo/Volanesorsen Open-Label Extension Period: Volanesorsen/Volanesorsen
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: score on scale
        number (not applicable)
    Notes
    [3] - Data for this endpoint was not collected due to the change in planned analysis.
    [4] - Data for this endpoint was not collected due to the change in planned analysis.
    No statistical analyses for this end point

    Secondary: Randomized Treatment Period: Patient-Reported Pain

    Close Top of page
    End point title
    Randomized Treatment Period: Patient-Reported Pain
    End point description
    Patient-reported pain was assessed by rating pain symptoms at its worst and least for the last 24 hours, on average, and at the moment, with 0 as the lowest score (no pain) and 10 as the highest score (worst pain as you can imagine). Patient-reported pain was also assessed by rating pain symptoms (rate pain on average, rate pain right now) that interfered with general activity, interfered with mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life, with 0 as the lowest score (did not interfered) and 10 as the highest score (completely interfered). The scores from each assessment time point were averaged for all of the below reported categories. FAS included all subjects who were randomized and received at least one dose of study drug in the randomized treatment period, and who had a baseline fasting TG assessment. Here, overall number of subjects analyzed (“N”) signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to Week 52
    End point values
    Randomized Treatment Period: Placebo Randomized Treatment Period: Volanesorsen
    Number of subjects analysed
    19
    20
    Units: score on a scale
    arithmetic mean (standard deviation)
        Rate Pain at its Worst Last 24 Hours
    3.28 ± 2.79
    3.57 ± 2.72
        Rate Pain at its Least Last 24 Hours
    2.45 ± 2.46
    2.59 ± 2.43
        Rate Pain on Average
    3.08 ± 2.62
    3.16 ± 2.47
        Rate Pain Right Now
    2.72 ± 2.59
    2.96 ± 2.50
        General Activity
    2.43 ± 2.80
    2.83 ± 2.57
        Interfere With Mood
    2.31 ± 2.88
    2.98 ± 2.59
        Walking Ability
    2.35 ± 2.96
    2.79 ± 2.59
        Normal Work
    2.37 ± 2.84
    2.89 ± 2.56
        Relations With Other People
    2.23 ± 2.79
    2.62 ± 2.67
        Sleep
    2.75 ± 2.95
    2.73 ± 2.75
        Enjoyment of Life
    2.42 ± 2.82
    2.68 ± 2.62
    No statistical analyses for this end point

    Secondary: Open Label Extension Period: Patient-Reported Pain

    Close Top of page
    End point title
    Open Label Extension Period: Patient-Reported Pain
    End point description
    Patient-reported pain was assessed by rating pain symptoms at its worst and least for the last 24 hours, on average, and at the moment, with 0 as the lowest score (no pain) and 10 as the highest score (worst pain as you can imagine). Patient-reported pain was also assessed by rating pain symptoms (rate pain on average, rate pain right now) that interfered with general activity, interfered with mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life, with 0 as the lowest score (did not interfered) and 10 as the highest score (completely interfered). The scores from each assessment time point were averaged for all of the below reported categories. FAS included all subjects who were randomized and received at least one dose of study drug in the randomized treatment period, and who had a baseline fasting TG assessment. Here, overall number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug in open label extension period up to Week 117
    End point values
    Open-Label Extension Period: Placebo/Volanesorsen Open-Label Extension Period: Volanesorsen/Volanesorsen
    Number of subjects analysed
    9
    9
    Units: score on a scale
    arithmetic mean (standard deviation)
        Rate Pain at its Worst Last 24 Hours
    1.70 ± 1.18
    3.82 ± 2.97
        Rate Pain at its Least Last 24 Hours
    0.95 ± 1.04
    2.78 ± 2.60
        Rate Pain on Average
    1.35 ± 1.22
    3.16 ± 2.72
        Rate Pain Right Now
    1.28 ± 1.18
    3.49 ± 2.99
        General Activity
    1.03 ± 1.45
    3.28 ± 2.90
        Interfere With Mood
    1.27 ± 1.46
    3.23 ± 2.94
        Walking Ability
    1.05 ± 1.50
    3.51 ± 2.83
        Normal Work
    1.08 ± 1.40
    3.48 ± 2.98
        Relations With Other People
    1.08 ± 1.48
    3.18 ± 3.09
        Sleep
    1.51 ± 1.83
    3.13 ± 3.35
        Enjoyment of Life
    1.23 ± 1.65
    3.33 ± 2.94
    No statistical analyses for this end point

    Secondary: Randomized Treatment Period: Patient-Reported Hunger

    Close Top of page
    End point title
    Randomized Treatment Period: Patient-Reported Hunger
    End point description
    Patient-reported hunger was assessed by subjects who completed a questionnaire about: how hungry you feel, how satisfied you feel, how full you feel, how much you think you can eat, like to eat something sweet, like to eat something salty, like to eat something savory and like to eat something fatty. Subjects also rated the palatability of meals that included visual appeal, smell, taste, and aftertaste. Scores of 1–39 were categorized as mild, 40–69 as moderate, and 70–100 as severe. The scores from each assessment time point were averaged for all of the below reported categories. FAS included all subjects who were randomized and received at least one dose of study drug in the randomized treatment period, and who had a baseline fasting TG assessment. Here, overall number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to Week 52
    End point values
    Randomized Treatment Period: Placebo Randomized Treatment Period: Volanesorsen
    Number of subjects analysed
    19
    20
    Units: score on a scale
    arithmetic mean (standard deviation)
        How Hungry You Feel
    29.4 ± 20.7
    29.6 ± 14.4
        How Satisfied You Feel
    56.8 ± 22.4
    57.5 ± 15.1
        How Full You Feel
    62.6 ± 20.5
    56.6 ± 18.4
        How Much You Think You Can Eat
    33.6 ± 22.1
    36.8 ± 15.4
        Like to Eat Something Sweet
    71.0 ± 20.8
    54.8 ± 27.1
        Like to Eat Something Salty
    66.9 ± 21.7
    69.0 ± 20.2
        Like to Eat Something Savory
    65.2 ± 21.4
    66.8 ± 21.9
        Like to Eat Something Fatty
    77.9 ± 18.4
    75.9 ± 22.2
        Visual Appeal
    28.6 ± 20.5
    34.5 ± 21.0
        Smell
    23.4 ± 16.2
    25.4 ± 15.5
        Taste
    25.5 ± 18.3
    29.1 ± 14.5
        Aftertaste
    58.9 ± 27.5
    51.0 ± 24.6
        Palatability
    31.3 ± 20.1
    32.2 ± 15.1
    No statistical analyses for this end point

    Secondary: Open Label Extension Period: Patient-Reported Hunger

    Close Top of page
    End point title
    Open Label Extension Period: Patient-Reported Hunger
    End point description
    Patient-reported hunger was assessed by subjects who completed a questionnaire about: how hungry you feel, how satisfied you feel, how full you feel, how much you think you can eat, like to eat something sweet, like to eat something salty, like to eat something savory and like to eat something fatty. Subjects also rated the palatability of meals that included visual appeal, smell, taste, and aftertaste. Scores of 1–39 were categorized as mild, 40–69 as moderate, and 70–100 as severe. The scores from each assessment time point were averaged for all of the below reported categories. FAS included all subjects who were randomized and received at least one dose of study drug in the open-label extension period, and who had a baseline fasting TG assessment. Here, overall number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug in open label extension period up to Week 117
    End point values
    Open-Label Extension Period: Placebo/Volanesorsen Open-Label Extension Period: Volanesorsen/Volanesorsen
    Number of subjects analysed
    9
    9
    Units: score on a scale
    arithmetic mean (standard deviation)
        How Hungry You Feel
    29.9 ± 23.3
    33.2 ± 23.2
        How Satisfied You Feel
    54.2 ± 23.3
    56.3 ± 20.2
        How Full You Feel
    59.7 ± 22.2
    52.9 ± 24.4
        How Much You Think You Can Eat
    34.0 ± 21.8
    34.9 ± 21.5
        Like to Eat Something Sweet
    73.7 ± 25.4
    57.9 ± 24.0
        Like to Eat Something Salty
    65.7 ± 28.1
    61.9 ± 22.1
        Like to Eat Something Savory
    65.4 ± 24.7
    62.7 ± 30.5
        Like to Eat Something Fatty
    80.7 ± 18.1
    68.0 ± 30.4
        Visual Appeal
    14.9 ± 16.1
    35.3 ± 25.9
        Smell
    13.1 ± 14.3
    29.6 ± 21.6
        Taste
    13.6 ± 15.1
    32.9 ± 25.0
        Aftertaste
    48.1 ± 38.6
    56.9 ± 29.3
        Palatability
    24.4 ± 23.4
    37.3 ± 20.6
    No statistical analyses for this end point

    Secondary: Randomized Treatment Period: Change From Baseline (CFB) in Mean Short Form-36 (SF-36) Weighted Sum of Scores

    Close Top of page
    End point title
    Randomized Treatment Period: Change From Baseline (CFB) in Mean Short Form-36 (SF-36) Weighted Sum of Scores
    End point description
    The SF-36 Health Survey is a 36-item, subject-reported survey of subject health. SF-36 consists of 8 health dimensions,which are weighted sums of the questions in each section. SF-36 included 36 questions related to 8 health dimensions:physical functioning, physical role functioning, bodily pain, general health perceptions, vitality, social role functioning,emotional role functioning, and mental health. Each dimension was scored on a scale of 0 to 100 where, higher score = better quality of life. A positive change from Baseline indicates improvement. FAS was used. “n”=subjects evaluable for this endpoint at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13, 26 and 52
    End point values
    Randomized Treatment Period: Placebo Randomized Treatment Period: Volanesorsen
    Number of subjects analysed
    19
    21
    Units: score on a scale
    arithmetic mean (standard deviation)
        Vitality: Change at Week 13 (n= 13, 14)
    -1.14 ± 7.33
    -0.21 ± 5.64
        Vitality: Change at Week 26 (n= 12, 15)
    -0.25 ± 9.00
    -0.79 ± 6.87
        Vitality: Change at Week 52 (n= 7, 9)
    -0.85 ± 6.11
    -3.30 ± 8.20
        Physical Functioning: Change at Week 13 (n=13, 14)
    -0.29 ± 4.81
    -0.41 ± 3.91
        Physical Functioning: Change at Week 26 (n=12, 15)
    -0.64 ± 6.49
    0.51 ± 5.29
        Physical Functioning: Change at Week 52 (n= 7, 9)
    -3.55 ± 4.05
    -2.76 ± 5.25
        Bodily Pain: Change at Week 13 (n= 13, 14)
    -0.46 ± 7.97
    0.75 ± 6.26
        Bodily Pain: Change at Week 26 (n= 12, 15)
    -1.98 ± 12.24
    0.19 ± 4.27
        Bodily Pain: Change at Week 52 (n= 7, 9)
    -0.29 ± 6.35
    -2.55 ± 8.48
        GH Perceptions: Change at Week 13 (n= 13, 14)
    -0.55 ± 5.57
    -0.58 ± 4.04
        GH Perceptions: Change at Week 26 (n= 12, 15)
    -1.59 ± 5.00
    0.54 ± 7.25
        GH Perceptions: Change at Week 52 (n= 7, 9)
    -1.50 ± 6.74
    -1.48 ± 4.53
        PR Functioning: Change at Week 13 (n= 13, 14)
    -0.52 ± 5.44
    -0.64 ± 4.61
        PR Functioning: Change at Week 26 (n= 12, 15)
    -2.06 ± 10.81
    0.75 ± 4.70
        PR Functioning: Change at Week 52 (n= 7, 9)
    -0.32 ± 2.02
    -2.00 ± 7.05
        ER Functioning: Change at Week 13 (n= 13, 14)
    -1.88 ± 4.63
    0.75 ± 6.85
        ER Functioning: Change at Week 26 (n= 12, 15)
    -2.90 ± 6.44
    0.23 ± 7.50
        ER Functioning: Change at Week 52 (n= 7, 9)
    -1.00 ± 5.94
    -5.42 ± 5.80
        SR Functioning: Change at Week 13 (n= 13, 14)
    -3.86 ± 9.85
    1.07 ± 4.02
        SR Functioning: Change at Week 26 (n= 12, 15)
    -5.01 ± 9.07
    -0.67 ± 3.21
        SR Functioning: Change at Week 52 (n= 7, 9)
    2.87 ± 4.89
    -2.79 ± 7.14
        Mental Health: Change at Week 13 (n= 13, 14)
    0.00 ± 6.67
    -0.19 ± 7.91
        Mental Health: Change at Week 26 (n= 12, 15)
    -2.18 ± 7.71
    1.05 ± 6.76
        Mental Health: Change at Week 52 (n= 7, 9)
    -0.37 ± 6.66
    -1.75 ± 6.13
    No statistical analyses for this end point

    Secondary: Open-Label Period: Change From Baseline in Mean SF-36 Weighted Sum of Scores

    Close Top of page
    End point title
    Open-Label Period: Change From Baseline in Mean SF-36 Weighted Sum of Scores
    End point description
    The SF-36 Health Survey is a 36-item, subject-reported survey of subject health. SF-36 consists of 8 health dimensions,which are weighted sums of the questions in each section. SF-36 included 36 questions related to 8 health dimensions:physical functioning, physical role functioning, bodily pain, general health perceptions, vitality, social role functioning,emotional role functioning, and mental health. Each dimension was scored on a scale of 0 to 100 where, higher score = better quality of life. A positive change from Baseline indicates improvement. FAS was used. “n”= subjects evaluable for this endpoint at specified time points “N”= signifies subjects who were evaluable for OLE Period. 99999= SD was not estimable as only 1 subject was evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 65, 78 and 104
    End point values
    Open-Label Extension Period: Placebo/Volanesorsen Open-Label Extension Period: Volanesorsen/Volanesorsen
    Number of subjects analysed
    12
    12
    Units: score on a scale
    arithmetic mean (standard deviation)
        Vitality: Change at Week 65 (n= 2, 7)
    4.46 ± 6.30
    -0.42 ± 13.88
        Vitality: Change at Week 78 (n= 2, 1)
    -2.98 ± 12.61
    -2.97 ± 99999
        Vitality: Change at Week 104 (n= 1, 1)
    2.97 ± 99999
    -5.94 ± 99999
        Physical Functioning: Change at Week 65 (n= 2, 7)
    -4.79 ± 6.77
    -1.37 ± 5.81
        Physical Functioning: Change at Week 78 (n= 2, 1)
    -3.83 ± 5.41
    0.00 ± 99999
        Physical Functioning: Change at Week 104 (n= 1, 1)
    0.00 ± 99999
    -1.91 ± 0
        Bodily Pain: Change at Week 65 (n= 2, 7)
    -2.42 ± 3.42
    0.40 ± 7.13
        Bodily Pain: Change at Week 78 (n= 2, 1)
    -7.26 ± 19.39
    -11.29 ± 99999
        Bodily Pain: Change at Week 104 (n= 1, 1)
    6.45 ± 99999
    -10.49 ± 99999
        GH Perceptions: Change at Week 65 (n= 2, 7)
    2.38 ± 3.36
    -2.38 ± 4.42
        GH Perceptions: Change at Week 78 (n= 2, 1)
    -2.86 ± 7.40
    -4.75 ± 99999
        GH Perceptions: Change at Week 104 (n= 1, 1)
    0 ± 99999
    -4.75 ± 99999
        PR Functioning: Change at Week 65 (n= 2, 7)
    0.00 ± 0.00
    -0.00 ± 6.22
        PR Functioning: Change at Week 78 (n= 2, 1)
    -10.11 ± 14.29
    -2.25 ± 99999
        PR Functioning: Change at Week 104 (n= 1, 1)
    0.00 ± 99999
    -4.50 ± 99999
        ER Functioning: Change at Week 65 (n= 2, 7)
    -1.74 ± 2.46
    -3.48 ± 11.37
        ER Functioning: Change at Week 78 (n= 2, 1)
    1.74 ± 2.46
    -10.45 ± 99999
        ER Functioning: Change at Week 104 (n=1, 1)
    3.48 ± 99999
    -10.45 ± 99999
        SR Functioning: Change at Week 65 (n= 2, 7)
    5.02 ± 7.09
    -2.15 ± 7.58
        SR Functioning: Change at Week 78 (n= 2, 1)
    -5.01 ± 7.09
    0.00 ± 99999
        SR Functioning: Change at Week 104 (n= 1, 1)
    0.00 ± 99999
    0.00 ± 99999
        Mental Health: Change at Week 65 (n= 2, 7)
    -5.23 ± 11.10
    -1.12 ± 13.67
        Mental Health: Change at Week 78 (n= 2, 1)
    6.54 ± 9.25
    -15.70 ± 99999
        Mental Health: Change at Week 104 (n= 1, 1)
    2.62 ± 99999
    0.00 ± 99999
    No statistical analyses for this end point

    Secondary: Randomized Treatment Period: Change From Baseline in Mean EQ-5D: Index Scores and Visual Analog Scale (VAS)

    Close Top of page
    End point title
    Randomized Treatment Period: Change From Baseline in Mean EQ-5D: Index Scores and Visual Analog Scale (VAS)
    End point description
    EQ-5D-5L is a standardized health-related quality of life questionnaire developed by EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. EQ-5D-5L consists of two components: a health state profile and VAS. EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state. EQ-5D-5L- VAS is designed to rate the subject’s current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. Negative CFB=worsening. Positive CFB=improvement. FAS was used. “n”=subjects evaluable for this endpoint at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13, 26 and 52
    End point values
    Randomized Treatment Period: Placebo Randomized Treatment Period: Volanesorsen
    Number of subjects analysed
    19
    21
    Units: score on a scale
    arithmetic mean (standard deviation)
        Index Score: Change at Week 13 (n= 8, 14)
    0.05 ± 0.10
    -0.02 ± 0.06
        Index Score: Change at Week 26 (n= 9, 15)
    -0.11 ± 0.19
    -0.02 ± 0.12
        Index Score: Change at Week 52 (n= 4, 9)
    -0.08 ± 0.10
    -0.05 ± 0.07
        EQ VAS Score: Change at Week 13 (n= 8, 14)
    -2 ± 13
    -2 ± 15
        EQ VAS Score: Change at Week 26 (n= 9, 15)
    -11 ± 17
    -2 ± 14
        EQ VAS Score: Change at Week 52 (n= 4, 9)
    -13 ± 18
    -4 ± 16
    No statistical analyses for this end point

    Secondary: Open-Label Period: Change From Baseline in Mean EQ-5D: Index and Visual Analog Scale (VAS) Scores

    Close Top of page
    End point title
    Open-Label Period: Change From Baseline in Mean EQ-5D: Index and Visual Analog Scale (VAS) Scores
    End point description
    EQ-5D-5L: standardized health-related QoL questionnaire to provide simple, generic measure of health for clinical and economic appraisal. EQ-5D-5L consists of 2 components: health state profile and VAS. EQ-5D health state profile comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. 5D-5L systems are converted into a single index utility score between 0 to 1, higher score=better health state. EQ-5D-5L- VAS is designed to rate subject’s current health state on a scale (0 to 100), where 0=worst imaginable health state and 100 =best imaginable health state. Negative CFB=worsening. Positive CFB=improvement. FAS was used. n=subjects evaluable at specified time points. N= subjects who were evaluable for OLE Period. 99999= SD was not estimable as only 1 subject was evaluable. 99999=Mean(SD) not evaluable where n=0.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 65, 78 and 104
    End point values
    Open-Label Extension Period: Placebo/Volanesorsen Open-Label Extension Period: Volanesorsen/Volanesorsen
    Number of subjects analysed
    12
    12
    Units: score on a scale
    arithmetic mean (standard deviation)
        Index Score: Change at Week 65 (n= 0, 7)
    99999 ± 99999
    -0.06 ± 0.08
        Index Score: Change at Week 78 (n= 2, 1)
    -0.02 ± 0.03
    -0.07 ± 99999
        Index Score: Change at Week 104 (n= 1, 1)
    0.00 ± 99999
    -0.27 ± 99999
        EQ VAS Score: Change at Week 65 (n= 0, 7)
    99999 ± 99999
    -4 ± 16
        EQ VAS Score: Change at Week 78 (n= 2, 1)
    -15 ± 22
    -6 ± 99999
        EQ VAS Score: Change at Week 104 (n= 1, 1)
    2 ± 99999
    0 ± 99999
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug to end of follow-up period [Up to Week 169]
    Adverse event reporting additional description
    Safety Population Set 1 included all subjects who were randomized and received at least one dose of study drug (volanesorsen or placebo) in the randomized treatment period. Safety Population Set 2 included all subjects who entered the OLE Period and received at least one dose of study drug (volanesorsen) in the OLE period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Randomized Treatment Period: Placebo
    Reporting group description
    Subjects received volanesorsen-matching placebo as a SC injection once-weekly from Weeks 1 to 52 of the randomized treatment period. Subjects were allowed dose adjustment based on monitoring rules.

    Reporting group title
    Randomized Treatment Period: Volanesorsen
    Reporting group description
    Subjects received 300 mg of volanesorsen as a SC injection once-weekly from Weeks 1 to 52 of the randomized treatment period. Subjects were allowed dose adjustment based on monitoring rules.

    Reporting group title
    Randomized Post-Treatment Follow-up: Placebo
    Reporting group description
    Following the randomized treatment period, subjects who received volanesorsen-matching placebo in randomized treatment period and did not enter the OLE period went straight to the 13-week post-treatment follow-up period.

    Reporting group title
    Randomized Post-Treatment Follow-up: Volanesorsen
    Reporting group description
    Following the randomized treatment period, subjects who received 300 mg of volanesorsen in randomized treatment period and did not enter in the OLE period went straight to the 13-week post-treatment follow-up period.

    Reporting group title
    OLE and OLE Post-Treatment Follow-up: Placebo/Volanesorsen
    Reporting group description
    Subjects in the Randomized Treatment Period: Placebo arm group who completed the randomized treatment period, received 300 mg of volanesorsen as a SC injection once-weekly for 52 weeks (from Weeks 53 to 104) in the OLE period. Subjects were allowed dose adjustment based on monitoring rules. After Week 104 of the OLE period, subjects had the option of continuing treatment with 300 mg of volanesorsen as a SC injection for up to an additional 52 weeks (from Week 105 to 156). Subjects who were not entered in the option for an additional 52 weeks of dosing in the OLE post-treatment period went straight to a 13-week post-treatment follow-up period after completion of the first 52 weeks (from Weeks 53 to 104) of the OLE. Subjects who were entered in the OLE post-treatment period went straight to a 13-week post-treatment follow-up period after completion of Week 156 of the OLE.

    Reporting group title
    OLE and OLE PT Follow-up: Volanesorsen/Volanesorsen
    Reporting group description
    Subjects in the Randomized Treatment Period: Volanesorsen arm group who completed the randomized treatment period, received 300 mg of volanesorsen as a SC injection once-weekly for 52 weeks (from Weeks 53 to 104) in the OLE period. Subjects were allowed dose adjustment based on monitoring rules. After Week 104 of the OLE period, subjects had the option of continuing treatment with 300 mg of volanesorsen as a SC injection for up to an additional 52 weeks (from Week 105 to 156). Subjects who were not entered in the option for an additional 52 weeks of dosing in the OLE post-treatment period went straight to a 13-week post-treatment follow-up period after completion of the first 52 weeks (from Weeks 53 to 104) of the OLE. Subjects who were entered in the OLE post-treatment period went straight to a 13-week post-treatment follow-up period after completion of Week 156 of the OLE.

    Serious adverse events
    Randomized Treatment Period: Placebo Randomized Treatment Period: Volanesorsen Randomized Post-Treatment Follow-up: Placebo Randomized Post-Treatment Follow-up: Volanesorsen OLE and OLE Post-Treatment Follow-up: Placebo/Volanesorsen OLE and OLE PT Follow-up: Volanesorsen/Volanesorsen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 19 (15.79%)
    6 / 21 (28.57%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    4 / 12 (33.33%)
    4 / 12 (33.33%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Sarcoidosis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Partial seizures
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medical device site inflammation
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis necrotising
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Randomized Treatment Period: Placebo Randomized Treatment Period: Volanesorsen Randomized Post-Treatment Follow-up: Placebo Randomized Post-Treatment Follow-up: Volanesorsen OLE and OLE Post-Treatment Follow-up: Placebo/Volanesorsen OLE and OLE PT Follow-up: Volanesorsen/Volanesorsen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 19 (94.74%)
    21 / 21 (100.00%)
    4 / 7 (57.14%)
    5 / 9 (55.56%)
    11 / 12 (91.67%)
    8 / 12 (66.67%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Surgical and medical procedures
    Asthma prophylaxis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cardiac pacemaker insertion
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Sinus operation
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hypersensitivity
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 19 (10.53%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    3
    0
    0
    0
    0
    Chills
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Fatigue
         subjects affected / exposed
    3 / 19 (15.79%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    2
    0
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    Injection site bruising
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 21 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    3 / 12 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    5
    0
    0
    7
    0
    Injection site discolouration
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 21 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    4
    0
    0
    2
    0
    Injection site discomfort
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injection site erythema
         subjects affected / exposed
    0 / 19 (0.00%)
    13 / 21 (61.90%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    7 / 12 (58.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    75
    0
    0
    20
    1
    Injection site extravasation
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Injection site induration
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    3 / 12 (25.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    37
    4
    Injection site mass
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 21 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    0
    1
    0
    Injection site nodule
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    6
    0
    0
    0
    1
    Injection site pain
         subjects affected / exposed
    3 / 19 (15.79%)
    7 / 21 (33.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    4 / 12 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    3
    53
    0
    0
    24
    2
    Injection site paraesthesia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Injection site pruritus
         subjects affected / exposed
    0 / 19 (0.00%)
    11 / 21 (52.38%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    3 / 12 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    30
    0
    0
    5
    0
    Injection site rash
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    8
    0
    0
    1
    0
    Injection site reaction
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 21 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    5
    0
    0
    0
    0
    Injection site swelling
         subjects affected / exposed
    0 / 19 (0.00%)
    8 / 21 (38.10%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    6 / 12 (50.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    23
    0
    0
    19
    4
    Injection site warmth
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    0
    3
    3
    Peripheral swelling
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Depression
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    2
    0
    0
    0
    2
    Insomnia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Sleep-related eating disorder
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Somnambulism
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Menstrual disorder
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Vulval disorder
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Arthropod sting
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Chest injury
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Concussion
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Exposure to toxic agent
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    Injury
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Laceration
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ligament sprain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Meniscus injury
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Muscle strain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Postoperative wound complication
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Splinter
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    Albumin urine present
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Bacterial test
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Biopsy muscle
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood creatinine decreased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood fibrinogen increased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood glucose fluctuation
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood magnesium decreased
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    1
    0
    0
    0
    2
    Blood phosphorus increased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood potassium decreased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood urine present
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Cardiac murmur
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Echocardiogram abnormal
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Glucose urine
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Haematocrit decreased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    0
    0
    0
    1
    International normalised ratio increased
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 19 (0.00%)
    5 / 21 (23.81%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    0
    8
    0
    0
    3
    10
    Protein total increased
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    3
    0
    0
    0
    1
    Red blood cells urine
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Rheumatoid factor increased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Synovial fluid white blood cells positive
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Urine protein, quantitative
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Urine protein/creatinine ratio increased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    Vitamin D decreased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    White blood cell count increased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Palpitations
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Congenital, familial and genetic disorders
    Muscular dystrophy
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    2
    0
    Epistaxis
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    1
    7
    0
    0
    1
    3
    Oropharyngeal pain
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    0
    0
    1
    0
    Pulmonary oedema
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Sinus congestion
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 21 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    3
    0
    0
    1
    1
    Lymphadenopathy
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Microcytosis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Splenomegaly
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 19 (5.26%)
    3 / 21 (14.29%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    3
    1
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Dysstasia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    2 / 19 (10.53%)
    4 / 21 (19.05%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    3 / 12 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    8
    0
    0
    3
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    0
    Eye swelling
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ocular discomfort
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Visual impairment
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Abdominal distension
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    0
    0
    1
    1
    Abdominal pain
         subjects affected / exposed
    3 / 19 (15.79%)
    4 / 21 (19.05%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    3
    9
    0
    0
    1
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    0
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 19 (10.53%)
    4 / 21 (19.05%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    7
    0
    0
    0
    3
    Dyspepsia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Epulis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Food poisoning
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Gastric polyps
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gingival bleeding
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    2 / 19 (10.53%)
    4 / 21 (19.05%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    3 / 12 (25.00%)
    4 / 12 (33.33%)
         occurrences all number
    4
    10
    0
    0
    10
    7
    Pancreatitis acute
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Subileus
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 19 (5.26%)
    3 / 21 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    1
    5
    0
    0
    8
    2
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Chromaturia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dysuria
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Micturition urgency
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nephrolithiasis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Proteinuria
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Erythema
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    5
    0
    0
    0
    2
    0
    Rash
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Skin lesion
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Swelling face
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Xanthoma
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    6
    0
    0
    0
    2
    Back pain
         subjects affected / exposed
    2 / 19 (10.53%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    2
    0
    0
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Flank pain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    Muscle fatigue
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    2 / 19 (10.53%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    2
    3
    0
    0
    2
    1
    Muscular weakness
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    7
    0
    Pain in extremity
         subjects affected / exposed
    5 / 19 (26.32%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    6
    2
    0
    0
    0
    3
    Plantar fasciitis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Thyroid mass
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Decreased appetite
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    Dehydration
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Diabetes mellitus
         subjects affected / exposed
    2 / 19 (10.53%)
    4 / 21 (19.05%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    4
    0
    0
    0
    0
    Dyslipidaemia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    2 / 19 (10.53%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    2
    0
    0
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    5 / 19 (26.32%)
    3 / 21 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    7
    8
    0
    0
    14
    2
    Insulin resistance
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Infections and infestations
    Acarodermatitis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Bacterial vaginosis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    0
    0
    1
    0
    Candida infection
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Fungal infection
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hordeolum
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Infection
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    0
    1
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 19 (5.26%)
    6 / 21 (28.57%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    2
    7
    0
    0
    1
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    Pulpitis dental
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    2 / 7 (28.57%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    Skin infection
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Streptococcal infection
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Tinea pedis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 19 (21.05%)
    5 / 21 (23.81%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    4
    6
    0
    0
    6
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 19 (0.00%)
    5 / 21 (23.81%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    8
    0
    3
    7
    1
    Vaginal infection
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Viral infection
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    0
    1

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jun 2016
    To add hematology blood draws so that platelet counts were measured every 2 weeks during the treatment period and every 2 weeks for first 6 weeks after last dose of study drug. To allow blood sampling at additional study visit weeks to be conducted by a home healthcare service. To add language that any case of a platelet count ≤ 50,000/cubic millimeters (mm^3) should be reported in an expedited way to the sponsor. To add language that if there was no reportable platelet count within 14 days, investigator would contact the patient to hold dosing until a new platelet count was obtained and reviewed. To add language that all platelet count results would be promptly reviewed by the investigator to ensure that the count had not met the stopping rule, and to determine whether the rate of decline was suggestive that the subject could be approaching the dose pause rule of 75,000/mm^3. To add language that each time a hematology lab was drawn and sent to the central laboratory for analysis, an additional sample should be collected in parallel and analyzed locally, to reduce the occurrence of unreportable hematology results. To change platelet dose pause/stopping rule from 50,000/mm^3 to 75,000/mm^3. To add that when platelet count returned to ≥ 100,000/mm^3 dosing may be continued but at a reduced dose frequency of 300 mg every 2 weeks or a reduced dose of 150 mg/week and only if approved by the sponsor medical monitor. To add language that in event of any platelet count less than 25,000/mm^3, or a platelet count less than 50,000/mm^3 that occurred while the subject was dosed at 300 mg every 2 weeks or 150 mg/week, then dosing of a subject with study drug would be stopped permanently. Platelet count would be monitored daily until 2 successive values showed improvement then monitored every 2–3 days until platelet count was stable. To add generic name, volanesorsen, for ISIS 304801. To add new name of the Sponsor, Ionis Pharmaceuticals, and collaborators, Akcea Therapeutics.
    08 Aug 2016
    To specify additional platelet monitoring and stopping rules. To provide updated blinded safety data from the ongoing studies of volanesorsen. To amend the inclusion and exclusion criteria to better identify subjects with FPL and Type 2 diabetes at entry into the study who could benefit from the study drug. To revise the stratification strategy for the study. To change the order of the secondary endpoints (i.e., elevate the importance of glycemic-related endpoints). To update the corresponding statistical analysis sections. To add a 12-month open-label extension period within this study instead of a separate elective study.
    17 Apr 2017
    To update the platelet safety monitoring rules.
    22 Aug 2017
    To revise the diabetic criteria consistent with more current guidelines, an increased HbA1c threshold of 12%, and require all subjects to be on antidiabetic agents (oral or injectable). To allow subjects in Group 1 and Group 2 subjects with TG levels of 200 mg/dL or greater to participate in the study, with evidence of fatty liver. To revise secondary endpoints (i.e., added patient-reported outcomes as a secondary endpoint, assessment of hepatic steatoses as first secondary endpoint, added reductions in pain medication or mood medication use). To add an option for an additional 52 weeks of open-label dosing. To add scoring of disease burden. To clarify actions to be taken regarding events of documented hypoglycemia and hyperglycemia. To add allowance for unblinding of TG values to both investigators and subject after 13 weeks on the open-label period of the study.

    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.
    The Sponsor decided to terminate the study early at a time point when sufficient data had been accumulated to inform a decision on further development of volanesorsen in subjects with FPL.
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA