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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of ISIS 304801 Administered Subcutaneously to Patients with Hypertriglyceridemia

    Summary
    EudraCT number
    		 2014-003434-93
    Trial protocol
    		 DE   NL   GB  
    Global end of trial date
    24 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Oct 2022
    First version publication date
    22 Oct 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ISIS-304801-CS16
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02300233
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ionis Pharmaceuticals, Inc.
    Sponsor organisation address
    2855 Gazelle Court, Carlsbad, CA, United States, 92010
    Public contact
    Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., +1 800-679-4747, patients@ionisph.com
    Scientific contact
    Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., +1 800-679-4747, patients@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
    24 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the efficacy and safety of volanesorsen given for 26 weeks in subjects with Hypertriglyceridemia.
    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
    05 Feb 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    United States: 50
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    France: 8
    Worldwide total number of subjects
    113
    EEA total number of subjects
    42
    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)
    101
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 114 subjects were randomised at multiple study centres worldwide.

    Pre-assignment
    Screening details
    		 114 subjects were randomised, and 113 received study drug. One subject was randomised, but discontinued before dosing. The study included a ≤ 8-week screening period (including a diet-stabilization period), a 26-week treatment period, and a 13-week-post-treatment evaluation period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Volanesorsen-matching placebo administered subcutaneously once-weekly for 26 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    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 subcutaneously once-weekly for 26 weeks.

    Arm title
    		 Volanesorsen 300 mg Weekly
    Arm description
    		 Volanesorsen 300 mg administered subcutaneously once-weekly for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Volanesorsen
    Investigational medicinal product code
    Other name
    ISIS 304801, ApoC-III, Approach, IONIS-APOCIIIRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Volanesorsen 300 mg administered subcutaneously once-weekly for 26 weeks.

    Arm title
    		 Volanesorsen 300 mg Biweekly, Post Week 13
    Arm description
    		 Volanesorsen 300 mg administered subcutaneously once-weekly for 13 weeks, then bi-weekly for 13 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Volanesorsen
    Investigational medicinal product code
    Other name
    ISIS 304801, ApoC-III, Approach, IONIS-APOCIIIRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Volanesorsen 300 mg administered subcutaneously once-weekly for 13 weeks, then bi-weekly for 13 weeks.

    Number of subjects in period 1
    		Placebo Volanesorsen 300 mg Weekly Volanesorsen 300 mg Biweekly, Post Week 13
    Started
    38
    25
    50
    Completed
    34
    24
    27
    Not completed
    4
    1
    23
         Consent withdrawn by subject
    1
    -
    3
         Investigator Judgement
    -
    -
    1
         Reason Not Specified
    -
    -
    5
         Adverse Event or Serious Adverse Event
    3
    1
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Volanesorsen-matching placebo administered subcutaneously once-weekly for 26 weeks.

    Reporting group title
    Volanesorsen 300 mg Weekly
    Reporting group description
    		 Volanesorsen 300 mg administered subcutaneously once-weekly for 26 weeks.

    Reporting group title
    Volanesorsen 300 mg Biweekly, Post Week 13
    Reporting group description
    		 Volanesorsen 300 mg administered subcutaneously once-weekly for 13 weeks, then bi-weekly for 13 weeks.

    Reporting group values
    		 Placebo Volanesorsen 300 mg Weekly Volanesorsen 300 mg Biweekly, Post Week 13 Total
    Number of subjects
    		 38 25 50 113
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53 ± 10 50 ± 9 51 ± 11 -
    Gender categorical
    Units: Subjects
        Female
    		 8 5 14 27
        Male
    		 30 20 36 86
    Race
    Units: Subjects
        White
    		 33 25 47 105
        Asian
    		 3 0 1 4
        American Indian or Alaskan Native
    		 0 0 1 1
        Other Race
    		 1 0 1 2
        Multiple
    		 1 0 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 1 0 2
        Not Hispanic or Latino
    		 37 24 50 111
    Fasting Triglycerides
    Units: milligrams per decilitre (mg/dL)
        arithmetic mean (standard deviation)
    		 1414 ± 1253 1046 ± 560 1251 ± 838 -
    Subject analysis sets

    Subject analysis set title
    Volanesorsen Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Volanesorsen 300 mg administered subcutaneously once-weekly for 26 weeks; or once-weekly for 13 weeks, then bi-weekly for 13 weeks.

    Subject analysis sets values
    		 Volanesorsen Total
    Number of subjects
    75
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    50 ± 10
    Gender categorical
    Units: Subjects
        Female
    19
        Male
    56
    Race
    Units: Subjects
        White
    72
        Asian
    1
        American Indian or Alaskan Native
    1
        Other Race
    1
        Multiple
    0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1
        Not Hispanic or Latino
    74
    Fasting Triglycerides
    Units: milligrams per decilitre (mg/dL)
        arithmetic mean (standard deviation)
    1183 ± 759

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Volanesorsen-matching placebo administered subcutaneously once-weekly for 26 weeks.

    Reporting group title
    Volanesorsen 300 mg Weekly
    Reporting group description
    		 Volanesorsen 300 mg administered subcutaneously once-weekly for 26 weeks.

    Reporting group title
    Volanesorsen 300 mg Biweekly, Post Week 13
    Reporting group description
    		 Volanesorsen 300 mg administered subcutaneously once-weekly for 13 weeks, then bi-weekly for 13 weeks.

    Subject analysis set title
    Volanesorsen Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Volanesorsen 300 mg administered subcutaneously once-weekly for 26 weeks; or once-weekly for 13 weeks, then bi-weekly for 13 weeks.

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

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    End point title
    		 Percent Change in Fasting Triglycerides (TG) From Baseline to Month 3 [1]
    End point description
    The full analysis set (FAS) included all subjects who were randomised, received at least one dose of study drug, and had a baseline TG assessment.
    End point type
    Primary
    End point timeframe
    Baseline to 3 months
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data was reported for "Volanesorsen Total" arm group (N=75) which is inclusive of "Volanesorsen 300 mg Weekly" (N=25) and "Volanesorsen 300 mg Biweekly, Post Week 13" (N=50) arm groups.
    End point values
    		 Placebo Volanesorsen Total
    Number of subjects analysed
    38
    75
    Units: percent change
        least squares mean (confidence interval 95%)
    -0.9 (-13.9 to 12.2)
    -71.2 (-79.3 to -63.2)
    Statistical analysis title
    		 Placebo vs Volanesorsen Total
    Comparison groups
    Placebo v Volanesorsen Total
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Squares Mean (LSM)
    Point estimate
    -70.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -85.4
         upper limit
    		 -55.3

    Secondary: Absolute Change in Fasting TG From Baseline to Month 3

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    End point title
    		 Absolute Change in Fasting TG From Baseline to Month 3 [2]
    End point description
    The FAS included all subjects who were randomised, received at least one dose of study drug, and had a baseline TG assessment. Volanesorsen 300 mg biweekly group includes subjects who received weekly dosing in first 13 weeks, and then bi-weekly for 13 weeks. For month 3 assessments, the results were combined since all subjects were on weekly dosing. And for month 6 assessments, the results were split to show the results in each dosing group.
    End point type
    Secondary
    End point timeframe
    Baseline to 3 months
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data was reported for "Volanesorsen Total" arm group (N=75) which is inclusive of "Volanesorsen 300 mg Weekly" (N=25) and "Volanesorsen 300 mg Biweekly, Post Week 13" (N=50) arm groups.
    End point values
    		 Placebo Volanesorsen Total
    Number of subjects analysed
    38
    75
    Units: mg/dL
        least squares mean (confidence interval 95%)
    74 (-138 to 285)
    -869 (-1018 to -720)
    Statistical analysis title
    		 Placebo vs Volanesorsen Total
    Comparison groups
    Placebo v Volanesorsen Total
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    -943
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1197
         upper limit
    		 -689

    Secondary: Treatment Response Rate Defined as Subjects With Fasting TG ≥ 40% Reduction From Baseline at Month 3

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    End point title
    		 Treatment Response Rate Defined as Subjects With Fasting TG ≥ 40% Reduction From Baseline at Month 3 [3]
    End point description
    The FAS included all subjects who were randomised, received at least one dose of study drug, and had a baseline TG assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to 3 months
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data was reported for "Volanesorsen Total" arm group (N=75) which is inclusive of "Volanesorsen 300 mg Weekly" (N=25) and "Volanesorsen 300 mg Biweekly, Post Week 13" (N=50) arm groups.
    End point values
    		 Placebo Volanesorsen Total
    Number of subjects analysed
    38
    75
    Units: Subjects
    5
    65
    Statistical analysis title
    		 Placebo vs Volanesorsen Total
    Comparison groups
    Placebo v Volanesorsen Total
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    96.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 19.71
         upper limit
    		 467.79

    Secondary: Percent Change in High-density Lipoprotein-cholesterol (HDL-C) From Baseline

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    End point title
    		 Percent Change in High-density Lipoprotein-cholesterol (HDL-C) From Baseline [4]
    End point description
    The FAS included all subjects who were randomised, received at least one dose of study drug, and had a baseline TG assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to 3 months
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data was reported for "Volanesorsen Total" arm group (N=75) which is inclusive of "Volanesorsen 300 mg Weekly" (N=25) and "Volanesorsen 300 mg Biweekly, Post Week 13" (N=50) arm groups.
    End point values
    		 Placebo Volanesorsen Total
    Number of subjects analysed
    38
    75
    Units: percent change
        least squares mean (confidence interval 95%)
    4.4 (-5.2 to 14.0)
    61.2 (54.2 to 68.3)
    Statistical analysis title
    		 Placebo vs Volanesorsen Total
    Comparison groups
    Placebo v Volanesorsen Total
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    56.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 45.1
         upper limit
    		 68.6

    Secondary: Treatment Response Rate Defined as Subjects With Fasting TG < 150 mg/dL Reduction From Baseline at Month 3

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    End point title
    		 Treatment Response Rate Defined as Subjects With Fasting TG < 150 mg/dL Reduction From Baseline at Month 3 [5]
    End point description
    The FAS included all subjects who were randomised, received at least one dose of study drug, and had a baseline TG assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to 3 months
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data was reported for "Volanesorsen Total" arm group (N=75) which is inclusive of "Volanesorsen 300 mg Weekly" (N=25) and "Volanesorsen 300 mg Biweekly, Post Week 13" (N=50) arm groups.
    End point values
    		 Placebo Volanesorsen Total
    Number of subjects analysed
    38
    75
    Units: subjects
    0
    11
    Statistical analysis title
    		 Placebo vs Volanesorsen Total
    Comparison groups
    Placebo v Volanesorsen Total
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0474
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    14.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.03
         upper limit
    		 215.88

    Secondary: Change From Baseline in Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR)

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    End point title
    		 Change From Baseline in Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR)
    End point description
    HOMA-IR was calculated using the following formula: Fasting insulin micro-international units per millimetre (μIU/mL) x fasting glucose [mg/dL]/405. A negative change from baseline indicates improvement; a positive change from baseline indicates worsening. The FAS included all subjects who were randomised, received at least one dose of study drug, and had a baseline TG assessment. Number analysed "n" indicates the number of subjects evaluated at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline to 3 and 6 months
    End point values
    		 Placebo Volanesorsen 300 mg Weekly Volanesorsen 300 mg Biweekly, Post Week 13
    Number of subjects analysed
    38
    25
    50
    Units: score
    arithmetic mean (standard deviation)
        Month 3 (n=36,24,42)
    -0.29 ± 3.12
    1.53 ± 4.89
    -0.45 ± 4.97
        Month 6 (n=35,24,38)
    -0.37 ± 3.18
    1.54 ± 7.69
    0.56 ± 2.97
    No statistical analyses for this end point

    Secondary: Change From Baseline in Glycated Haemoglobin (HbA1c) in Type 2 Diabetes Mellitus (T2DM) Subjects

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    End point title
    		 Change From Baseline in Glycated Haemoglobin (HbA1c) in Type 2 Diabetes Mellitus (T2DM) Subjects
    End point description
    The FAS included all subjects who were randomised, received at least one dose of study drug, and had a baseline TG assessment. Number analysed "n" indicates the number of T2DM subjects evaluated at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline to 3 and 6 months
    End point values
    		 Placebo Volanesorsen 300 mg Weekly Volanesorsen 300 mg Biweekly, Post Week 13
    Number of subjects analysed
    14
    9
    21
    Units: percentage
    arithmetic mean (standard deviation)
        Month 3 (n=13,9,21)
    -0.0 ± 0.5
    0.4 ± 0.6
    0.1 ± 0.5
        Month 6 (n=12,9,19)
    -0.2 ± 0.6
    0.8 ± 0.9
    0.3 ± 0.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 39 weeks
    Adverse event reporting additional description
    The safety set included all randomised subjects who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Volanesorsen-matching placebo administered subcutaneously once-weekly for 26 weeks.

    Reporting group title
    Volanesorsen 300 mg Weekly
    Reporting group description
    		 Volanesorsen 300 mg administered subcutaneously once-weekly for 26 weeks.

    Reporting group title
    Volanesorsen 300 mg Biweekly, Post Week 13
    Reporting group description
    		 Volanesorsen 300 mg administered subcutaneously once-weekly for 13 weeks, then bi-weekly for 13 weeks.

    Serious adverse events
    		 Placebo Volanesorsen 300 mg Weekly Volanesorsen 300 mg Biweekly, Post Week 13
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 25 (8.00%)
    6 / 50 (12.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Ulna fracture
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Serum sickness
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus paralytic
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis relapsing
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pancreas infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Volanesorsen 300 mg Weekly Volanesorsen 300 mg Biweekly, Post Week 13
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 38 (81.58%)
    24 / 25 (96.00%)
    49 / 50 (98.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    2
    0
    1
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    2 / 38 (5.26%)
    23 / 25 (92.00%)
    38 / 50 (76.00%)
         occurrences all number
    2
    198
    262
    Injection site pain
         subjects affected / exposed
    2 / 38 (5.26%)
    10 / 25 (40.00%)
    29 / 50 (58.00%)
         occurrences all number
    2
    98
    199
    Injection site swelling
         subjects affected / exposed
    1 / 38 (2.63%)
    12 / 25 (48.00%)
    24 / 50 (48.00%)
         occurrences all number
    1
    73
    105
    Injection site pruritus
         subjects affected / exposed
    0 / 38 (0.00%)
    10 / 25 (40.00%)
    17 / 50 (34.00%)
         occurrences all number
    0
    52
    106
    Injection site discolouration
         subjects affected / exposed
    0 / 38 (0.00%)
    12 / 25 (48.00%)
    11 / 50 (22.00%)
         occurrences all number
    0
    44
    41
    Injection site induration
         subjects affected / exposed
    2 / 38 (5.26%)
    7 / 25 (28.00%)
    11 / 50 (22.00%)
         occurrences all number
    2
    18
    56
    Injection site discomfort
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 25 (8.00%)
    11 / 50 (22.00%)
         occurrences all number
    1
    12
    38
    Fatigue
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 25 (8.00%)
    7 / 50 (14.00%)
         occurrences all number
    15
    4
    11
    Injection site bruising
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 25 (4.00%)
    10 / 50 (20.00%)
         occurrences all number
    2
    3
    34
    Injection site rash
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 25 (12.00%)
    6 / 50 (12.00%)
         occurrences all number
    0
    5
    19
    Pyrexia
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 25 (8.00%)
    5 / 50 (10.00%)
         occurrences all number
    2
    6
    6
    Injection site reaction
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 25 (16.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    20
    7
    Injection site warmth
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 25 (8.00%)
    6 / 50 (12.00%)
         occurrences all number
    0
    26
    21
    Asthenia
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 25 (12.00%)
    2 / 50 (4.00%)
         occurrences all number
    2
    9
    4
    Injection site haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 25 (8.00%)
    5 / 50 (10.00%)
         occurrences all number
    0
    2
    8
    Injection site hypoaesthesia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 25 (4.00%)
    5 / 50 (10.00%)
         occurrences all number
    0
    1
    9
    Injection site inflammation
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 25 (8.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    20
    7
    Pain
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    2
    0
    2
    Injection site mass
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 25 (8.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    7
    9
    Injection site oedema
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 25 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    3
    0
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 25 (8.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    2
    4
    Investigations
    Red blood cell sedimentation rate increased
         subjects affected / exposed
    4 / 38 (10.53%)
    6 / 25 (24.00%)
    5 / 50 (10.00%)
         occurrences all number
    4
    6
    6
    C-reactive protein increased
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 25 (12.00%)
    5 / 50 (10.00%)
         occurrences all number
    0
    3
    7
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 25 (12.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    3
    4
    Platelet count decreased
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 25 (4.00%)
    2 / 50 (4.00%)
         occurrences all number
    3
    1
    2
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 25 (4.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    1
    3
    Blood creatinine increased
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 25 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 25 (8.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    3
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 25 (8.00%)
    5 / 50 (10.00%)
         occurrences all number
    5
    2
    15
    Dizziness
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 25 (8.00%)
    2 / 50 (4.00%)
         occurrences all number
    2
    2
    2
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 25 (8.00%)
    8 / 50 (16.00%)
         occurrences all number
    2
    2
    9
    Anaemia
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 25 (8.00%)
    2 / 50 (4.00%)
         occurrences all number
    3
    3
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 38 (10.53%)
    5 / 25 (20.00%)
    5 / 50 (10.00%)
         occurrences all number
    11
    17
    6
    Abdominal pain
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 25 (4.00%)
    9 / 50 (18.00%)
         occurrences all number
    1
    1
    13
    Nausea
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 25 (4.00%)
    6 / 50 (12.00%)
         occurrences all number
    1
    2
    8
    Vomiting
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 25 (4.00%)
    4 / 50 (8.00%)
         occurrences all number
    1
    1
    4
    Abdominal pain upper
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    3
    0
    2
    Dry mouth
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 25 (4.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    1
    3
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 25 (8.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 25 (8.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    3
    2
    Rash
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 25 (12.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    3
    0
    Actinic keratosis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    8
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 25 (8.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Renal and urinary disorders
    Albuminuria
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 25 (8.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 38 (10.53%)
    4 / 25 (16.00%)
    8 / 50 (16.00%)
         occurrences all number
    7
    5
    9
    Arthralgia
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 25 (8.00%)
    7 / 50 (14.00%)
         occurrences all number
    0
    3
    7
    Pain in extremity
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 25 (8.00%)
    5 / 50 (10.00%)
         occurrences all number
    1
    2
    5
    Myalgia
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 25 (8.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    6
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 38 (13.16%)
    8 / 25 (32.00%)
    4 / 50 (8.00%)
         occurrences all number
    6
    12
    5
    Bronchitis
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 25 (4.00%)
    3 / 50 (6.00%)
         occurrences all number
    3
    1
    3
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 25 (8.00%)
    2 / 50 (4.00%)
         occurrences all number
    2
    2
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 25 (8.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    3
    0
    Influenza
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    2
    0
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 25 (4.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    1
    3
    Gout
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    1
    Type 2 diabetes mellitus
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 25 (8.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    2
    0
    Decreased appetite
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 25 (8.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    6
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Apr 2015
    Changes included: increased the number of randomised subjects to 105; for statistical considerations, modifications were made to the population definition and missing data handling descriptions.
    11 Apr 2016
    Modified the clinical experience safety language to reflect updated blinded safety data from ongoing studies; allowed subjects who screen-failed in ISIS 304801-CS6 to enter ISIS 304801-CS16 (per sponsor approval, in consultation with investigator) if qualified, and for screening and qualification assessments from the ISIS 304801-CS6 study to be used for enrolment into ISIS 304801-CS16; allowed subjects with familial chylomicronaemia syndrome (FCS), as defined in ISIS 304801-CS6 study, and who satisfactorily complete ISIS 304801-CS16, to be considered for eligibility in ISIS 304801-CS7 (i.e., FCS) open-label extension (OLE) study; indicated that, data and safety monitoring board (DSMB) was independent; revised the contraceptive requirements to state that abstinence was only acceptable as true abstinence, i.e., when it was in line with the preferred and usual lifestyle of the subject; increased the frequency of pregnancy testing; added haematology blood draws at Weeks 12, 16, 22 and 25 to more frequently assess platelet counts; allowed blood sampling at Weeks 4, 8, 12, 16, 19, 22, 25, and 32 to be conducted by a home healthcare nurse; added language that each time a haematology lab was drawn and sent to the central laboratory for analysis, an additional sample would be collected in parallel and analysed locally, to reduce the occurrence of unreportable haematology results; provided guidance that the length of fasting should preferably not be more than 12 hours; updated platelet monitoring rule language to allow for more frequent monitoring as determined by the sponsor medical monitor in consultation with the investigator; provided guidance on monitoring for insulin, oral antidiabetic medication and glucose; added a safety monitoring rule and guidance for severe hypoglycaemia; clarified guidance on determining relatedness of a suspected unexpected serious adverse event (SUSAR); modified the statistical analyses methods in accordance with regulatory agency requests.
    05 May 2016
    Changes included: added language that any case of a platelet count ≤ 50,000/cubic millimetre (mm^3) should be reported in an expedited fashion to the sponsor; added language regarding the frequency of obtaining platelet counts after a study drug dose pause and subsequent rechallenge; added language that any unreportable platelet count result must have been rechecked and determined not to have met a stopping rule before dosing could continue.
    06 Jun 2016
    Haematology blood draws so that platelet counts (PCs) were measured every 2 weeks (Ws) during treatment (T) period and every 2 Ws for first 6 Ws after last dose (D) of study drug; updated platelet safety monitoring rules; indicated that if there were no reportable PC within 14 days of last PC, investigator (Iv) would contact subject (S) to hold dosing until a new PC was obtained and reviewed; indicated that all PC results would be promptly reviewed by Iv to ensure that C had not met stopping rule and to determine whether rate of decline was suggestive that S could be approaching D pause rule of 75000/mm3 (M); changed platelet D pause/stopping rule from 50000/M to 75000/M and added that when PC returned to ≥100000/M dosing could be continued but at a reduced D frequency of 300mg every 2 Ws or a reduced D of 150mg/W and only if approved by sponsor medical monitor; indicated that in event of any PC less than 25000/M, or a PC less than 50000/M that occurred while S was on dosing at 300mg every 2 Ws or 150mg/W, then dosing of a S with study drug (volanesorsen or placebo) would be stopped permanently; PC would be monitored daily until 2 successive values showed improvement, then monitored every 2-3days until PC was stable; indicated that administration of steroids was recommended for Ss whose PC was less than 25000/M and provided T guidelines for administration of steroids; added a table summarising actions to be taken in event of a low PC; indicated that all Ss would have D frequency reduced to 300mg every 2 Ws or D reduced to 150mg/W after 13 Ws of T (exemptions were Ss who had completed ≥5 months of dosing as of 27 May 2016); added effect of gender on pharmacokinetics (PK) by separate population PK analysis (A) rather than descriptive statistics for a robust assessment and to estimate half-life by separate population PKA rather than non- compartmental analysis.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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