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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of AKCEA‑APOCIII‑LRx Administered Subcutaneously to Patients With Familial Chylomicronemia Syndrome (FCS)

    Summary
    EudraCT number
    		 2020-002536-67
    Trial protocol
    		 DE   SE   NO   FR   PT   SK   HU   NL   ES   IT  
    Global end of trial date
    17 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Nov 2024
    First version publication date
    03 Nov 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ISIS 678354-CS3
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04568434
    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 Clinical Trial Information, Ionis Pharmaceuticals, Inc, +1 760-603-2346 , globalregulatoryaffairs@ionis.com
    Scientific contact
    Ionis Clinical Trial Information, Ionis Pharmaceuticals, Inc, +1 760-603-2346 , globalregulatoryaffairs@ionis.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
    17 Oct 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the study was to evaluate the efficacy of olezarsen as compared to placebo on the percent change in fasting triglycerides (TG) from baseline.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Nov 2020
    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
    Canada: 10
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 19
    Worldwide total number of subjects
    66
    EEA total number of subjects
    35
    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)
    60
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at investigative sites in the United States, Canada, France, Italy, Netherlands, Norway, Portugal, Slovakia, Spain, Sweden and the United Kingdom from 18 November 2020 to 17 October 2023.

    Pre-assignment
    Screening details
    		 Participants with familial chylomicronemia syndrome were enrolled and randomized to receive either olezarsen (50 milligrams [mg] or 80 mg) or olezarsen-matching placebo for a 53-week treatment period. Participants completing treatment had an option to enroll in the Open-label Extension (OLE) Study ISIS 678354-CS13 (NCT05130450).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received olezarsen-matching placebo, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Olezarsen-matching placebo was administered by SC injection.

    Arm title
    		 Olezarsen 50 mg
    Arm description
    		 Subjects received olezarsen 50 mg, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olezarsen
    Investigational medicinal product code
    ISIS 678354
    Other name
    AKCEA‑APOCIII‑LRx
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Olezarsen was administered by SC injection.

    Arm title
    		 Olezarsen 80 mg
    Arm description
    		 Subjects received olezarsen 80 mg, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olezarsen
    Investigational medicinal product code
    ISIS 678354
    Other name
    AKCEA‑APOCIII‑LRx
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Olezarsen was administered by SC injection.

    Number of subjects in period 1
    		Placebo Olezarsen 50 mg Olezarsen 80 mg
    Started
    23
    21
    22
    Completed This Study, Entered OLE Study
    22
    19
    19
    Completed
    22
    19
    19
    Not completed
    1
    2
    3
         Adverse event, non-fatal
    -
    -
    2
         Adverse Events (AE) or Serious Adverse Event (SAE)
    -
    1
    -
         voluntary withdrawl
    -
    1
    1
         Reason not Specified
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received olezarsen-matching placebo, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.

    Reporting group title
    Olezarsen 50 mg
    Reporting group description
    		 Subjects received olezarsen 50 mg, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.

    Reporting group title
    Olezarsen 80 mg
    Reporting group description
    		 Subjects received olezarsen 80 mg, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.

    Reporting group values
    		 Placebo Olezarsen 50 mg Olezarsen 80 mg Total
    Number of subjects
    		 23 21 22
    Age Categorical
    Units: Subjects
    Age continuous
    Full Analysis Set (FAS) included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo.
    Units: years
        arithmetic mean (standard deviation)
    		 44.0 ( 14.67 ) 43.2 ( 12.11 ) 47.7 ( 13.30 ) -
    Gender categorical
    Units: Subjects
        Male
    		 11 6 11 28
        Female
    		 12 15 11 38
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 3 3 1 7
        Not Hispanic or Latino
    		 20 18 21 59
        Unknown or Not Reported
    		 0 0 0 0
    Race
    Units: Subjects
        White
    		 22 17 17 56
        Asian
    		 0 3 3 6
        Native Hawaiian or Other Pacific Islander
    		 0 1 0 1
        Other
    		 1 0 2 3
    Fasting Triglycerides (TG)
    Units: milligrams per deciliter (mg/dL)
        arithmetic mean (standard deviation)
    		 2595.7 ( 1255.72 ) 2683.8 ( 1235.06 ) 2613.1 ( 1498.96 ) -
    Subject analysis sets

    Subject analysis set title
    Pooled Olezarsen
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 50 mg or 80 mg olezarsen, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.

    Subject analysis sets values
    		 Pooled Olezarsen
    Number of subjects
    43
    Age Categorical
    Units: Subjects
    Age continuous
    Full Analysis Set (FAS) included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo.
    Units: years
        arithmetic mean (standard deviation)
    45.5 ( 12.79 )
    Gender categorical
    Units: Subjects
        Male
    17
        Female
    26
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    4
        Not Hispanic or Latino
    39
        Unknown or Not Reported
    0
    Race
    Units: Subjects
        White
    34
        Asian
    6
        Native Hawaiian or Other Pacific Islander
    1
        Other
    2
    Fasting Triglycerides (TG)
    Units: milligrams per deciliter (mg/dL)
        arithmetic mean (standard deviation)
    2647.6 ( 1360.54 )

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received olezarsen-matching placebo, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.

    Reporting group title
    Olezarsen 50 mg
    Reporting group description
    		 Subjects received olezarsen 50 mg, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.

    Reporting group title
    Olezarsen 80 mg
    Reporting group description
    		 Subjects received olezarsen 80 mg, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.

    Subject analysis set title
    Pooled Olezarsen
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 50 mg or 80 mg olezarsen, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.

    Primary: Percent Change From Baseline in Fasting TG at Month 6

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    End point title
    		 Percent Change From Baseline in Fasting TG at Month 6
    End point description
    FAS included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo.
    End point type
    Primary
    End point timeframe
    Baseline, Month 6
    End point values
    		 Placebo Olezarsen 50 mg Olezarsen 80 mg
    Number of subjects analysed
    23
    21
    22
    Units: percent change
        least squares mean (confidence interval 95%)
    11.52 (-5.321 to 28.356)
    -10.85 (-27.797 to 6.095)
    -31.99 (-49.031 to -14.940)
    Statistical analysis title
    		 Percent Change From Baseline at Month 6
    Comparison groups
    Olezarsen 80 mg v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0009 [1]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -43.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -69.085
         upper limit
    		 -17.921
    Notes
    [1] - Nominally significant. ANCOVA model included effects of treatment (olezarsen 80 mg, olezarsen 50 mg, or placebo): dependent variable, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline TG: covariate.
    Statistical analysis title
    		 Percent Change From Baseline at Month 6
    Comparison groups
    Olezarsen 50 mg v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0775 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Least square (LS) mean difference
    Point estimate
    -22.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -47.2
         upper limit
    		 2.463
    Notes
    [2] - Analysis of covariance (ANCOVA) model included effects of treatment (olezarsen 80 mg, olezarsen 50 mg, or placebo): dependent variable, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline TG: covariate.

    Secondary: Percent Change From Baseline in Fasting TG at Month 12

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    End point title
    		 Percent Change From Baseline in Fasting TG at Month 12
    End point description
    FAS included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Placebo Olezarsen 50 mg Olezarsen 80 mg
    Number of subjects analysed
    23
    21
    22
    Units: percent change
        least squares mean (confidence interval 95%)
    20.89 (1.016 to 40.764)
    -22.92 (-42.505 to -3.336)
    -38.50 (-58.187 to -18.815)
    Statistical analysis title
    		 Percent Change From Baseline at Month 12
    Comparison groups
    Olezarsen 50 mg v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0044 [3]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -43.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -73.928
         upper limit
    		 -13.692
    Notes
    [3] - Nominally significant. ANCOVA model included percent change from baseline in fasting TG at Month 12: dependent variable, treatment group, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline TG: covariate.
    Statistical analysis title
    		 Percent Change From Baseline at Month 12
    Comparison groups
    Olezarsen 80 mg v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -59.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -90.663
         upper limit
    		 -28.119
    Notes
    [4] - Nominally significant. ANCOVA model included percent change from baseline in fasting TG at Month 12: dependent variable, treatment group, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline TG: covariate

    Secondary: Percent Change From Baseline in Fasting Apolipoprotein C-III (apoC-III) at Months 6 and 12

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    End point title
    		 Percent Change From Baseline in Fasting Apolipoprotein C-III (apoC-III) at Months 6 and 12
    End point description
    FAS included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6 and 12
    End point values
    		 Placebo Olezarsen 50 mg Olezarsen 80 mg
    Number of subjects analysed
    23
    21
    22
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 6
    7.57 (-5.229 to 20.359)
    -57.91 (-71.193 to -44.631)
    -66.13 (-79.437 to -52.823)
        Month 12
    17.08 (2.149 to 32.009)
    -59.98 (-75.163 to -44.795)
    -64.20 (-79.408 to -48.984)
    Statistical analysis title
    		 Percent Change from Baseline at Month 6
    Comparison groups
    Olezarsen 50 mg v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -65.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -82.634
         upper limit
    		 -48.32
    Notes
    [5] - Nominally significant. ANCOVA model included percent change from baseline in fasting TG at Month 12: dependent variable, treatment group, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline TG: covariate
    Statistical analysis title
    		 Percent Change from Baseline at Month 12
    Comparison groups
    Olezarsen 80 mg v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -81.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -104.656
         upper limit
    		 -57.894
    Notes
    [6] - Nominally significant. ANCOVA model included percent change from baseline in fasting TG at Month 12: dependent variable, treatment group, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline TG: covariate
    Statistical analysis title
    		 Percent Change from Baseline at Month 12
    Comparison groups
    Olezarsen 50 mg v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -77.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -98.938
         upper limit
    		 -55.177
    Notes
    [7] - Nominally significant. ANCOVA model included percent change from baseline in fasting TG at Month 12: dependent variable, treatment group, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline TG: covariate
    Statistical analysis title
    		 Percent Change from Baseline at Month 6
    Comparison groups
    Olezarsen 80 mg v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -73.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -94.553
         upper limit
    		 -52.837
    Notes
    [8] - Nominally significant. ANCOVA model included percent change from baseline in fasting TG at Month 12: dependent variable, treatment group, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline TG: covariate

    Secondary: Percentage of Subjects With ≥ 40% Reduction in Fasting TG at Month 6

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    End point title
    		 Percentage of Subjects With ≥ 40% Reduction in Fasting TG at Month 6
    End point description
    Percentages are rounded off to the nearest single decimal place. FAS included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 Placebo Olezarsen 50 mg Olezarsen 80 mg
    Number of subjects analysed
    23
    21
    22
    Units: percentage of subjects
        number (not applicable)
    4.3
    33.3
    40.9
    Statistical analysis title
    		 Percent Change from Baseline at Month 6
    Comparison groups
    Placebo v Olezarsen 50 mg
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.186 [9]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -33.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -82.612
         upper limit
    		 16.041
    Notes
    [9] - ANCOVA model included percent change from baseline in fasting apoB-48 to Month 6: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects & log-transformed baseline apoB-48: covariate.
    Statistical analysis title
    		 Percent Change from Baseline at Month 6
    Comparison groups
    Placebo v Olezarsen 80 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.0019 [11]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -83.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -136.949
         upper limit
    		 -30.982
    Notes
    [10] - ANCOVA model included percent change from baseline in fasting apoB-48 to Month 6: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects & log-transformed baseline apoB-48: covariate.
    [11] - Nominally significant as described in SAP.
    Statistical analysis title
    		 Percent Change from Baseline at Month 12
    Comparison groups
    Placebo v Olezarsen 50 mg
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4219 [12]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -32.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -113.254
         upper limit
    		 47.459
    Notes
    [12] - ANCOVA model included percent change from baseline in fasting apoB-48 to Month 12: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects & log-transformed baseline apoB-48: covariate.
    Statistical analysis title
    		 Percent Change from Baseline at Month 12
    Comparison groups
    Placebo v Olezarsen 80 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.056 [13]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -75.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -153.195
         upper limit
    		 1.927
    Notes
    [13] - ANCOVA model included percent change from baseline in fasting apoB-48 to Month 12: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects & log-transformed baseline apoB-48: covariate.

    Secondary: Percent Change From Baseline in Fasting Apolipoprotein B-48 (apoB-48) at Months 6 and 12

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    End point title
    		 Percent Change From Baseline in Fasting Apolipoprotein B-48 (apoB-48) at Months 6 and 12
    End point description
    FAS included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6 and 12
    End point values
    		 Placebo Olezarsen 50 mg Olezarsen 80 mg
    Number of subjects analysed
    23
    21
    22
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 6
    24.50 (-9.972 to 58.973)
    -8.78 (-42.976 to 25.406)
    -59.46 (-93.164 to 25.765)
        Month 12
    -3.52 (-53.159 to 46.124)
    -36.41 (-77.689 to 4.860)
    -79.15 (-118.442 to -39.861)
    Statistical analysis title
    		 Percent Change from Baseline at Month 6
    Statistical analysis description
    ANCOVA model included percent change from baseline in fasting apoB-48 to Month 6: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects & log-transformed baseline apoB-48: covariate.
    Comparison groups
    Olezarsen 50 mg v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.186
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -33.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -82.612
         upper limit
    		 16.041
    Statistical analysis title
    		 Percent Change from Baseline at Month 12
    Statistical analysis description
    ANCOVA model included percent change from baseline in fasting apoB-48 to Month 12: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects & log-transformed baseline apoB-48: covariate.
    Comparison groups
    Olezarsen 80 mg v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.056
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -75.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -153.195
         upper limit
    		 1.927
    Statistical analysis title
    		 Percent Change from Baseline at Month 12
    Statistical analysis description
    ANCOVA model included percent change from baseline in fasting apoB-48 to Month 12: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects & log-transformed baseline apoB-48: covariate.
    Comparison groups
    Olezarsen 50 mg v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4219
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -32.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -113.254
         upper limit
    		 47.459
    Statistical analysis title
    		 Percent Change from Baseline at Month 6
    Statistical analysis description
    ANCOVA model included percent change from baseline in fasting apoB-48 to Month 6: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects & log-transformed baseline apoB-48: covariate.
    Comparison groups
    Olezarsen 80 mg v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0019
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -83.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -136.949
         upper limit
    		 -30.982

    Secondary: Percent Change From Baseline in Fasting Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Months 6 and 12

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    End point title
    		 Percent Change From Baseline in Fasting Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Months 6 and 12
    End point description
    FAS included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6 and 12
    End point values
    		 Placebo Olezarsen 50 mg Olezarsen 80 mg
    Number of subjects analysed
    23
    21
    22
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 6
    5.33 (-5.345 to 16.014)
    -12.35 (-23.541 to -1.163)
    -18.86 (-29.952 to -7.774)
        Month 12
    12.01 (-2.480 to 26.494)
    -17.84 (-32.128 to -3.545)
    -27.69 (-41.722 to -13.664)
    Statistical analysis title
    		 Percent Change from Baseline Month 6
    Comparison groups
    Olezarsen 50 mg v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.0401 [15]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -17.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.571
         upper limit
    		 -0.801
    Notes
    [14] - ANCOVA model included percent change from baseline in fasting non-HDL-C to Month 6: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects & log-transformed baseline non-HDL-C: covariate.
    [15] - Nominally significant as described in SAP.
    Statistical analysis title
    		 Percent Change from Baseline at Month 12
    Comparison groups
    Olezarsen 80 mg v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.0009 [17]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -39.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -63.108
         upper limit
    		 -16.292
    Notes
    [16] - ANCOVA model included percent change from baseline in fasting non-HDL-C to Month 12: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects & log-transformed baseline non-HDL-C: covariate.
    [17] - Nominally significant as described in SAP.
    Statistical analysis title
    		 Percent Change from Baseline at Month 12
    Comparison groups
    Olezarsen 50 mg v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.0134 [19]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -29.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -53.49
         upper limit
    		 -6.198
    Notes
    [18] - ANCOVA model included percent change from baseline in fasting non-HDL-C to Month 12: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects & log-transformed baseline non-HDL-C: covariate.
    [19] - Nominally significant as described in SAP.
    Statistical analysis title
    		 Percent Change from Baseline Month 6
    Comparison groups
    Olezarsen 80 mg v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.0036 [21]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -24.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.484
         upper limit
    		 -7.911
    Notes
    [20] - ANCOVA model included percent change from baseline in fasting non-HDL-C to Month 6: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects & log-transformed baseline non-HDL-C: covariate.
    [21] - Nominally significant as described in SAP.

    Secondary: Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Subject-Years During the Treatment Period (Week 1 Through Week 53) in Subjects With Prior History of Pancreatitis

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    End point title
    		 Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Subject-Years During the Treatment Period (Week 1 Through Week 53) in Subjects With Prior History of Pancreatitis [22]
    End point description
    All AEs & SAEs that consistently occurred during study with an event of acute pancreatitis were adjudicated by a blinded independent committee according to Atlanta classification of acute pancreatitis as outlined in the Acute Pancreatitis Adjudication Committee (PAC) Charter. These events were categorized: documented pancreatitis, probable pancreatitis, possible pancreatitis, unable to adjudicate, no diagnosis of acute pancreatitis. Adjudicated event rate represents average number of events per 100 subject-years during treatment period. FAS included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo. 'Subjects analyzed' indicates the number of subjects with a history of pancreatitis within 10 years prior to screening. As prespecified in the protocol, data for this endpoint was collected and reported in a pooled manner for olezarsen (combined Olezarsen 50 mg + Olezarsen 80 mg).
    End point type
    Secondary
    End point timeframe
    During the treatment period Week 1 through Week 53
    Notes
    [22] - 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: This endpoint was analysed only in subjects who received Placebo and Pooled Olezarsen.
    End point values
    		 Placebo Pooled Olezarsen
    Number of subjects analysed
    15
    32
    Units: events per 100 subject-years
        arithmetic mean (confidence interval 95%)
    66.22 (30.490 to 143.817)
    6.73 (1.612 to 28.087)
    Statistical analysis title
    		 Adjudicated Acute Pancreatitis Mean Event Rate
    Statistical analysis description
    Regression model: treatment group & previous treatment (volanesorsen):factors adjudicated acute pancreatitis events in 5 years prior enrollment:covariate. Logarithm of time in year that each participant was observed from Week 1to53:offset variable.
    Comparison groups
    Placebo v Pooled Olezarsen
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.0052 [24]
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Mean Rate Ratio
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.506
    Notes
    [23] - Regression model: treatment group & previous treatment (volanesorsen):factors adjudicated acute pancreatitis events in 5 years prior enrollment:covariate. Logarithm of time in year that each participant was observed from Week 1 to 53:offset variable.
    [24] - Nominally significant as described in SAP.

    Secondary: Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Subject-Years During the Treatment Period (Week 1 Through Week 53)

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    End point title
    		 Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Subject-Years During the Treatment Period (Week 1 Through Week 53) [25]
    End point description
    All AEs & SAEs that consistently occurred during study with an event of acute pancreatitis were adjudicated by a blinded independent committee according to Atlanta classification of acute pancreatitis as outlined in the PAC Charter. These events were categorized as documented pancreatitis, probable pancreatitis, possible pancreatitis, unable to adjudicate, and no diagnosis of acute pancreatitis. Adjudicated event rate represents average number of events per 100 subjects-years during treatment period. FAS included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo. As prespecified in the protocol, data for this endpoint was collected and reported in a pooled manner for olezarsen (combined Olezarsen 50 mg + Olezarsen 80 mg).
    End point type
    Secondary
    End point timeframe
    During the treatment period Week 1 through Week 53
    Notes
    [25] - 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: This endpoint was analysed only in subjects who received Placebo and Pooled Olezarsen.
    End point values
    		 Placebo Pooled Olezarsen
    Number of subjects analysed
    23
    43
    Units: events per 100 subject-years
        arithmetic mean (confidence interval 95%)
    36.31 (14.700 to 89.685)
    4.37 (0.942 to 20.298)
    Statistical analysis title
    		 Adjudicated Acute Pancreatitis Mean Event Rate
    Comparison groups
    Placebo v Pooled Olezarsen
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.0144 [27]
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Mean Rate Ratio
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.022
         upper limit
    		 0.656
    Notes
    [26] - Regression model: treatment group & previous treatment (volanesorsen):factors adjudicated acute pancreatitis events in 5 years prior enrollment:covariate. Logarithm of time in year that each participant was observed from Week 1to53:offset variable.
    [27] - Nominally significant as described in SAP.

    Secondary: Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Subject-Years During Week 13 Through Week 53 in Subjects With Prior History of Pancreatitis

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    End point title
    		 Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Subject-Years During Week 13 Through Week 53 in Subjects With Prior History of Pancreatitis [28]
    End point description
    All AEs & SAEs that consistently occurred during study with an event of acute pancreatitis were adjudicated by a blinded independent committee according to Atlanta classification of acute pancreatitis as outlined in the PAC Charter. These events were categorized as documented pancreatitis, probable pancreatitis, possible pancreatitis, unable to adjudicate, and no diagnosis of acute pancreatitis. Adjudicated event rate represents average number of events per 100 subject-years during specified duration. FAS included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo. 'Subjects analyzed' indicates number of subjects with a history of pancreatitis within 10 years prior to screening. As prespecified in the protocol, data for this endpoint was collected and reported in a pooled manner for olezarsen (combined Olezarsen 50 mg + Olezarsen 80 mg).
    End point type
    Secondary
    End point timeframe
    Week 13 through Week 53
    Notes
    [28] - 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: This endpoint was analysed only in subjects who received Placebo and Pooled Olezarsen.
    End point values
    		 Placebo Pooled Olezarsen
    Number of subjects analysed
    15
    32
    Units: events per 100 subject-years
        arithmetic mean (confidence interval 95%)
    57.89 (24.469 to 136.972)
    8.17 (1.952 to 34.177)
    Statistical analysis title
    		 Adjudicated Acute Pancreatitis Mean Event Rate
    Statistical analysis description
    Regression model: treatment group & previous treatment (volanesorsen):factors adjudicated acute pancreatitis events in 5 years prior enrollment:covariate. Logarithm of time in year that each participant was observed from Week13to53:offset variable.
    Comparison groups
    Placebo v Pooled Olezarsen
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.0174 [30]
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Mean Rate Ratio
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.028
         upper limit
    		 0.709
    Notes
    [29] - Regression model: treatment group & previous treatment (volanesorsen):factors adjudicated acute pancreatitis events in 5 years prior enrollment:covariate. Logarithm of time in year that each participant was observed from Week 13 to 53:offset variable.
    [30] - Nominally significant as described in SAP.

    Secondary: Adjudicated Acute Pancreatitis Mean Event Rate Per 100-Subject Years During Week 13 to Week 53

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    End point title
    		 Adjudicated Acute Pancreatitis Mean Event Rate Per 100-Subject Years During Week 13 to Week 53 [31]
    End point description
    All AEs & SAEs that consistently occurred during study with an event of acute pancreatitis were adjudicated by a blinded independent committee according to Atlanta classification of acute pancreatitis as outlined in the PAC Charter. These events were categorized as documented pancreatitis, probable pancreatitis, possible pancreatitis, unable to adjudicate, and no diagnosis of acute pancreatitis. Adjudicated event rate represents average number of events per 100 subject-years during treatment period. FAS included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo. As prespecified in the protocol, data for this endpoint was collected and reported in a pooled manner for olezarsen (combined Olezarsen 50 mg + Olezarsen 80 mg)
    End point type
    Secondary
    End point timeframe
    Week 13 through Week 53
    Notes
    [31] - 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: This endpoint was analysed only in subjects who received Placebo and Pooled Olezarsen.
    End point values
    		 Placebo Pooled Olezarsen
    Number of subjects analysed
    23
    43
    Units: events per 100-subject years
        arithmetic mean (confidence interval 95%)
    33.43 (13.250 to 84.321)
    5.42 (1.229 to 23.897)
    Statistical analysis title
    		 Adjudicated Acute Pancreatitis Mean Event Rate
    Statistical analysis description
    Regression model :treatment group & previous treatment (volanesorsen):factors adjudicated acute pancreatitis events in 5 years prior enrollment:covariate. Logarithm of time in year that each participant was observed from Week13to53:offset variable.
    Comparison groups
    Placebo v Pooled Olezarsen
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [32]
    P-value
    		 = 0.0314 [33]
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Mean Rate Ratio
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.031
         upper limit
    		 0.85
    Notes
    [32] - Regression model: treatment group & previous treatment (volanesorsen): factors adjudicated acute pancreatitis events in 5 years prior enrollment: covariate. Logarithm of time in year that each participant was observed from Week 13 to 53:offset variable.
    [33] - Nominally significant as described in SAP.

    Secondary: Percentage of Subjects With ≥ 70% Reduction in Fasting TG at Month 6

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    End point title
    		 Percentage of Subjects With ≥ 70% Reduction in Fasting TG at Month 6
    End point description
    Percentages are rounded off to the nearest single decimal place. FAS included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 Placebo Olezarsen 50 mg Olezarsen 80 mg
    Number of subjects analysed
    23
    21
    22
    Units: percentage of subjects
        number (not applicable)
    0
    4.8
    9.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Fasting TG ≤ 880 mg/dL at Month 6

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    End point title
    		 Percentage of Subjects With Fasting TG ≤ 880 mg/dL at Month 6
    End point description
    Percentages are rounded off to the nearest single decimal place. FAS included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo. 'Subjects analyzed' indicates the number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 Placebo Olezarsen 50 mg Olezarsen 80 mg
    Number of subjects analysed
    21
    20
    21
    Units: percentage of subjects
        number (not applicable)
    0
    10.0
    14.3
    No statistical analyses for this end point

    Secondary: Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Subject-Years During Treatment Period in Subjects With ≥ 2 Events in 5 Years Prior to Enrollment

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    End point title
    		 Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Subject-Years During Treatment Period in Subjects With ≥ 2 Events in 5 Years Prior to Enrollment [34]
    End point description
    All AEs & SAEs that consistently occurred during study with an event of acute pancreatitis were adjudicated by a blinded independent committee according to Atlanta classification of acute pancreatitis as outlined in the PAC Charter. These events were categorized as documented pancreatitis, probable pancreatitis, possible pancreatitis, unable to adjudicate, and no diagnosis of acute pancreatitis. Adjudicated event rate represents average number of events per 100 subject-years during treatment period. FAS included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo. 'Subjects analyzed' indicates the number of subjects with ≥ 2 adjudicated acute pancreatitis events in 5 years prior to enrollment. As prespecified in the protocol, data for this endpoint was collected and reported in a pooled manner for olezarsen (combined Olezarsen 50 mg + Olezarsen 80 mg).
    End point type
    Secondary
    End point timeframe
    During the treatment period Week 1 through Week 53
    Notes
    [34] - 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: This endpoint was analysed only in subjects who received Placebo and Pooled Olezarsen.
    End point values
    		 Placebo Pooled Olezarsen
    Number of subjects analysed
    9
    12
    Units: events per 100 subject-years
        arithmetic mean (confidence interval 95%)
    118.59 (61.226 to 229.698)
    16.59 (4.051 to 67.948)
    Statistical analysis title
    		 Adjudicated Acute Pancreatitis Mean Event Rate
    Statistical analysis description
    Regression model:treatment group & previous treatment (volanesorsen):factors adjudicated acute pancreatitis events in 5 years prior enrollment:covariate. Logarithm of time in year that each participant was observed from Week 1 to 53:offset variable.
    Comparison groups
    Placebo v Pooled Olezarsen
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 = 0.0137 [36]
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Mean Rate Ratio
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.029
         upper limit
    		 0.669
    Notes
    [35] - Regression model:treatment group & previous treatment (volanesorsen):factors adjudicated acute pancreatitis events in 5 years prior enrollment:covariate. Logarithm of time in year that each participant was observed from Week 1 to 53: offset variable.
    [36] - Nominally significant as described in SAP.

    Secondary: Adjudicated Acute Pancreatitis Mean Event Rate Per 100-Subject Years From Week 13 to Week 53 in Subjects With ≥ 2 Events in 5 Years Prior to Enrollment

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    End point title
    		 Adjudicated Acute Pancreatitis Mean Event Rate Per 100-Subject Years From Week 13 to Week 53 in Subjects With ≥ 2 Events in 5 Years Prior to Enrollment [37]
    End point description
    All AEs & SAEs that consistently occurred during study with an event of acute pancreatitis were adjudicated by a blinded independent committee according to Atlanta classification of acute pancreatitis as outlined in the PAC Charter. These events were categorized as documented pancreatitis, probable pancreatitis, possible pancreatitis, unable to adjudicate, and no diagnosis of acute pancreatitis. Adjudicated event rate represents average number of events per 100 subject-years during the specified duration. FAS: all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo. 'Subjects analyzed' indicates the number of subjects with ≥ 2 adjudicated acute pancreatitis events in 5 years prior to enrollment. As prespecified in the protocol, data for this endpoint was collected and reported in a pooled manner for olezarsen (combined Olezarsen 50 mg + Olezarsen 80 mg).
    End point type
    Secondary
    End point timeframe
    Week 13 through Week 53
    Notes
    [37] - 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: This endpoint was analysed only in subjects who received Placebo and Pooled Olezarsen.
    End point values
    		 Placebo Pooled Olezarsen
    Number of subjects analysed
    9
    12
    Units: events per 100-subject years
        arithmetic mean (confidence interval 95%)
    106.91 (50.204 to 227.682)
    21.36 (5.233 to 87.219)
    Statistical analysis title
    		 Adjudicated Acute Pancreatitis Mean Event Rate
    Statistical analysis description
    Regression model:treatment group & previous treatment (volanesorsen):factors adjudicated acute pancreatitis events in 5 years prior enrollment:covariate. Logarithm of time in year that each participant was observed from Week 13to53:offset variable.
    Comparison groups
    Placebo v Pooled Olezarsen
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.048 [38]
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Mean Rate Ratio
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.986
    Notes
    [38] - Nominally significant as described in SAP.

    Secondary: Percentage of Subjects With Fasting TG ≤ 500 mg/dL at Month 6

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    End point title
    		 Percentage of Subjects With Fasting TG ≤ 500 mg/dL at Month 6
    End point description
    Percentages are rounded off to the nearest single decimal place. FAS included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo. Subjects analyzed indicates the number of subjects with data available for the analyses.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 Placebo Olezarsen 50 mg Olezarsen 80 mg
    Number of subjects analysed
    22
    21
    22
    Units: percentage of subjects
        number (not applicable)
    0
    0
    13.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug up to end of the follow-up (up to Week 66)
    Adverse event reporting additional description
    Safety analysis set included all subjects that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received olezarsen-matching placebo, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.

    Reporting group title
    Olezarsen 80 mg
    Reporting group description
    		 Subjects received olezarsen 80 mg, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.

    Reporting group title
    Olezarsen 50 mg
    Reporting group description
    		 Subjects received olezarsen 50 mg, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.

    Serious adverse events
    		 Placebo Olezarsen 80 mg Olezarsen 50 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 23 (39.13%)
    3 / 22 (13.64%)
    4 / 21 (19.05%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of the oral cavity
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 21 (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
    Injury, poisoning and procedural complications
    Intentional overdose
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
         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
    Sudden death
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    4 / 23 (17.39%)
    1 / 22 (4.55%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric varices
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 21 (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
    Gastric varices haemorrhage
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 21 (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
    Gastritis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 21 (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
    Intestinal perforation
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (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
    Pancreatitis acute
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis necrotising
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 21 (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
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (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
    Infections and infestations
    Gastroenteritis bacterial
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 21 (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
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 21 (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
    Hypoglycaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 21 (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
    Pancreatogenous diabetes
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 21 (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 Olezarsen 80 mg Olezarsen 50 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 23 (82.61%)
    18 / 22 (81.82%)
    17 / 21 (80.95%)
    Investigations
    Platelet count decreased
         subjects affected / exposed
    1 / 23 (4.35%)
    3 / 22 (13.64%)
    1 / 21 (4.76%)
         occurrences all number
    1
    3
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Skin laceration
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 22 (4.55%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    1
    Nervous system disorders
    Migraine
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    1
    Headache
         subjects affected / exposed
    3 / 23 (13.04%)
    1 / 22 (4.55%)
    4 / 21 (19.05%)
         occurrences all number
    4
    3
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 22 (9.09%)
    0 / 21 (0.00%)
         occurrences all number
    1
    2
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 22 (9.09%)
    1 / 21 (4.76%)
         occurrences all number
    1
    2
    3
    Injection site pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    6
    Fatigue
         subjects affected / exposed
    4 / 23 (17.39%)
    1 / 22 (4.55%)
    1 / 21 (4.76%)
         occurrences all number
    4
    1
    3
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 22 (9.09%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    2
    Abdominal distension
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 22 (9.09%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    Abdominal pain
         subjects affected / exposed
    8 / 23 (34.78%)
    4 / 22 (18.18%)
    3 / 21 (14.29%)
         occurrences all number
    14
    5
    5
    Vomiting
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 22 (9.09%)
    1 / 21 (4.76%)
         occurrences all number
    0
    2
    1
    Nausea
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 22 (4.55%)
    2 / 21 (9.52%)
         occurrences all number
    1
    1
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Diarrhoea
         subjects affected / exposed
    6 / 23 (26.09%)
    2 / 22 (9.09%)
    1 / 21 (4.76%)
         occurrences all number
    12
    2
    1
    Dental caries
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    2
    Cough
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 22 (9.09%)
    2 / 21 (9.52%)
         occurrences all number
    2
    2
    2
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    0
    6
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 23 (4.35%)
    3 / 22 (13.64%)
    2 / 21 (9.52%)
         occurrences all number
    1
    4
    2
    Back pain
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    Arthralgia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    3 / 21 (14.29%)
         occurrences all number
    0
    1
    3
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 22 (4.55%)
    3 / 21 (14.29%)
         occurrences all number
    2
    1
    3
    Cellulitis
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    COVID-19
         subjects affected / exposed
    8 / 23 (34.78%)
    3 / 22 (13.64%)
    6 / 21 (28.57%)
         occurrences all number
    8
    3
    6
    Nasopharyngitis
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 22 (4.55%)
    2 / 21 (9.52%)
         occurrences all number
    2
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    3 / 21 (14.29%)
         occurrences all number
    0
    1
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Aug 2020
    Added 50 mg every 4 weeks dosing cohort, with target enrollment of 30 subjects in each cohort. Each cohort was randomized 2:1 to receive olezarsen or matching placebo every 4 weeks. Updated Study Design and Treatment Schema to include 2 study cohorts (Cohorts A and B). Updated secondary objectives to specify the analysis time points for each objective. Added secondary endpoints for percentage change from Baseline in fasting TG at 12 months and for proportion of subjects who achieve ≥ 70% reduction in fasting TG from Baseline.
    29 Oct 2020
    Updated dosing for Cohort A to continue on 50 mg every 4 weeks or placebo up to Month 12 instead of up-titration to 80 mg every 4 weeks at Month 6. Added Patient-Reported Outcomes Measurement Information System (PROMIS) Short Form v2.0 Cognitive Function 4a as optional evaluation. Updated Exclusion Criterion 3 to allow up to 2 retests at Screening and Qualification for patients with platelet counts < 100,000 per cubic millimeter (mm^3). Removed exclusion criterion related to history of oligonucleotide associated platelet count < 75,000/mm3 (Exclusion Criterion 6 in original Study Protocol). Simplified Inclusion Criterion 7 by cross-referencing section on patient-reported outcomes (PROs). Added language for lab alerts to clarify safety monitoring criteria. Clarified confirmation window, criteria to restart treatment for patients with low platelet count. Updated stopping rules for liver chemistry elevations to note that ALT and AST levels were to be ≤ 3*ULN before treatment can be restarted in patients meeting liver stopping rules. An FCS Symptoms Two Week Recall questionnaire was added at Screening to obtain symptom data prior to randomization into the study.
    21 Dec 2020
    Clarified Exclusion Criterion 11 does not apply to vaccines (both mRNA and Viral Vector). Added sections on Additional Risks During the COVID-19 Pandemic and Allowances in the Circumstance of a Public Health Emergency. Added section on monitoring for LDL-C elevations. Added RDW and MPV to hematology laboratory analytes.
    11 Mar 2021
    Updated Exclusion Criterion 3e (and corresponding renal function safety monitoring criteria) to UPCR of ≥ 0.5 mg/mg or UACR of ≥ 300 mg/g. Added COVID-19 infection not resolved by Study Day 1 to Exclusion Criterion 6. Updated safety monitoring for renal function including UACR (>300 mg/g, or > 50% Baseline whichever was greater) and UPCR levels (> 0.500 mg/mg, or > 50% Baseline whichever was greater). Updated LDL-C thresholds in monitoring criteria (and added conditional to > 100 mg/dL criterion to include either T2DM or CAD with Baseline LDL-C > 100 mg/dL). Added Day 15 ADA and PK sample collections, ADA sample collections on Follow-up Day 4 and 8, and Day 169 PK sample collection at 2h ± 15 min post-dose.
    16 Apr 2021
    Updated Exclusion Criterion 11 to allow a 4-month washout for treatment with a single dose of an oligonucleotide plus a “booster” (i.e., second) dose and to clarify this exclusion does not apply to any vaccine. Clarified conditions under which local repeat testing for hematology samples may be conducted. Clarified that site of injection for study drug should not be the same as injection site for COVID-19 vaccine. Clarified that Day 15 PK sample was collected Anytime rather than Pre-dose.
    25 Oct 2021
    Added ER visit to the definition of history on pancreatitis for Inclusion Criterion 5. Increased enrollment cap for patients without a recorded history of pancreatitis. Change/Rationale for Amendments. Removed GLP agonists from Exclusion Criteria 10b and 12b. Changed washout period for oligonucleotides in Exclusion Criterion 11 to 4 months prior to Screening, or 5 half-lives, whichever is longer. Clarified that race and ethnicity data were to be included in demographic information collected at screening. Clarified that the collection period of pancreatitis medical history was within 10 years prior to Screening with independent adjudication of information collected about events within 5 years prior to Screening. Clarified treatment of redacted documents during database lock. Clarified landmark visits in appendices.
    26 Oct 2022
    Added secondary endpoints for adjudicated pancreatitis event rates from Weeks 13 to 53. Clarified blinding to lipid data in study design. Added allowance for COVID-19 antiviral treatments under EUA outside of trial. Added true abstinence for males as acceptable method of contraception in the inclusion criteria and prevention of pregnancy sections. Adjusted contraceptive requirement period from 30 weeks to 17 weeks post-final dose based on updated PK modeling, fertility/early embryonic development study data. Provided additional guidance on highly effective contraception. Changed platelet count monitoring from weekly to every 2 weeks with platelet count ≥ 100,000/mm3 to < 140,000/mm3. Added language to note that patients who experience persistent or increasing constitutional symptoms should be tested for ADA. Added language to clarify safety monitoring for hypersensitivity reactions (symptoms, procedures). Clarified that spontaneous abortion/miscarriage is an SAE. Added 2 new secondary endpoints for adjudicated acute pancreatitis event rate to be measured from Week 13 to 53, and with ≥ 2 events of adjudicated acute pancreatitis in 5 years prior to enrollment. Added language clarifying that urine collection should not be performed during menstruation.
    19 Jun 2023
    Added secondary endpoints measuring percent change in apoC-III and non-HDL-C, and updated the order of the study objectives. Clarified symptoms of hypersensitivity reactions and applicable lab assessments for monitoring. Updated AESI definitions to include pre-treatment to avoid a hypersensitivity reaction. Removed requirement for at least 1 post-Baseline TG assessment from Full Analysis Set definition. Updated secondary endpoint testing sequence. Clarified that sensitivity analysis in Per Protocol Set would occur for primary analysis, and secondary endpoints would be assessed in the Full Analysis Set alone.
    02 Aug 2023
    Added secondary endpoints for adjudicated acute pancreatitis event rates during Treatment Period (Weeks 1 to 53) and from Weeks 13 to 53 in a subset of the Full Analysis Set with prior history of pancreatitis in 10 years prior to Screening. Revised secondary endpoints containing cutoff fasting TG ≤ 750 mg/dL to cutoff of ≤ 880 mg/dL (per inclusion criteria at screening).

    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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