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    Clinical Trial Results:
    A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study to Evaluate the Safety, Tolerability and Pharmacodynamics of ISIS 484137 (ISIS-DGAT2Rx, an Antisense Inhibitor of Diacylglycerol Acyltransferase 2) Administered Once-Weekly for 13 Weeks on Hepatic Steatosis in Adult Patients with Type 2 Diabetes

    Summary
    EudraCT number
    		 2017-003197-13
    Trial protocol
    		 HU  
    Global end of trial date
    28 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jan 2020
    First version publication date
    04 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ISIS484137-CS2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03334214
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ionis Pharmaceuticals, Inc.
    Sponsor organisation address
    2855 Gazelle Court, Carlsbad, United States, CA 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
    28 Nov 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives are: 1. To evaluate the safety and tolerability of ISIS 484137 250 mg per week subcutaneous (SC) injection in adult subjects with type 2 diabetes mellitus (T2DM) 2. To evaluate the pharmacodynamic effects of ISIS 484137 250 mg per week SC injection on the absolute reduction of liver fat (assessed by magnetic resonance imaging [MRI] proton density fat fraction [PDFF]) in adult subjects with T2DM
    Protection of trial subjects
    Each subject, or legally acceptable representative, signed an informed consent form before participating in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Nov 2017
    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?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Hungary: 25
    Country: Number of subjects enrolled
    Canada: 2
    Worldwide total number of subjects
    44
    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)
    26
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 44 subjects were randomised at 3 study centres in Canada, Hungary and Poland.

    Pre-assignment
    Screening details
    		 A total of 173 subjects were screened for the study and 44 subjects were randomised and received study drug.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks.
    Arm type
    		 Experimental

    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
    Subjects received ISIS 484137 matching-placebo, by subcutaneous (SC) injection, once weekly for 13 weeks.

    Arm title
    		 IONIS DGAT2Rx 250 mg
    Arm description
    		 Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IONIS DGAT2Rx
    Investigational medicinal product code
    ISIS 484137
    Other name
    ISIS-DGAT2Rx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received ISIS 484137 250 mg, by SC injection, once weekly for 13 weeks.

    Number of subjects in period 1
    		Placebo IONIS DGAT2Rx 250 mg
    Started
    15
    29
    Completed
    14
    25
    Not completed
    1
    4
         Ineligibility
    -
    1
         Voluntary withdrawal
    1
    -
         Adverse Event or Serious Adverse Event
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks.

    Reporting group title
    IONIS DGAT2Rx 250 mg
    Reporting group description
    		 Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.

    Reporting group values
    		 Placebo IONIS DGAT2Rx 250 mg Total
    Number of subjects
    		 15 29 44
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63 ( 6 ) 62 ( 7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 14 22
        Male
    		 7 15 22
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 15 29 44
        Unknown or Not Reported
    		 0 0 0
    Race
    Units: Subjects
        White
    		 15 29 44
    Liver Fat Percentage
    Units: percentage
        arithmetic mean (standard deviation)
    		 19.54 ( 5.68 ) 18.48 ( 6.04 ) -
    Subject analysis sets

    Subject analysis set title
    Placebo (per protocol)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol set included all randomised subjects who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.

    Subject analysis set title
    IONIS DGAT2Rx 250 mg (per protocol)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol set included all randomised subjects who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.

    Subject analysis sets values
    		 Placebo (per protocol) IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects
    12
    25
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male
    Ethnicity
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    Race
    Units: Subjects
        White
    Liver Fat Percentage
    Units: percentage
        arithmetic mean (standard deviation)
    19.77 ( 6.03 )
    18.22 ( 6.05 )

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks.

    Reporting group title
    IONIS DGAT2Rx 250 mg
    Reporting group description
    		 Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.

    Subject analysis set title
    Placebo (per protocol)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol set included all randomised subjects who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.

    Subject analysis set title
    IONIS DGAT2Rx 250 mg (per protocol)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol set included all randomised subjects who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.

    Primary: Percentage of Subjects With Adverse Events That Were Related to Treatment With IONIS DGAT2Rx

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    End point title
    		 Percentage of Subjects With Adverse Events That Were Related to Treatment With IONIS DGAT2Rx [1]
    End point description
    An adverse event (AE) is any unfavourable and unintended sign (including a clinically-significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. The safety set included all randomised subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 176 days
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this endpoint.
    End point values
    		 Placebo IONIS DGAT2Rx 250 mg
    Number of subjects analysed
    15
    29
    Units: Percentage of subjects
        number (not applicable)
    13.3
    48.3
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Adverse Events, Graded by Severity, That Were Related to Treatment With IONIS DGAT2Rx

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    End point title
    		 Percentage of Subjects With Adverse Events, Graded by Severity, That Were Related to Treatment With IONIS DGAT2Rx [2]
    End point description
    AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, June 2010. Grades: mild - the event is easily tolerated by the subject and does not affect the subject’s usual daily activities; moderate - the event causes the subject more discomfort and interrupts the subject’s usual daily activities; severe - the event is incapacitating and causes considerable interference with the subject’s usual daily activities. The safety set included all randomised subject who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 176 days
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this endpoint.
    End point values
    		 Placebo IONIS DGAT2Rx 250 mg
    Number of subjects analysed
    15
    29
    Units: Percentage of subjects
    number (not applicable)
        Mild
    6.7
    37.9
        Moderate
    6.7
    6.9
        Severe
    0.0
    3.4
    No statistical analyses for this end point

    Primary: Absolute Change in Liver Fat Percentage

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    End point title
    		 Absolute Change in Liver Fat Percentage
    End point description
    Absolute change in liver fat percentage as quantified by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) from baseline to post-treatment MRI. The randomised population included all subjects who are randomised into the study regardless of whether they received the study drug. Per protocol set included all randomised subjects who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.
    End point type
    Primary
    End point timeframe
    Baseline to Week 15
    End point values
    		 Placebo IONIS DGAT2Rx 250 mg Placebo (per protocol) IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects analysed
    15
    26
    12
    25
    Units: Liver fat percentage
        arithmetic mean (standard deviation)
    -0.04 ( 5.82 )
    -5.37 ( 5.41 )
    -0.64 ( 6.11 )
    -5.15 ( 5.40 )
    Statistical analysis title
    		 Placebo v IONIS DGAT2Rx 250 mg (Randomized Set)
    Comparison groups
    Placebo v IONIS DGAT2Rx 250 mg
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Placebo v IONIS DGAT2Rx 250 mg (per protocol)
    Comparison groups
    Placebo (per protocol) v IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026
    Method
    		 ANOVA
    Confidence interval

    Secondary: Percent Change in Liver Fat Percentage

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    End point title
    		 Percent Change in Liver Fat Percentage
    End point description
    Relative percent change in liver fat percentage from baseline to post-treatment MRI. The per protocol set included all randomised subjects who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 15
    End point values
    		 Placebo (per protocol) IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects analysed
    12
    25
    Units: Percent change
        arithmetic mean (standard deviation)
    -2.4 ( 28.8 )
    -25.5 ( 26.5 )
    Statistical analysis title
    		 Placebo v IONIS DGAT2Rx 250 mg
    Comparison groups
    Placebo (per protocol) v IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 ANOVA
    Confidence interval

    Secondary: Percentage of Subjects With ≥ 30% Relative Reduction in Liver Fat Percentage

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    End point title
    		 Percentage of Subjects With ≥ 30% Relative Reduction in Liver Fat Percentage
    End point description
    Percentage of subjects with ≥ 30% relative reduction in liver fat percentage from baseline to post-treatment. The per protocol set included all randomised subjects who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.
    End point type
    Secondary
    End point timeframe
    Week 15
    End point values
    		 Placebo (per protocol) IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects analysed
    12
    25
    Units: percentage of subjects
        number (not applicable)
    16.7
    48.0
    Statistical analysis title
    		 Placebo v IONIS DGAT2Rx 250 mg
    Comparison groups
    Placebo (per protocol) v IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0774 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [3] - The p-value is obtained using Cochran-Mantel-Haenszel (CMH) test stratified by the baseline liver fat stratum (<20%, ≥20%) stratification factor.

    Secondary: Percent Change in Plasma Lipoprotein Profile

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    End point title
    		 Percent Change in Plasma Lipoprotein Profile
    End point description
    Percent change in plasma lipoprotein profile (total cholesterol, apolipoprotein B [apoB], high density lipoprotein (HDL), low density lipoprotein cholesterol [LDL-C], non-HDL, triglycerides, and very low density lipoproteins [VLDL]) from baseline to the average of the post-treatment values assessed 1 and 2 weeks after the last dose (Post-Treatment 1 and Post-Treatment 2 visits). The per protocol set included all randomised subjects who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.
    End point type
    Secondary
    End point timeframe
    Week 15
    End point values
    		 Placebo (per protocol) IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects analysed
    12
    25
    Units: Percent change
    arithmetic mean (standard deviation)
        Total cholesterol
    -4.4 ( 9.6 )
    -2.9 ( 14.2 )
        apoB
    -8.1 ( 9.5 )
    -6.7 ( 15.3 )
        HDL
    1.0 ( 6.3 )
    2.2 ( 11.6 )
        LDL-C
    -8.8 ( 14.9 )
    -3.8 ( 24.1 )
        Non-HDL
    -7.1 ( 13.4 )
    -3.8 ( 18.7 )
        Triglycerides
    -0.8 ( 20.3 )
    2.8 ( 20.1 )
        VLDL-C
    -0.7 ( 20.3 )
    2.0 ( 18.5 )
    Statistical analysis title
    		 Placebo v IONIS DGAT2Rx 250 mg
    Statistical analysis description
    Total Cholesterol
    Comparison groups
    Placebo (per protocol) v IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.682
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Placebo v IONIS DGAT2Rx 250 mg
    Statistical analysis description
    apoB
    Comparison groups
    Placebo (per protocol) v IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.716
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Placebo v IONIS DGAT2Rx 250 mg
    Statistical analysis description
    HDL
    Comparison groups
    Placebo (per protocol) v IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.717
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Placebo v IONIS DGAT2Rx 250 mg
    Statistical analysis description
    LDL-C
    Comparison groups
    Placebo (per protocol) v IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.463
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Placebo v IONIS DGAT2Rx 250 mg
    Statistical analysis description
    Non-HDL
    Comparison groups
    Placebo (per protocol) v IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.555
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Placebo v IONIS DGAT2Rx 250 mg
    Statistical analysis description
    Triglycerides
    Comparison groups
    Placebo (per protocol) v IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.619
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Placebo, IONIS DGAT2Rx 250 mg
    Statistical analysis description
    VLDL-C
    Comparison groups
    Placebo (per protocol) v IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.698
    Method
    		 ANOVA
    Confidence interval

    Secondary: Percent Change in Parameters of Insulin Resistance (IR)

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    End point title
    		 Percent Change in Parameters of Insulin Resistance (IR)
    End point description
    Percent change in parameters of IR (fasting plasma glucose [FPG], homeostatic model assessment - insulin resistance [HOMA-IR], and insulin) from baseline to post-treatment. The per protocol set included all randomised subjects who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations. "n" is the number of subjects with data available for analysis at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Week 14
    End point values
    		 Placebo (per protocol) IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects analysed
    12
    25
    Units: Percent change
    arithmetic mean (standard deviation)
        FPG (n= 12, 24)
    -6.3 ( 23.1 )
    -6.9 ( 16.1 )
        HOMA-IR (n= 12, 24)
    -16.9 ( 29.7 )
    2.6 ( 46.8 )
        Insulin (n= 12, 24)
    -10.3 ( 21.7 )
    10.1 ( 44.8 )
    Statistical analysis title
    		 Placebo v IONIS DGAT2Rx 250 mg
    Statistical analysis description
    FPG
    Comparison groups
    Placebo (per protocol) v IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.902
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Placebo v IONIS DGAT2Rx 250 mg
    Statistical analysis description
    HOMA-IR
    Comparison groups
    Placebo (per protocol) v IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.267
    Method
    		 Van Elteren test
    Confidence interval
    Statistical analysis title
    		 Placebo v IONIS DGAT2Rx 250 mg
    Statistical analysis description
    Insulin
    Comparison groups
    Placebo (per protocol) v IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2
    Method
    		 Van Elteren test
    Confidence interval

    Secondary: Absolute Change in Haemoglobin A1C (HbA1C)

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    End point title
    		 Absolute Change in Haemoglobin A1C (HbA1C)
    End point description
    Absolute change in HbA1C from baseline to post-treatment. The per protocol set included all randomised subjects who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.
    End point type
    Secondary
    End point timeframe
    Week 14
    End point values
    		 Placebo (per protocol) IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects analysed
    12
    25
    Units: percentage of total haemoglobin
        arithmetic mean (standard deviation)
    -0.2 ( 0.7 )
    -0.2 ( 0.6 )
    Statistical analysis title
    		 Placebo v IONIS DGAT2Rx 250 mg
    Comparison groups
    Placebo (per protocol) v IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.933
    Method
    		 ANOVA
    Confidence interval

    Secondary: Percent Change in Liver Volume

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    End point title
    		 Percent Change in Liver Volume
    End point description
    Assessed from Baseline MRI to Post-Treatment MRI. The per protocol set included all randomised subjects who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 15
    End point values
    		 Placebo (per protocol) IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects analysed
    12
    25
    Units: percent change
        arithmetic mean (standard deviation)
    -1.9 ( 7.2 )
    -6.3 ( 9.8 )
    Statistical analysis title
    		 Placebo v IONIS DGAT2Rx 250 mg
    Comparison groups
    Placebo (per protocol) v IONIS DGAT2Rx 250 mg (per protocol)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.183
    Method
    		 ANOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 176 days
    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
    21.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks.

    Reporting group title
    IONIS DGAT2Rx 250 mg
    Reporting group description
    		 Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.

    Serious adverse events
    		 Placebo IONIS DGAT2Rx 250 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 29 (13.79%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Blood triglycerides increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic cerebral infarction
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo IONIS DGAT2Rx 250 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 15 (66.67%)
    20 / 29 (68.97%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Joint dislocation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Carotid arteriosclerosis
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Headache
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 29 (3.45%)
         occurrences all number
    1
    4
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    0 / 15 (0.00%)
    10 / 29 (34.48%)
         occurrences all number
    0
    45
    Injection site bruising
         subjects affected / exposed
    1 / 15 (6.67%)
    4 / 29 (13.79%)
         occurrences all number
    1
    18
    Injection site swelling
         subjects affected / exposed
    0 / 15 (0.00%)
    5 / 29 (17.24%)
         occurrences all number
    0
    11
    Injection site pain
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 29 (13.79%)
         occurrences all number
    0
    14
    Injection site pruritus
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 29 (13.79%)
         occurrences all number
    0
    24
    Fatigue
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 29 (6.90%)
         occurrences all number
    2
    7
    Oedema peripheral
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 15 (20.00%)
    2 / 29 (6.90%)
         occurrences all number
    3
    2
    Constipation
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Reproductive system and breast disorders
    Vulvovaginal pruritus
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    Musculoskeletal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    0
    3
    Myalgia
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Joint swelling
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    0
    4
    Urinary tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 29 (6.90%)
         occurrences all number
    1
    3
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 29 (10.34%)
         occurrences all number
    1
    3
    Decreased appetite
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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