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    Clinical Trial Results:
    A Double Blind, Placebo-Controlled, Phase 2A Mechanistic Study to Evaluate the Effect of ISIS 449884 (ISIS-GCGRRX an Antisense Inhibitor of the Glucagon Receptor) on Hepatic Lipid and Glycogen Content in Patients with Type 2 Diabetes Being Treated with Metformin

    Summary
    EudraCT number
    		 2015-003337-10
    Trial protocol
    		 HU   SK   AT  
    Global end of trial date
    22 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Nov 2019
    First version publication date
    27 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ISIS449884-CS3
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02824003
    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
    01 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the pharmacodynamic (PD) effects of glucagon receptor (GCGR) reduction by ISIS 449884 (100 milligrams [mg]) on hepatic lipid and glycogen content.
    Protection of trial subjects
    Each subject, or legally acceptable representative, signed an informed consent form before participating in the study.
    Background therapy
    		 Subjects were on a stable dose of metformin (at least 1000 mg/day) for a minimum of 3 months prior to screening evaluations and continued their stable dose throughout the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Mar 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    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)
    12
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 15 subjects were randomised at 1 study centre in Austria.

    Pre-assignment
    Screening details
    		 50 subjects were screened for the study and 15 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, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received ISIS 449884 matching-placebo, by subcutaneous (SC) injection, on Days 1, 3 and 5 of Week 1 as loading doses followed by once weekly from Week 2 through Week 13.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received ISIS 449884 matching-placebo, by SC injection, on Days 1, 3 and 5 of Week 1 as loading doses followed by once weekly from Week 2 through Week 13.

    Arm title
    		 ISIS 449884 100 mg
    Arm description
    		 Subjects received 100 milligrams (mg) ISIS 449884, by SC injection, on Days 1, 3 and 5 of Week 1 as loading doses followed by once weekly from Week 2 through Week 13.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS 449884
    Investigational medicinal product code
    Other name
    IONIS-GCGRRX
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 100 mg ISIS 449884, by SC injection, on Days 1, 3 and 5 of Week 1 as loading doses followed by once weekly from Week 2 through Week 13.

    Number of subjects in period 1
    		Placebo ISIS 449884 100 mg
    Started
    5
    10
    Per-Protocol Set (PPS)
    5
    8
    Completed
    5
    8
    Not completed
    0
    2
         Adverse event, non-fatal
    -
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received ISIS 449884 matching-placebo, by subcutaneous (SC) injection, on Days 1, 3 and 5 of Week 1 as loading doses followed by once weekly from Week 2 through Week 13.

    Reporting group title
    ISIS 449884 100 mg
    Reporting group description
    		 Subjects received 100 milligrams (mg) ISIS 449884, by SC injection, on Days 1, 3 and 5 of Week 1 as loading doses followed by once weekly from Week 2 through Week 13.

    Reporting group values
    		 Placebo ISIS 449884 100 mg Total
    Number of subjects
    		 5 10 15
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54 ( 10 ) 57 ( 6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 5 7
        Male
    		 3 5 8

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received ISIS 449884 matching-placebo, by subcutaneous (SC) injection, on Days 1, 3 and 5 of Week 1 as loading doses followed by once weekly from Week 2 through Week 13.

    Reporting group title
    ISIS 449884 100 mg
    Reporting group description
    		 Subjects received 100 milligrams (mg) ISIS 449884, by SC injection, on Days 1, 3 and 5 of Week 1 as loading doses followed by once weekly from Week 2 through Week 13.

    Subject analysis set title
    Placebo (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects received ISIS 449884 matching-placebo, by SC injection, on Days 1, 3 and 5 of Week 1 as loading doses followed by once weekly from Week 2 through Week 13.

    Subject analysis set title
    ISIS 449884 100 mg (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects received 100 mg ISIS 449884, by SC injection, on Days 1, 3 and 5 of Week 1 as loading doses followed by once weekly from Week 2 through Week 13.

    Primary: Change from Baseline in Fasting Hepatic Glycogen Content (HGC)

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    End point title
    		 Change from Baseline in Fasting Hepatic Glycogen Content (HGC)
    End point description
    Fasting hepatic glycogen levels were evaluated over time using magnetic resonance spectroscopy (MRS). The Per-Protocol Set (PPS) included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments.
    End point type
    Primary
    End point timeframe
    Baseline, Week 6, and Week 14
    End point values
    		 Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    8
    Units: millimoles per litre (mmol/L)
    arithmetic mean (standard deviation)
        Baseline
    211.50 ( 31.74 )
    207.55 ( 28.04 )
        Change from baseline to Week 6
    24.22 ( 30.06 )
    23.66 ( 24.57 )
        Change from baseline to Week 14
    -20.16 ( 34.01 )
    15.11 ( 39.30 )
    Statistical analysis title
    		 Week 6
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.833
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 14
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.093
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Percent Change from Baseline in Fasting HGC

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    End point title
    		 Percent Change from Baseline in Fasting HGC
    End point description
    Fasting hepatic glycogen levels were evaluated over time using magnetic resonance spectroscopy (MRS). The Per-Protocol Set (PPS) included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments.
    End point type
    Primary
    End point timeframe
    Baseline, Week 6, and Week 14
    End point values
    		 Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    8
    Units: percent change in Fasting HGC
    arithmetic mean (standard deviation)
        Percent change from baseline to Week 6
    11.5 ( 13.5 )
    11.4 ( 13.4 )
        Percent change from baseline to Week 14
    -8.3 ( 15.7 )
    7.2 ( 18.8 )
    Statistical analysis title
    		 Week 6
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.943
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 14
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.093
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Change from Baseline in Fasting Hepatic Lipid Content (HLC)

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    End point title
    		 Change from Baseline in Fasting Hepatic Lipid Content (HLC)
    End point description
    Fasting hepatic lipid levels were evaluated over time using MRS. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments.
    End point type
    Primary
    End point timeframe
    Baseline, Week 6, and Week 14
    End point values
    		 Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    8
    Units: percent lipid content
    arithmetic mean (standard deviation)
        Baseline
    23.02 ( 6.31 )
    13.01 ( 6.04 )
        Change from baseline to Week 6
    -2.38 ( 2.52 )
    3.01 ( 2.95 )
        Change from baseline to Week 14
    -2.68 ( 3.49 )
    4.15 ( 3.74 )
    Statistical analysis title
    		 Week 6
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 14
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Percent Change from Baseline in Fasting HLC

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    End point title
    		 Percent Change from Baseline in Fasting HLC
    End point description
    Description: Fasting hepatic lipid levels were evaluated over time using MRS. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments.
    End point type
    Primary
    End point timeframe
    Baseline, Week 6, and Week 14
    End point values
    		 Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    8
    Units: percent change in fasting HLC
    arithmetic mean (standard deviation)
        Percent change from baseline to Week 6
    -12.5 ( 11.7 )
    28.2 ( 34.2 )
        Percent change from baseline to Week 14
    -12.2 ( 16.0 )
    35.2 ( 35.0 )
    Statistical analysis title
    		 Week 6
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    ISIS 449884 100 mg (PPS) v Placebo (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 14
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Change from Baseline in Fasting Plasma Glucagon

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    End point title
    		 Change from Baseline in Fasting Plasma Glucagon
    End point description
    Fasting plasma glucagon levels were evaluated over time using laboratory analysis. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments. "n" is the number of subjects with data available for analysis at specified timepoint.
    End point type
    Primary
    End point timeframe
    Baseline to Week 14
    End point values
    		 Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    8
    Units: picograms per millilitre (pg/ml)
    arithmetic mean (standard deviation)
        Baseline
    160.6 ( 23.0 )
    114.5 ( 54.5 )
        Change from baseline to Week 14 (n= 5,7)
    -24.4 ( 27.4 )
    91.7 ( 140.9 )
    Statistical analysis title
    		 Week 14
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.048
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Percent Change from Baseline in Fasting Plasma Glucagon

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    End point title
    		 Percent Change from Baseline in Fasting Plasma Glucagon
    End point description
    Fasting plasma glucagon levels were evaluated over time using laboratory analysis. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments.
    End point type
    Primary
    End point timeframe
    Baseline to Week 14
    End point values
    		 Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    7
    Units: percent change in Fasting Glucagon
        arithmetic mean (standard deviation)
    -15.8 ( 17.2 )
    82.7 ( 97.6 )
    Statistical analysis title
    		 Week 14
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    ISIS 449884 100 mg (PPS) v Placebo (PPS)
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Change from Baseline in Fasting Plasma Total Active Glucagon-like Peptide-1 (GLP-1)

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    End point title
    		 Change from Baseline in Fasting Plasma Total Active Glucagon-like Peptide-1 (GLP-1)
    End point description
    Fasting plasma GLP-1 levels were evaluated over time using laboratory analysis. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments. "n" is the number of subjects with data available for analysis at specified timepoint.
    End point type
    Primary
    End point timeframe
    Baseline to Week 14
    End point values
    		 Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    8
    Units: picomoles per litre (pmol/L)
    arithmetic mean (standard deviation)
        Baseline
    3.27 ( 1.46 )
    3.97 ( 2.48 )
        Change from baseline to Week 14 (n= 5,7)
    1.13 ( 2.65 )
    1.67 ( 2.73 )
    Statistical analysis title
    		 Week 14
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.755
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Percent Change from Baseline in Fasting Plasma Total Active GLP-1

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    End point title
    		 Percent Change from Baseline in Fasting Plasma Total Active GLP-1
    End point description
    Fasting plasma GLP-1 levels were evaluated over time using laboratory analysis. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments.
    End point type
    Primary
    End point timeframe
    Baseline to Week 14
    End point values
    		 Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    8
    Units: percent change in fasting total GLP-1
        arithmetic mean (standard deviation)
    36.6 ( 65.9 )
    71.1 ( 146.1 )
    Statistical analysis title
    		 Week 14
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.876
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Change from Baseline in Glycated Haemoglobin (HbA1c)

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    End point title
    		 Change from Baseline in Glycated Haemoglobin (HbA1c)
    End point description
    HbA1c levels were evaluated over time using laboratory analysis. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments. The Full Analysis Set (FAS) included all randomised subjects who received at least 1 dose of study drug and had at least 1 post-baseline efficacy or PD assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 6, and Week 14
    End point values
    		 Placebo ISIS 449884 100 mg Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    10
    5
    8
    Units: percent of HbA1c
    arithmetic mean (standard deviation)
        Baseline
    8.7 ( 0.9 )
    7.9 ( 0.5 )
    8.7 ( 0.9 )
    8.1 ( 0.5 )
        Change from baseline to Week 6
    -0.4 ( 0.4 )
    -0.6 ( 0.3 )
    -0.4 ( 0.4 )
    -0.6 ( 0.3 )
        Change from baseline to Week 14
    -0.6 ( 0.4 )
    -0.9 ( 0.5 )
    -0.6 ( 0.4 )
    -1.0 ( 0.6 )
    Statistical analysis title
    		 Week 6 (FAS)
    Statistical analysis description
    A superiority test was evaluated using ANOVA to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo v ISIS 449884 100 mg
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.303
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Week 14 (FAS)
    Statistical analysis description
    A superiority test was evaluated using ANOVA to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    ISIS 449884 100 mg v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.207
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Week 6 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.235
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 14 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.139
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Percent Change from Baseline in HbA1c

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    End point title
    		 Percent Change from Baseline in HbA1c
    End point description
    HbA1c levels were evaluated over time using laboratory analysis. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments. The FAS included all randomised subjects who received at least 1 dose of study drug and had at least 1 post-baseline efficacy or PD assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 6, and Week 14
    End point values
    		 Placebo ISIS 449884 100 mg Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    10
    5
    8
    Units: percent change in HbA1c
    arithmetic mean (standard deviation)
        Percent change from baseline to Week 6
    -4.2 ( 4.8 )
    -7.3 ( 3.6 )
    -4.2 ( 4.8 )
    -7.6 ( 4.0 )
        Percent change from baseline to Week 14
    -6.3 ( 4.5 )
    -11.4 ( 6.3 )
    -6.3 ( 4.5 )
    -12.4 ( 6.7 )
    Statistical analysis title
    		 Week 6 (FAS)
    Statistical analysis description
    A superiority test was evaluated using ANOVA to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    ISIS 449884 100 mg v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.185
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Week 14 (FAS)
    Statistical analysis description
    A superiority test was evaluated using ANOVA to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    ISIS 449884 100 mg v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.134
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Week 6 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.171
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 14 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.085
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Change from Baseline in Fasting Plasma Glucose (FPG)

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    End point title
    		 Change from Baseline in Fasting Plasma Glucose (FPG)
    End point description
    FPG was monitored daily by the subject, using a study glucometer. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments. The FAS included all randomised subjects who received at least 1 dose of study drug and had at least 1 post-baseline efficacy or PD assessment. "n" is the number of subjects with data available for analysis at specified timepoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 6, and Week 14
    End point values
    		 Placebo ISIS 449884 100 mg Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    10
    5
    8
    Units: milligrams per decilitre (mg/dL)
    arithmetic mean (standard deviation)
        Baseline
    212 ( 17 )
    171 ( 39 )
    212 ( 17 )
    170 ( 43 )
        Change from baseline to Week 6
    -22 ( 36 )
    -26 ( 26 )
    -22 ( 36 )
    -26 ( 27 )
        Change from baseline to Week 14 (n= 5, 9; 5, 7)
    -29 ( 24 )
    -33 ( 28 )
    -29 ( 24 )
    -32 ( 27 )
    Statistical analysis title
    		 Week 6 (FAS)
    Statistical analysis description
    A superiority test was evaluated using ANOVA to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    ISIS 449884 100 mg v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.779
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Week 14 (FAS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo v ISIS 449884 100 mg
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.699
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 6 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 14 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.876
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Percent Change from Baseline in FPG

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    End point title
    		 Percent Change from Baseline in FPG
    End point description
    FPG was monitored daily by the subject, using a study glucometer. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments. The FAS included all randomised subjects who received at least 1 dose of study drug and had at least 1 post-baseline efficacy or PD assessment. "n" is the number of subjects with data available for analysis at specified timepoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 6, and Week 14
    End point values
    		 Placebo ISIS 449884 100 mg Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    10
    5
    8
    Units: percent change in FPG
    arithmetic mean (standard deviation)
        Percent change from baseline to Week 6
    -9.4 ( 16.7 )
    -13.9 ( 11.4 )
    -9.4 ( 16.7 )
    -13.4 ( 11.9 )
        Percent change from baseline to Week 14(n=5,9;5,7)
    -13.3 ( 10.2 )
    -17.7 ( 13.3 )
    -13.3 ( 10.2 )
    -16.9 ( 12.3 )
    Statistical analysis title
    		 Week 6 (FAS)
    Statistical analysis description
    A superiority test was evaluated using ANOVA to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo v ISIS 449884 100 mg
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.543
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Week 14 (FAS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    ISIS 449884 100 mg v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.438
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 6 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.724
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 14 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.53
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Change from Baseline in Fasting Plasma Insulin

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    End point title
    		 Change from Baseline in Fasting Plasma Insulin
    End point description
    Fasting plasma insulin levels were evaluated over time using laboratory analysis. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments. The FAS included all randomised subjects who received at least 1 dose of study drug and had at least 1 post-baseline efficacy or PD assessment. "n" is the number of subjects with data available for analysis at specified timepoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 6, and Week 14
    End point values
    		 Placebo ISIS 449884 100 mg Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    10
    5
    8
    Units: micro International Units (μIU)/mL
    arithmetic mean (standard deviation)
        Baseline
    11.5 ( 2.7 )
    11.0 ( 4.2 )
    11.5 ( 2.7 )
    10.3 ( 4.4 )
        Change from baseline to Week 6
    1.1 ( 2.2 )
    -0.9 ( 4.5 )
    1.1 ( 2.2 )
    -1.6 ( 4.8 )
        Change from baseline to Week 14 (n= 5,9; 5,7)
    0.1 ( 2.4 )
    0.5 ( 4.6 )
    0.1 ( 2.4 )
    -0.2 ( 4.6 )
    Statistical analysis title
    		 Week 6 (FAS)
    Statistical analysis description
    A superiority test was evaluated using ANOVA to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo v ISIS 449884 100 mg
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.366
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Week 14 (FAS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo v ISIS 449884 100 mg
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.797
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 6 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.414
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 14 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Percent Change from Baseline in Fasting Plasma Insulin

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    End point title
    		 Percent Change from Baseline in Fasting Plasma Insulin
    End point description
    Fasting plasma insulin levels were evaluated over time using laboratory analysis. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments. The FAS included all randomised subjects who received at least 1 dose of study drug and had at least 1 post-baseline efficacy or PD assessment. "n" is the number of subjects with data available for analysis at specified timepoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 6, and Week 14
    End point values
    		 Placebo ISIS 449884 100 mg Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    10
    5
    8
    Units: percent change in fasting plasma Insulin
    arithmetic mean (standard deviation)
        Percent change from baseline to Week 6
    11.7 ( 20.7 )
    -1.7 ( 35.2 )
    11.7 ( 20.7 )
    -5.7 ( 38.8 )
        Percent change from baseline to Week 14(n=5,9;5,7)
    2.5 ( 18.3 )
    8.6 ( 35.3 )
    2.5 ( 18.3 )
    5.5 ( 38.0 )
    Statistical analysis title
    		 Week 6 (FAS)
    Statistical analysis description
    A superiority test was evaluated using ANOVA to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    ISIS 449884 100 mg v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.449
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Week 14 (FAS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    ISIS 449884 100 mg v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.699
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 6 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.524
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 14 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Change from Baseline in Fasting Plasma C-peptide

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    End point title
    		 Change from Baseline in Fasting Plasma C-peptide
    End point description
    Fasting plasma C-peptide levels were evaluated over time using laboratory analysis. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments. The FAS included all randomised subjects who received at least 1 dose of study drug and had at least 1 post-baseline efficacy or PD assessment. "n" is the number of subjects with data available for analysis at specified timepoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 6, and Week 14
    End point values
    		 Placebo ISIS 449884 100 mg Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    10
    5
    8
    Units: nanograms/millilitre (ng/mL)
    arithmetic mean (standard deviation)
        Baseline
    3.81 ( 0.98 )
    3.39 ( 0.56 )
    3.81 ( 0.98 )
    3.25 ( 0.53 )
        Change from baseline to Week 6
    0.08 ( 0.28 )
    -0.25 ( 0.48 )
    0.08 ( 0.28 )
    -0.21 ( 0.47 )
        Change from baseline to Week 14 (n= 5,9; 5,7)
    0.07 ( 0.37 )
    -0.02 ( 0.62 )
    0.07 ( 0.37 )
    -0.07 ( 0.52 )
    Statistical analysis title
    		 Week 6 (FAS)
    Statistical analysis description
    A superiority test was evaluated using ANOVA to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo v ISIS 449884 100 mg
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.183
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Week 14 (FAS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    ISIS 449884 100 mg v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.898
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 6 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.284
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 14 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.876
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Percent Change from Baseline in Fasting Plasma C-peptide

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    End point title
    		 Percent Change from Baseline in Fasting Plasma C-peptide
    End point description
    Fasting plasma C-peptide levels were evaluated over time using laboratory analysis. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments. The FAS included all randomised subjects who received at least 1 dose of study drug and had at least 1 post-baseline efficacy or PD assessment. "n" is the number of subjects with data available for analysis at specified timepoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 6, and Week 14
    End point values
    		 Placebo ISIS 449884 100 mg Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    10
    5
    8
    Units: percent change in fasting C-peptide
    arithmetic mean (standard deviation)
        Percent change from baseline to Week 6
    3.3 ( 8.6 )
    -5.9 ( 13.8 )
    3.3 ( 8.6 )
    -4.9 ( 14.1 )
        Percent change from baseline to Week 14(n=5,9;5,7)
    0.6 ( 11.6 )
    -0.7 ( 17.4 )
    0.6 ( 11.6 )
    -2.2 ( 15.5 )
    Statistical analysis title
    		 Week 6 (FAS)
    Statistical analysis description
    A superiority test was evaluated using ANOVA to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    ISIS 449884 100 mg v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.199
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Week 14 (FAS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo v ISIS 449884 100 mg
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 6 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.284
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 14 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Change from Baseline in Weekly Average Fasting Self-monitored Plasma Glucose (SMPG)

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    End point title
    		 Change from Baseline in Weekly Average Fasting Self-monitored Plasma Glucose (SMPG)
    End point description
    SMPG was measured daily at home using the study glucometer. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments. The FAS included all randomised subjects who received at least 1 dose of study drug and had at least 1 post-baseline efficacy or PD assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 6, and Week 14
    End point values
    		 Placebo ISIS 449884 100 mg Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    10
    5
    8
    Units: milligrams per decilitre (mg/dl)
    arithmetic mean (standard deviation)
        Baseline
    182.94 ( 28.62 )
    159.70 ( 25.44 )
    182.94 ( 28.62 )
    159.26 ( 27.83 )
        Change from baseline to Week 6
    -19.75 ( 37.42 )
    -21.08 ( 16.05 )
    -19.75 ( 37.42 )
    -19.42 ( 14.89 )
        Change from baseline to Week 14
    -30.15 ( 24.79 )
    -24.39 ( 17.37 )
    -30.15 ( 24.79 )
    -26.86 ( 16.16 )
    Statistical analysis title
    		 Week 6 (FAS)
    Statistical analysis description
    A superiority test was evaluated using ANOVA to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo v ISIS 449884 100 mg
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.923
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Week 14 (FAS)
    Statistical analysis description
    A superiority test was evaluated using ANOVA to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo v ISIS 449884 100 mg
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.607
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Week 6 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    ISIS 449884 100 mg (PPS) v Placebo (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.435
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 14 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.833
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Percent Change from Baseline in Weekly Average Fasting SMPG

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    End point title
    		 Percent Change from Baseline in Weekly Average Fasting SMPG
    End point description
    SMPG was measured daily at home using the study glucometer. The PPS included all randomised subjects who received at least 11 doses (the first 4 doses must have occurred in the first 14 days) of study drug within 70 days of the first dose, completed protocol-required MRS procedures, and had no significant protocol deviations that would have been expected to affect efficacy assessments. The FAS included all randomised subjects who received at least 1 dose of study drug and had at least 1 post-baseline efficacy or PD assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 6, and Week 14
    End point values
    		 Placebo ISIS 449884 100 mg Placebo (PPS) ISIS 449884 100 mg (PPS)
    Number of subjects analysed
    5
    10
    5
    8
    Units: percent change in fasting SMPG
    arithmetic mean (standard deviation)
        Percent change from baseline to Week 6
    -9.3 ( 21.7 )
    -12.5 ( 8.7 )
    -9.3 ( 21.7 )
    -11.6 ( 8.1 )
        Percent change from baseline to Week 14
    -16.3 ( 15.3 )
    -14.3 ( 8.9 )
    -16.3 ( 15.3 )
    -15.9 ( 7.5 )
    Statistical analysis title
    		 Week 6 (FAS)
    Statistical analysis description
    A superiority test was evaluated using ANOVA to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    ISIS 449884 100 mg v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.684
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Week 14 (FAS)
    Statistical analysis description
    A superiority test was evaluated using ANOVA to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    ISIS 449884 100 mg v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.752
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Week 6 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.622
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Week 14 (PPS)
    Statistical analysis description
    A superiority test was evaluated using the Exact Wilcoxon Rank Sum Test to assess the difference between subjects in the Placebo group and ISIS 449884 group.
    Comparison groups
    Placebo (PPS) v ISIS 449884 100 mg (PPS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Exact Wilcoxon Rank Sum Test
    Confidence interval

    Primary: Percentage of Subjects with Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Percentage of Subjects with Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    An adverse event (AE) was 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 was considered related to the investigational drug product. An AE was considered a treatment-emergent adverse event (TEAE) if it was present prior to the first dose of Study Drug and subsequently worsened or was not present prior to the first dose of Study Drug and subsequently appeared. The Safety Set included all subjects who were randomized and received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 13 weeks
    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: Descriptive statistics only.
    End point values
    		 Placebo ISIS 449884 100 mg
    Number of subjects analysed
    5
    10
    Units: percentage of subjects
        number (not applicable)
    100
    100
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 13 weeks
    Adverse event reporting additional description
    The Safety Set included all subjects who were randomised and received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received ISIS 449884 matching-placebo, by SC injection, on Days 1, 3 and 5 of Week 1 as loading doses followed by once weekly from Week 2 through Week 13.

    Reporting group title
    ISIS 449884 100 mg
    Reporting group description
    		 Subjects received 100 mg ISIS 449884, by SC injection, on Days 1, 3 and 5 of Week 1 as loading doses followed by once weekly from Week 2 through Week 13.

    Serious adverse events
    		 Placebo ISIS 449884 100 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo ISIS 449884 100 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    10 / 10 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    7 / 10 (70.00%)
         occurrences all number
    0
    41
    Injection site pain
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 10 (30.00%)
         occurrences all number
    0
    7
    Injection site pruritus
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 10 (30.00%)
         occurrences all number
    0
    5
    Injection site swelling
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    4
    Injection site discolouration
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    Injection site induration
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Ovarian cyst
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Shared psychotic disorder
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 10 (30.00%)
         occurrences all number
    1
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 10 (30.00%)
         occurrences all number
    1
    8
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    White blood cell count increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Wound
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Eye disorders
    Diabetic retinal oedema
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 10 (20.00%)
         occurrences all number
    1
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia areata
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Diffuse alopecia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Eczema
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Haematuria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Renal impairment
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Back pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 5 (60.00%)
    0 / 10 (0.00%)
         occurrences all number
    6
    0
    Bacteriuria
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Acarodermatitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Asymptomatic bacteriuria
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jul 2015
    Clarified inclusion criterion #6 with regard to eligibility of subjects who had been on a stable dose of metformin plus a sulfonylurea (SU) or dipeptidyl peptidase-4 (DPPIV) inhibitor; deleted exclusion criterion #22 for waist circumference because it was not a contraindication for the MRS procedure; added safety monitoring rules for platelet count results for consistency with other ongoing protocols; and to clarify addition of "Initiation of new or change in dose" to Disallowed Concomitant Therapy #5.
    23 May 2016
    Revised the platelet monitoring criteria to ensure an uninterpretable platelet value was repeated and available for physician review prior to the next scheduled dose per protocol.

    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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