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    Clinical Trial Results:
    A Double-Blind, Randomized Placebo-Controlled, Parallel-Group, 12 Week Study to Investigate the Effects of Epanova® and Dapagliflozin on Liver Fat Content in Type 2 Diabetic Patients: Effect II

    Summary
    EudraCT number
    		 2014-003638-26
    Trial protocol
    		 SE  
    Global end of trial date
    29 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2016
    First version publication date
    18 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5883C00004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Pepparedsleden 1, Mölndal, Sweden, SE-431 83
    Public contact
    Stefan Carlsson, AstraZeneca, 46 317762017, Stefan.C.Carlsson@astrazeneca.com
    Scientific contact
    Stefan Carlsson, AstraZeneca, 46 317762017, Stefan.C.Carlsson@astrazeneca.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
    29 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary aim of this study was to evaluate the efficacy of the combination of Epanova and dapagliflozin as compared to placebo with respect to reduction in liver fat content (%) at the end of 12 weeks of double-blind treatment in Type 2 diabetics with increased liver fat content as defined by >5.5% (assessed by MRI).
    Protection of trial subjects
    Treated in routine care.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Jan 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 84
    Worldwide total number of subjects
    84
    EEA total number of subjects
    84
    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)
    28
    From 65 to 84 years
    56
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in 5 centers in Sweden between 20 January 2015 and 11 December 2015.

    Pre-assignment
    Screening details
    		 The study duration was up to 15 weeks, consisting of an initial screening period lasting up to 2 weeks, a 12-week treatment period, and a follow-up visit 1 week after the last dose of 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
    		 Investigator, Monitor, Carer, Data analyst, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Epanova + Dapagliflozin
    Arm description
    		 Epanova 4 g/day + Dapagliflozin 10 mg/day
    Arm type
    		 Experimental

    Investigational medicinal product name
    Epanova
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 x 1 g capsules once daily in the morning

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablet once daily in the morning

    Arm title
    		 Dapagliflozin
    Arm description
    		 Dapagliflozin 10 mg/day + placebo to Epanova
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablet once daily in the morning

    Investigational medicinal product name
    Placebo to Epanova
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 x 1g capsules once daily in the morning

    Arm title
    		 Epanova
    Arm description
    		 Epanova 4 g/day + placebo to Dapagliflozin
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo to Dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablet once daily in the morning

    Investigational medicinal product name
    Epanova
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 x 1 g capsules once daily in the morning

    Arm title
    		 Placebo
    Arm description
    		 Placebo to Epanova and placebo to Dapagliflozin
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to Dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablet once daily in the morning

    Investigational medicinal product name
    Placebo to Epanova
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 x 1g capsules once daily in the morning

    Number of subjects in period 1
    		Epanova + Dapagliflozin Dapagliflozin Epanova Placebo
    Started
    22
    21
    20
    21
    Completed
    20
    20
    15
    20
    Not completed
    2
    1
    5
    1
         Consent withdrawn by subject
    1
    -
    1
    1
         Adverse event, non-fatal
    1
    1
    2
    -
         Couldn't swallow IP; noncompliance
    -
    -
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Epanova + Dapagliflozin
    Reporting group description
    		 Epanova 4 g/day + Dapagliflozin 10 mg/day

    Reporting group title
    Dapagliflozin
    Reporting group description
    		 Dapagliflozin 10 mg/day + placebo to Epanova

    Reporting group title
    Epanova
    Reporting group description
    		 Epanova 4 g/day + placebo to Dapagliflozin

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to Epanova and placebo to Dapagliflozin

    Reporting group values
    		 Epanova + Dapagliflozin Dapagliflozin Epanova Placebo Total
    Number of subjects
    		 22 21 20 21 84
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 9 7 6 6 28
        From 65-84 years
    		 13 14 14 15 56
        85 years and over
    		 0 0 0 0 0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 65 ( 5.42 ) 65 ( 6.54 ) 66.2 ( 5.94 ) 65.6 ( 6.1 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 7 5 9 4 25
        Male
    		 15 16 11 17 59
    Age, Customized
    Units: Subjects
        <50
    		 0 1 0 0 1
        >=50 - <65
    		 9 6 6 6 27
        >=65
    		 13 14 14 15 56
    Subject analysis sets

    Subject analysis set title
    Full
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized patients, regardless of whether they took trial medication or not.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients in the Full Analysis Set who received at least 1 dose of study medication.

    Subject analysis set title
    Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The subset of the Full Analysis Set who completed the 12-week double-blind treatment period without any important protocol deviations.

    Subject analysis sets values
    		 Full Safety Per protocol
    Number of subjects
    84
    84
    68
    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)
    65 ( 5.42 )
    66.2 ( 5.94 )
    65.8 ( 5.88 )
    Gender, Male/Female
    Units: Participants
        Female
        Male
    Age, Customized
    Units: Subjects
        <50
        >=50 - <65
        >=65

    End points

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    End points reporting groups
    Reporting group title
    Epanova + Dapagliflozin
    Reporting group description
    		 Epanova 4 g/day + Dapagliflozin 10 mg/day

    Reporting group title
    Dapagliflozin
    Reporting group description
    		 Dapagliflozin 10 mg/day + placebo to Epanova

    Reporting group title
    Epanova
    Reporting group description
    		 Epanova 4 g/day + placebo to Dapagliflozin

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to Epanova and placebo to Dapagliflozin

    Subject analysis set title
    Full
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized patients, regardless of whether they took trial medication or not.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients in the Full Analysis Set who received at least 1 dose of study medication.

    Subject analysis set title
    Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The subset of the Full Analysis Set who completed the 12-week double-blind treatment period without any important protocol deviations.

    Primary: Change from Baseline to Week 12 in % liver fat as assessed by MRI (comparison versus placebo)

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    End point title
    		 Change from Baseline to Week 12 in % liver fat as assessed by MRI (comparison versus placebo) [1]
    End point description
    To evaluate the efficacy of the combination therapy (Epanova + Dapagliflozin) when compared to placebo with respect to reduction in liver fat content (%) at the end of 12 weeks of double-blinded treatment.
    End point type
    Primary
    End point timeframe
    12 weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: not all arms are evaluated for each endpoint, so for this study, the data is correct and the warnings must remain
    End point values
    		 Epanova + Dapagliflozin Placebo
    Number of subjects analysed
    20
    19
    Units: ratio of % liver fat
        geometric mean (confidence interval 95%)
    0.79 (0.69 to 0.9)
    0.97 (0.9 to 1.04)
    Statistical analysis title
    		 Mixed effects model (comparison versus placebo)
    Comparison groups
    Placebo v Epanova + Dapagliflozin
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.046 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric mean ratio for difference
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1
    Notes
    [2] - Hypotheses tested using Dunnett’s multiple testing procedure with a family-wise error rate of 5%, adjusting for 3 pairwise comparisons versus a single control (placebo).

    Secondary: Change from Baseline to Week 12 in % liver fat (comparison between active treatment groups)

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    End point title
    		 Change from Baseline to Week 12 in % liver fat (comparison between active treatment groups) [3]
    End point description
    To evaluate the relative efficacy of the combination of Epanova and dapagliflozin versus Epanova alone and dapagliflozin alone with respect to reduction in % liver fat at the end of 12 weeks of double-blind treatment.
    End point type
    Secondary
    End point timeframe
    12 weeks
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: not all arms are evaluated for each endpoint, so for this study, the data is correct and the warnings must remain
    End point values
    		 Epanova + Dapagliflozin Dapagliflozin Epanova
    Number of subjects analysed
    20
    19
    15
    Units: ratio of % liver fat
        geometric mean (confidence interval 95%)
    0.79 (0.69 to 0.9)
    0.87 (0.77 to 0.99)
    0.85 (0.78 to 0.92)
    Statistical analysis title
    		 Mixed effects model (active treatment)
    Comparison groups
    Epanova + Dapagliflozin v Dapagliflozin
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.502 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric mean ratio for difference
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.11
    Notes
    [4] - Conditional upon rejection of at least 1 of the 3 hypotheses for the primary analysis, secondary hypotheses are tested using Tukey's multiple testing procedure with a family-wise error rate of 5%, adjusting for 3 pairwise comparisons.
    Statistical analysis title
    		 Mixed effects model (active treatment)
    Comparison groups
    Epanova + Dapagliflozin v Epanova
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.562 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric mean ratio for difference
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.13
    Notes
    [5] - Conditional upon rejection of at least 1 of the hypotheses for the primary analysis, secondary hypotheses are tested using Tukey's multiple testing procedure with a family-wise error rate of 5%, adjusting for 3 pairwise comparisons.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from visit 2 (randomization) throughout the treatment period until Visit 5 (end of treatment).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Epanova + Dapagliflozin
    Reporting group description
    		 Epanova 4 g/day + Dapagliflozin 10 mg/day

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to Epanova and placebo to Dapagliflozin

    Reporting group title
    Dapagliflozin
    Reporting group description
    		 Dapagliflozin 10 mg/day + placebo to Epanova

    Reporting group title
    Epanova
    Reporting group description
    		 Epanova 4 g/day + placebo to Dapagliflozin

    Serious adverse events
    		 Epanova + Dapagliflozin Placebo Dapagliflozin Epanova
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Epanova + Dapagliflozin Placebo Dapagliflozin Epanova
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 22 (63.64%)
    7 / 21 (33.33%)
    8 / 21 (38.10%)
    12 / 20 (60.00%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 21 (4.76%)
    5 / 21 (23.81%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    5
    1
    Headache
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 21 (9.52%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    3
    0
    0
    2
    Constipation
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    2 / 21 (9.52%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    2
    1
    Diarrhoea
         subjects affected / exposed
    11 / 22 (50.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    7 / 20 (35.00%)
         occurrences all number
    12
    0
    1
    7
    Nausea
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 21 (9.52%)
    0 / 21 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    2
    2
    0
    3
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 21 (4.76%)
    2 / 21 (9.52%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    2
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 21 (4.76%)
    1 / 21 (4.76%)
    2 / 20 (10.00%)
         occurrences all number
    2
    2
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Nov 2014
    Minor edits and corrections for clarity and accuracy.
    23 Mar 2015
    Revision of inclusion and exclusion critieria to capture the target population for the study.
    25 Jun 2015
    Reduction of sample size and revision of statistical analyses.

    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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