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    Clinical Trial Results:
    A 28-week, Multicenter, Randomized, Double-Blind, Active-Controlled, Phase 3 Study with a 24-week Extension Phase Followed by a 52-week Extension Phase to Evaluate the Efficacy and Safety of Simultaneous Administration of Exenatide Once Weekly 2 mg and Dapagliflozin Once Daily 10 mg Compared to Exenatide Once Weekly 2 mg Alone and Dapagliflozin Once Daily 10 mg Alone in Patients with Type 2 Diabetes who have Inadequate Glycemic Control on Metformin

    Summary
    EudraCT number
    2014-003503-29
    Trial protocol
    SK   HU  
    Global end of trial date
    28 Dec 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Dec 2018
    First version publication date
    22 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5553C00003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02229396
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    One MedImmune Way, Gaithersburg, United States, MD 20878
    Public contact
    Global Clinical Leader, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Global Clinical Leader, AstraZeneca, ClinicalTrialTransparency@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
    28 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the change from baseline in hemoglobin A1c (HbA1c) at 28 weeks between exenatide once weekly (EQW) 2 milligrams (mg) and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Dapagliflozin was administered orally and EQW as subcutaneous (SC) injection.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples.
    Background therapy
    Patients continued to administer the same type and dose of metformin therapy they were using at study entry (at least 1500 mg/day).
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Sep 2014
    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
    United States: 394
    Country: Number of subjects enrolled
    Hungary: 78
    Country: Number of subjects enrolled
    Slovakia: 71
    Country: Number of subjects enrolled
    Romania: 70
    Country: Number of subjects enrolled
    Poland: 24
    Country: Number of subjects enrolled
    South Africa: 58
    Worldwide total number of subjects
    695
    EEA total number of subjects
    243
    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)
    608
    From 65 to 84 years
    87
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study conducted between 04 September 2014 and 28 December 2017. 118 centers in 6 countries randomized patients in the study. A Primary Analysis was performed following completion of the 28-week Treatment Period with a data cut-off date of 26 April 2016. All Primary and Secondary End Points were reported at the time of the Primary Analysis.

    Pre-assignment
    Screening details
    The study had a Screening Visit, a 1-week placebo Lead-in Period, a Randomization Visit, and 9 further visits at 1- to 4-week intervals during a 28-week Treatment Period. Patients then entered a 24-week Extension Period 1 and subsequent 52-week Extension Period 2. A follow-up visit occurred 10 weeks after last dose of study medication.

    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, Subject, Assessor
    Blinding implementation details
    Patients received single-blind dapagliflozin and exenatide placebo during the Lead-in Period. From the Randomization Visit and throughout the 28-week Treatment Period, the study was double-blind. The Sponsor and its applicable representatives were unblinded in the Extension Periods (ie, from Week 28 onwards). Sites and patients remained blinded during the Extension Periods.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dapagliflozin + Placebo
    Arm description
    Dapagliflozin 10 mg tablet administered orally once daily + matching placebo for exenatide administered as SC injection once weekly. Patients continued to administer the same type and dose of metformin therapy they were using at study entry.
    Arm type
    Active comparator

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Farxiga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablets administered once daily.

    Investigational medicinal product name
    Placebo-matched exenatide once weekly
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo powder for injection administered once weekly.

    Arm title
    Exenatide + Dapagliflozin
    Arm description
    Exenatide once weekly (EQW) 2 mg administered as SC injection + dapagliflozin 10 mg tablet administered orally once daily. Patients continued to administer the same type and dose of metformin therapy they were using at study entry.
    Arm type
    Experimental

    Investigational medicinal product name
    Exenatide once weekly
    Investigational medicinal product code
    Other name
    EQW, Bydureon
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2.0 mg powder for injection administered once weekly.

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Farxiga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablets administered once daily.

    Arm title
    Exenatide + Placebo
    Arm description
    Exenatide once weekly (EQW) 2 mg administered as SC injection + matching placebo for dapagliflozin tablet administered orally once daily. Patients continued to administer the same type and dose of metformin therapy they were using at study entry.
    Arm type
    Active comparator

    Investigational medicinal product name
    Placebo-matched dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets administered once daily.

    Investigational medicinal product name
    Exenatide once weekly
    Investigational medicinal product code
    Other name
    EQW, Bydureon
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2.0 mg powder for injection administered once weekly.

    Number of subjects in period 1
    Dapagliflozin + Placebo Exenatide + Dapagliflozin Exenatide + Placebo
    Started
    233
    231
    231
    Randomization Code Allocated
    233
    231
    231
    Safety Analysis Set
    233
    231
    230
    Intent-to-Treat (ITT) Analysis Set
    230
    228
    227
    Completed 28-Week Study Period
    208
    202
    193
    Completed 52-Week Study Period
    194
    193
    177
    Completed
    155
    154
    136
    Not completed
    78
    77
    95
         Protocol deviation
             2
             1
             -
         Study-Specific Withdrawal Criteria
             -
             1
             3
         Adverse event, serious fatal
             2
             3
             1
         Patient Incorrectly Randomized
             -
             -
             1
         Adverse event, non-fatal
             6
             12
             12
         Consent withdrawn by subject
             42
             28
             41
         Unspecified
             10
             18
             15
         Withdrew; No Record on Termination Page
             2
             -
             1
         Lost to follow-up
             14
             14
             21

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dapagliflozin + Placebo
    Reporting group description
    Dapagliflozin 10 mg tablet administered orally once daily + matching placebo for exenatide administered as SC injection once weekly. Patients continued to administer the same type and dose of metformin therapy they were using at study entry.

    Reporting group title
    Exenatide + Dapagliflozin
    Reporting group description
    Exenatide once weekly (EQW) 2 mg administered as SC injection + dapagliflozin 10 mg tablet administered orally once daily. Patients continued to administer the same type and dose of metformin therapy they were using at study entry.

    Reporting group title
    Exenatide + Placebo
    Reporting group description
    Exenatide once weekly (EQW) 2 mg administered as SC injection + matching placebo for dapagliflozin tablet administered orally once daily. Patients continued to administer the same type and dose of metformin therapy they were using at study entry.

    Reporting group values
    Dapagliflozin + Placebo Exenatide + Dapagliflozin Exenatide + Placebo Total
    Number of subjects
    233 231 231 695
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    206 200 202 608
        From 65-84 years
    27 31 29 87
        85 years and over
    0 0 0 0
    Gender, Male/Female
    Units: Subjects
        Female
    121 128 114 363
        Male
    112 103 117 332
    Race, Customized
    Units: Subjects
        American Indian Or Alaska Native|
    0 0 2 2
        Asian|
    1 3 1 5
        Black Or African American|
    33 36 27 96
        Other|
    7 1 3 11
        White|
    192 191 198 581

    End points

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    End points reporting groups
    Reporting group title
    Dapagliflozin + Placebo
    Reporting group description
    Dapagliflozin 10 mg tablet administered orally once daily + matching placebo for exenatide administered as SC injection once weekly. Patients continued to administer the same type and dose of metformin therapy they were using at study entry.

    Reporting group title
    Exenatide + Dapagliflozin
    Reporting group description
    Exenatide once weekly (EQW) 2 mg administered as SC injection + dapagliflozin 10 mg tablet administered orally once daily. Patients continued to administer the same type and dose of metformin therapy they were using at study entry.

    Reporting group title
    Exenatide + Placebo
    Reporting group description
    Exenatide once weekly (EQW) 2 mg administered as SC injection + matching placebo for dapagliflozin tablet administered orally once daily. Patients continued to administer the same type and dose of metformin therapy they were using at study entry.

    Primary: Change in HbA1c from baseline to Week 28

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    End point title
    Change in HbA1c from baseline to Week 28
    End point description
    To compare the change from baseline to Week 28 in HbA1c between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
    End point type
    Primary
    End point timeframe
    Baseline to Week 28
    End point values
    Dapagliflozin + Placebo Exenatide + Dapagliflozin Exenatide + Placebo
    Number of subjects analysed
    230
    228
    227
    Units: % HbA1c
        least squares mean (confidence interval 95%)
    -1.39 (-1.57 to -1.21)
    -1.98 (-2.16 to -1.79)
    -1.60 (-1.79 to -1.41)
    Statistical analysis title
    Change in HbA1c - baseline to Week 28
    Statistical analysis description
    Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.
    Comparison groups
    Exenatide + Dapagliflozin v Exenatide + Placebo
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.63
         upper limit
    -0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.129
    Statistical analysis title
    Change in HbA1c - baseline to Week 28
    Statistical analysis description
    Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.
    Comparison groups
    Dapagliflozin + Placebo v Exenatide + Dapagliflozin
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.84
         upper limit
    -0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.127

    Secondary: Change in body weight from baseline to Week 28

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    End point title
    Change in body weight from baseline to Week 28
    End point description
    To compare the change from baseline to Week 28 in body weight between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 28
    End point values
    Dapagliflozin + Placebo Exenatide + Dapagliflozin Exenatide + Placebo
    Number of subjects analysed
    230
    228
    227
    Units: kilogram
        least squares mean (confidence interval 95%)
    -2.22 (-2.78 to -1.66)
    -3.55 (-4.12 to -2.99)
    -1.56 (-2.13 to -0.98)
    Statistical analysis title
    Change in body weight - baseline to Week 28
    Statistical analysis description
    Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.
    Comparison groups
    Exenatide + Dapagliflozin v Exenatide + Placebo
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.79
         upper limit
    -1.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.406
    Statistical analysis title
    Change in body weight - baseline to Week 28
    Statistical analysis description
    Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.
    Comparison groups
    Dapagliflozin + Placebo v Exenatide + Dapagliflozin
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.12
         upper limit
    -0.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4

    Secondary: Change in fasting plasma glucose from baseline to Week 28

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    End point title
    Change in fasting plasma glucose from baseline to Week 28
    End point description
    To compare the change from baseline to Week 28 in fasting plasma glucose (FPG) between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 28
    End point values
    Dapagliflozin + Placebo Exenatide + Dapagliflozin Exenatide + Placebo
    Number of subjects analysed
    230
    228
    227
    Units: milligrams/deciliter (mg/dL)
        least squares mean (confidence interval 95%)
    -49.19 (-54.91 to -43.47)
    -65.83 (-71.60 to -60.06)
    -45.75 (-51.67 to -39.83)
    Statistical analysis title
    Change in FPG - baseline to Week 28
    Statistical analysis description
    Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.
    Comparison groups
    Exenatide + Dapagliflozin v Exenatide + Placebo
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -20.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -27.95
         upper limit
    -12.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.007
    Statistical analysis title
    Change in FPG - baseline to Week 28
    Statistical analysis description
    Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.
    Comparison groups
    Dapagliflozin + Placebo v Exenatide + Dapagliflozin
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -16.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -24.39
         upper limit
    -8.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.947

    Secondary: Change from baseline to Week 28 in 2-hour postprandial glucose after a standard Meal Tolerance Test

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    End point title
    Change from baseline to Week 28 in 2-hour postprandial glucose after a standard Meal Tolerance Test
    End point description
    To compare the change from baseline to Week 28 in 2-hour postprandial glucose (PPG) after a standard Meal Tolerance Test (MTT) between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 28
    End point values
    Dapagliflozin + Placebo Exenatide + Dapagliflozin Exenatide + Placebo
    Number of subjects analysed
    230
    228
    227
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -61.05 (-69.10 to -53.00)
    -87.83 (-95.83 to -79.84)
    -60.09 (-68.48 to -51.71)
    Statistical analysis title
    Change in 2 hr PPG - baseline to Week 28
    Statistical analysis description
    Treatment, region, and baseline HbA1c stratum (<9.0% or ≥9.0%), as fixed factors; baseline value as covariate.
    Comparison groups
    Exenatide + Dapagliflozin v Exenatide + Placebo
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -27.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -37.89
         upper limit
    -17.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.168
    Statistical analysis title
    Change in 2 hr PPG - baseline to Week 28
    Statistical analysis description
    Treatment, region, and baseline HbA1c stratum (<9.0% or ≥9.0%), as fixed factors; baseline value as covariate.
    Comparison groups
    Dapagliflozin + Placebo v Exenatide + Dapagliflozin
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -26.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -36.78
         upper limit
    -16.78
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.09

    Secondary: Percentage of patients achieving weight loss ≥5.0% at Week 28

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    End point title
    Percentage of patients achieving weight loss ≥5.0% at Week 28
    End point description
    To compare the percentage of patients achieving weight loss ≥5.0% at 28 weeks between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 28
    End point values
    Dapagliflozin + Placebo Exenatide + Dapagliflozin Exenatide + Placebo
    Number of subjects analysed
    230
    228
    227
    Units: % of patients
        number (confidence interval 95%)
    20.0 (14.8 to 25.2)
    33.3 (27.2 to 39.5)
    13.7 (9.2 to 18.1)
    Statistical analysis title
    Percentage of patients achieving weight loss >=5%
    Statistical analysis description
    Treatment comparison at Week 28 is based on a Cochran-Mantel-Haenszel test, stratified by baseline HbA1c (<9.0% or ≥9.0%).
    Comparison groups
    Exenatide + Dapagliflozin v Exenatide + Placebo
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [1]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - Difference in percentages = 19.7
    Statistical analysis title
    Percentage of patients achieving weight loss >=5%
    Statistical analysis description
    A Cochran-Mantel-Haenszel analysis was performed at Week 28, stratified by baseline HbA1c (<9.0% or ≥9.0%).
    Comparison groups
    Dapagliflozin + Placebo v Exenatide + Dapagliflozin
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [2]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [2] - Difference in percentages = 13.3

    Secondary: Change in fasting plasma glucose from baseline to Week 2

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    End point title
    Change in fasting plasma glucose from baseline to Week 2
    End point description
    To compare the change from baseline to Week 2 in FPG between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 2
    End point values
    Dapagliflozin + Placebo Exenatide + Dapagliflozin Exenatide + Placebo
    Number of subjects analysed
    230
    228
    227
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -26.31 (-31.42 to -21.20)
    -41.34 (-46.48 to -36.20)
    -21.08 (-26.29 to -15.86)
    Statistical analysis title
    Change in FPG - baseline to Week 2
    Statistical analysis description
    Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.
    Comparison groups
    Exenatide + Dapagliflozin v Exenatide + Placebo
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -20.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -27.12
         upper limit
    -13.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.494
    Statistical analysis title
    Change in FPG - baseline to Week 2
    Statistical analysis description
    Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.
    Comparison groups
    Dapagliflozin + Placebo v Exenatide + Dapagliflozin
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [3]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -15.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.85
         upper limit
    -8.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.477
    Notes
    [3] - This is a nominal p-value.

    Secondary: Percentage of patients achieving HbA1c <7% at Week 28

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    End point title
    Percentage of patients achieving HbA1c <7% at Week 28
    End point description
    To compare the percentage of patients achieving HbA1c <7% at 28 weeks between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 28
    End point values
    Dapagliflozin + Placebo Exenatide + Dapagliflozin Exenatide + Placebo
    Number of subjects analysed
    230
    228
    227
    Units: % of patients
        number (confidence interval 95%)
    19.1 (14.1 to 24.2)
    44.7 (38.3 to 51.2)
    26.9 (21.1 to 32.6)
    Statistical analysis title
    Percentage of patients achieving HbA1c <7%
    Statistical analysis description
    A Cochran-Mantel-Haenszel analysis was performed at Week 28, stratified by baseline HbA1c (<9.0% or ≥9.0%).
    Comparison groups
    Exenatide + Dapagliflozin v Exenatide + Placebo
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [4]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [4] - Difference in percentages = 17.9
    Statistical analysis title
    Percentage of patients achieving HbA1c <7%
    Statistical analysis description
    A Cochran-Mantel-Haenszel analysis was performed at Week 28, stratified by baseline HbA1c (<9.0% or ≥9.0%).
    Comparison groups
    Dapagliflozin + Placebo v Exenatide + Dapagliflozin
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [5]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [5] - Difference in percentages = 25.6

    Secondary: Change in systolic blood pressure from baseline to Week 28

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    End point title
    Change in systolic blood pressure from baseline to Week 28
    End point description
    To compare the change from baseline to Week 28 in systolic blood pressure between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 28
    End point values
    Dapagliflozin + Placebo Exenatide + Dapagliflozin Exenatide + Placebo
    Number of subjects analysed
    230
    228
    227
    Units: millimeters of mercury (mmHg)
        least squares mean (confidence interval 95%)
    -1.8 (-3.4 to -0.3)
    -4.3 (-5.8 to -2.7)
    -1.2 (-2.8 to 0.4)
    Statistical analysis title
    Change in SBP - baseline to Week 28
    Statistical analysis description
    Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.
    Comparison groups
    Exenatide + Dapagliflozin v Exenatide + Placebo
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.2
         upper limit
    -0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.08
    Statistical analysis title
    Change in SBP - baseline to Week 28
    Statistical analysis description
    Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.
    Comparison groups
    Dapagliflozin + Placebo v Exenatide + Dapagliflozin
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.022
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.5
         upper limit
    -0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.06

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline (Day 1) up to Week 104 (28-week Treatment Period + 24-week Extension Period 1 + 52-week Extension Period 2).
    Adverse event reporting additional description
    Treatment-emergent adverse event (AE) data is reported for the Safety Analysis set defined as all randomized patients receiving at least 1 dose of study medication. One patient who was randomized did not receive study medication (the patient was randomized in error); this patient was not counted as completing or discontinuing treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Dapagliflozin + Placebo
    Reporting group description
    Dapagliflozin 10 mg tablet administered orally once daily + matching placebo for exenatide administered as SC injection once weekly. Patients continued to administer the same type and dose of metformin therapy they were using at study entry.

    Reporting group title
    Exenatide + Placebo
    Reporting group description
    Exenatide once weekly (EQW) 2 mg administered as SC injection + matching placebo for dapagliflozin tablet administered orally once daily. Patients continued to administer the same type and dose of metformin therapy they were using at study entry.

    Reporting group title
    Exenatide + Dapagliflozin
    Reporting group description
    Exenatide once weekly (EQW) 2 mg administered as SC injection + dapagliflozin 10 mg tablet administered orally once daily. Patients continued to administer the same type and dose of metformin therapy they were using at study entry.

    Serious adverse events
    Dapagliflozin + Placebo Exenatide + Placebo Exenatide + Dapagliflozin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 233 (7.73%)
    18 / 230 (7.83%)
    17 / 231 (7.36%)
         number of deaths (all causes)
    2
    1
    3
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 230 (0.43%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 233 (0.43%)
    1 / 230 (0.43%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 233 (0.43%)
    1 / 230 (0.43%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Rib fracture
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 230 (0.43%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 230 (0.43%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Spinal compression fracture
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 233 (0.00%)
    2 / 230 (0.87%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 233 (0.86%)
    1 / 230 (0.43%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 230 (0.43%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    1 / 233 (0.43%)
    2 / 230 (0.87%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 233 (0.00%)
    2 / 230 (0.87%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 230 (0.43%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Diabetic neuropathy
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 233 (0.43%)
    1 / 230 (0.43%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic necrosis
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary dyskinesia
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 230 (0.43%)
    2 / 231 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Exostosis
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Pituitary-dependent Cushing's syndrome
         subjects affected / exposed
    0 / 233 (0.00%)
    0 / 230 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 230 (0.43%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 230 (0.43%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 230 (0.43%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 230 (0.00%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 230 (0.43%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Dapagliflozin + Placebo Exenatide + Placebo Exenatide + Dapagliflozin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    73 / 233 (31.33%)
    78 / 230 (33.91%)
    87 / 231 (37.66%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 233 (5.15%)
    12 / 230 (5.22%)
    16 / 231 (6.93%)
         occurrences all number
    12
    12
    18
    General disorders and administration site conditions
    Injection site nodule
         subjects affected / exposed
    13 / 233 (5.58%)
    14 / 230 (6.09%)
    20 / 231 (8.66%)
         occurrences all number
    22
    24
    40
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    11 / 233 (4.72%)
    17 / 230 (7.39%)
    13 / 231 (5.63%)
         occurrences all number
    14
    25
    17
    Nausea
         subjects affected / exposed
    10 / 233 (4.29%)
    26 / 230 (11.30%)
    13 / 231 (5.63%)
         occurrences all number
    12
    29
    14
    Vomiting
         subjects affected / exposed
    7 / 233 (3.00%)
    12 / 230 (5.22%)
    8 / 231 (3.46%)
         occurrences all number
    7
    15
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 233 (5.15%)
    8 / 230 (3.48%)
    15 / 231 (6.49%)
         occurrences all number
    15
    10
    17
    Upper respiratory tract infection
         subjects affected / exposed
    22 / 233 (9.44%)
    17 / 230 (7.39%)
    15 / 231 (6.49%)
         occurrences all number
    25
    29
    22
    Urinary tract infection
         subjects affected / exposed
    16 / 233 (6.87%)
    15 / 230 (6.52%)
    19 / 231 (8.23%)
         occurrences all number
    23
    24
    31

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Oct 2014
    -Exclusion/inclusion criteria amended for clarification of patients that could be included in the study (those on antihypertensive agents, thyroid replacement therapy and antidepressant agents were eligible if on a stable treatment regimen for 2 months prior to Visit 1). -Exclusion criterion amended to reduce threshold for exclusion based on calcitonin levels to align with new project-wide criteria. -Exclusion criterion amended to correct errors in exclusionary laboratory values for serum creatinine. -Methods for ensuring blinding amended to clarify blinding during the Extension Periods and blinding procedures for central laboratory results updated to help prevent indirect unblinding of study treatment. -Restrictions updated to clarify substances and activities from which patients were to abstain for 24 hours prior to visits. -Procedures for discontinuation amended to allow patients that temporarily stop drug treatment due to an AE or other significant event to continue participating in the trial. -Study Plan and Timing of Procedures updated. -Treatment period and study assessment text amended to clarify procedures for performing the 6-point self-monitored blood glucose profile for patients receiving rescue therapy. -Removed requirement that patients take doses of study medication during clinic visits. -Study assessment text regarding the MTT updated to include additional instruction on timing and to clarify the sequence of steps of the MTT. -Urinalysis text updated to specify that urine glucose results were blinded to reduce the possibility of study treatment unblinding. -Text added to clarify procedures for monitoring and assessing potential liver injuries. -Text updated to clarify Hy’s Law information to conform with updated Sponsor standards. -Updated description of hypoglycaemia assessment and reporting to clarify that classification would be done programmatically rather than by Investigators.
    20 Feb 2015
    -Exclusion criterion modified to be less restrictive with respect to prior study participation. -Study Plan and Timing of Procedures were updated. -Review of potential cardiovascular (CV) event triggers was added to all visits where AEs and concomitant medication were reviewed. -Text was added to indicate that metformin should be taken with the next meal, and does not need to be taken at the study site, and that urine should be collected right before time 0 of the MTT. -Extension Period Visit text was amended so that instead of plasma fasting glucose, HbA1c levels were used to determine the need for rescue during the extension period. -New section regarding paternal exposure was added to align with current AstraZeneca protocol template language. -New section regarding CV adjudication was added to enable assessment of CV risk across the exenatide clinical program.
    02 Sep 2015
    -A 52-week extension (Extension Period 2) was added to the study. -Sample collection during the End of Treatment Period Visit or Early Termination or Rescue during Treatment Period was amended to state that blood samples were to be collected after administration of dapagliflozin and that a between visit telephone contact was to take place between Visit 12 to 13 for safety information. -Sample collection and storage of biological samples for future research was amended for clarification.

    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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