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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-controlled, Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of Dapagliflozin as an Add-on to Insulin Therapy in Subjects with Type 1 Diabetes Mellitus - Study Two

    Summary
    EudraCT number
    		 2014-004599-49
    Trial protocol
    		 SE   GB   DE   NL   PL   BE  
    Global end of trial date
    18 Apr 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Apr 2019
    First version publication date
    03 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MB102-230
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Pepparedsleden 1, MoIndal, Sweden, 431 83
    Public contact
    Anna Maria Langkilde, AstraZeneca AB, +46 31 7761000, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Anna Maria Langkilde, AstraZeneca, +46 31 7761000, 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
    17 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to compare the change from baseline in HbA1c after 24 weeks of double-blinded treatment with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin.
    Protection of trial subjects
    Independent Data Monitoring Committee
    Background therapy
    		 Insulin
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jul 2015
    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?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 141
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Canada: 73
    Country: Number of subjects enrolled
    Chile: 25
    Country: Number of subjects enrolled
    Germany: 96
    Country: Number of subjects enrolled
    Japan: 225
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Poland: 188
    Country: Number of subjects enrolled
    Russian Federation: 95
    Country: Number of subjects enrolled
    Sweden: 56
    Country: Number of subjects enrolled
    Switzerland: 20
    Country: Number of subjects enrolled
    United Kingdom: 35
    Country: Number of subjects enrolled
    United States: 494
    Worldwide total number of subjects
    1465
    EEA total number of subjects
    392
    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)
    1376
    From 65 to 84 years
    89
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The results on this form are from the 24 week short-term double-blind treatment period. This study was conducted at 148 centers in 13 countries from 8 July 2015 to 2 Sep 2017.

    Pre-assignment
    Screening details
    		 815 participants were randomized. Of the 195 participants not randomized: 97 No longer met study criteria, 44 withdrew consent, 13 were lost to follow-up, and 41 did not continue for other reasons. Two participants did not receive any study drug and were excluded from analyses. Thus, the total number of subjects is 813.

    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
    Blinding implementation details
    Double-blind

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DAPA 5 MG + INS
    Arm description
    		 Dapagliflozin 5 mg plus insulin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Farxiga
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg oral administration

    Arm title
    		 DAPA 10 MG + INS
    Arm description
    		 Dapagliflozin 10 mg plus insulin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Farxiga
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg oral administration

    Arm title
    		 PLA + INS
    Arm description
    		 Placebo plus insulin
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration

    Number of subjects in period 1 [1]
    		DAPA 5 MG + INS DAPA 10 MG + INS PLA + INS
    Started
    271
    270
    272
    Completed
    244
    245
    239
    Not completed
    27
    25
    33
         Consent withdrawn by subject
    5
    5
    14
         Discontinued due to DKA/hypoglycemia
    2
    5
    4
         Adverse event, non-fatal
    17
    11
    11
         Pregnancy
    -
    -
    2
         Lost to follow-up
    2
    3
    1
         Protocol deviation
    1
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of enrolled subjects will generally be higher than the number of subjects in the baseline period since not all enrolled subjects actually make it into the study

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DAPA 5 MG + INS
    Reporting group description
    		 Dapagliflozin 5 mg plus insulin

    Reporting group title
    DAPA 10 MG + INS
    Reporting group description
    		 Dapagliflozin 10 mg plus insulin

    Reporting group title
    PLA + INS
    Reporting group description
    		 Placebo plus insulin

    Reporting group values
    		 DAPA 5 MG + INS DAPA 10 MG + INS PLA + INS Total
    Number of subjects
    		 271 270 272 813
    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)
    		 258 258 261 777
        From 65-84 years
    		 13 12 11 36
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 42.7 ± 13.35 42.4 ± 12.80 43.0 ± 13.73 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 153 149 153 455
        Male
    		 118 121 119 358
    Race/Ethnicity, Customized
    Units: Subjects
        White|
    		 210 219 208 637
        Black or African-American|
    		 4 7 1 12
        Asian|
    		 57 44 59 160
        Other|
    		 0 0 4 4
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    		 3 17 11 31
        Non-Hispanic/Latino
    		 78 63 65 206
        Not reported
    		 190 190 196 576
    Age Categorization by Tertiles
    Units: Subjects
        <65 years
    		 258 258 261 777
        >=65 - <75 years
    		 12 12 11 35
        >=75 years
    		 1 0 0 1
    Age Categorization 2 by Tertiles
    Units: Subjects
        <35 years
    		 81 79 84 244
        >=35 - <50 years
    		 94 110 95 299
        >=50 years
    		 96 81 93 270
    Body Mass Index
    Units: Subjects
        <=23 Kg/m2
    		 58 47 52 157
        >23 Kg/m2 - <=25 Kg/m2
    		 42 43 44 129
        >25 Kg/m2 - <=27 Kg/m2
    		 47 44 45 136
        >27 Kg/m2 - <=30 Kg/m2
    		 59 69 50 178
        >30 Kg/m2
    		 65 67 81 213
    Body Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 78.74 ± 17.384 80.06 ± 18.302 78.88 ± 18.867 -
    Body Mass Index
    Units: Kg/m2
        arithmetic mean (standard deviation)
    		 27.27 ± 5.128 27.80 ± 5.525 27.62 ± 5.414 -
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects who took at least one dose of double-blind study medication during the short-term double-blind period.

    Subject analysis sets values
    		 Full Analysis Set
    Number of subjects
    813
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    777
        From 65-84 years
    36
        85 years and over
    0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    42.7 ± 13.29
    Sex: Female, Male
    Units: Subjects
        Female
    455
        Male
    358
    Race/Ethnicity, Customized
    Units: Subjects
        White|
    637
        Black or African-American|
    12
        Asian|
    160
        Other|
    4
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    31
        Non-Hispanic/Latino
    206
        Not reported
    576
    Age Categorization by Tertiles
    Units: Subjects
        <65 years
    777
        >=65 - <75 years
    35
        >=75 years
    1
    Age Categorization 2 by Tertiles
    Units: Subjects
        <35 years
    244
        >=35 - <50 years
    299
        >=50 years
    270
    Body Mass Index
    Units: Subjects
        <=23 Kg/m2
    157
        >23 Kg/m2 - <=25 Kg/m2
    129
        >25 Kg/m2 - <=27 Kg/m2
    136
        >27 Kg/m2 - <=30 Kg/m2
    178
        >30 Kg/m2
    213
    Body Weight
    Units: kg
        arithmetic mean (standard deviation)
    79.22 ± 18.183
    Body Mass Index
    Units: Kg/m2
        arithmetic mean (standard deviation)
    27.56 ± 5.357

    End points

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    End points reporting groups
    Reporting group title
    DAPA 5 MG + INS
    Reporting group description
    		 Dapagliflozin 5 mg plus insulin

    Reporting group title
    DAPA 10 MG + INS
    Reporting group description
    		 Dapagliflozin 10 mg plus insulin

    Reporting group title
    PLA + INS
    Reporting group description
    		 Placebo plus insulin

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects who took at least one dose of double-blind study medication during the short-term double-blind period.

    Primary: Adjusted mean change from baseline in HbA1c at Week 24

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    End point title
    		 Adjusted mean change from baseline in HbA1c at Week 24
    End point description
    To compare the change from baseline in HbA1c between dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
    End point type
    Primary
    End point timeframe
    Baseline and 24 weeks
    End point values
    		 DAPA 5 MG + INS DAPA 10 MG + INS PLA + INS
    Number of subjects analysed
    266
    267
    267
    Units: HbA1c (%)
        least squares mean (confidence interval 95%)
    -0.34 (-0.43 to -0.25)
    -0.39 (-0.48 to -0.30)
    0.03 (-0.06 to 0.12)
    Statistical analysis title
    		 Primary Endpoint Analysis
    Statistical analysis description
    Difference vs. placebo in adjusted mean change from baseline
    Comparison groups
    PLA + INS v DAPA 5 MG + INS
    Number of subjects included in analysis
    533
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 -0.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0579
    Statistical analysis title
    		 Primary Endpoint Analysis
    Statistical analysis description
    Difference vs. placebo in adjusted mean change from baseline
    Comparison groups
    DAPA 10 MG + INS v PLA + INS
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 -0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0578

    Secondary: Adjusted mean percentage change from baseline in total daily insulin dose at Week 24

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    End point title
    		 Adjusted mean percentage change from baseline in total daily insulin dose at Week 24
    End point description
    To compare the percent change from baseline in total daily insulin dose with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
    End point type
    Secondary
    End point timeframe
    Baseline and 24 weeks
    End point values
    		 DAPA 5 MG + INS DAPA 10 MG + INS PLA + INS
    Number of subjects analysed
    270
    267
    266
    Units: Percentage change
        least squares mean (confidence interval 95%)
    -8.73 (-11.09 to -6.31)
    -9.05 (-11.43 to -6.60)
    2.29 (-0.41 to 5.06)
    Statistical analysis title
    		 First Secondary Endpoint Analysis
    Statistical analysis description
    Difference vs. placebo in adjusted mean percentage change from baseline
    Comparison groups
    DAPA 5 MG + INS v PLA + INS
    Number of subjects included in analysis
    536
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -10.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.73
         upper limit
    		 -7.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.5291
    Statistical analysis title
    		 First Secondary Endpoint Analysis
    Statistical analysis description
    Difference vs. placebo in adjusted mean percentage change from baseline
    Comparison groups
    DAPA 10 MG + INS v PLA + INS
    Number of subjects included in analysis
    533
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -11.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.04
         upper limit
    		 -8.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.5331

    Secondary: Adjusted mean percentage change from baseline in body weight at Week 24

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    End point title
    		 Adjusted mean percentage change from baseline in body weight at Week 24
    End point description
    To compare the percentage change from baseline in body weight with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
    End point type
    Secondary
    End point timeframe
    Baseline and 24 weeks
    End point values
    		 DAPA 5 MG + INS DAPA 10 MG + INS PLA + INS
    Number of subjects analysed
    269
    269
    272
    Units: Percentage change
        least squares mean (confidence interval 95%)
    -3.22 (-3.76 to -2.69)
    -3.76 (-4.29 to -3.22)
    -0.02 (-0.57 to 0.54)
    Statistical analysis title
    		 Second Secondary Endpoint Analysis
    Statistical analysis description
    Difference vs. placebo in adjusted mean percentage change from baseline
    Comparison groups
    DAPA 5 MG + INS v PLA + INS
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.96
         upper limit
    		 -2.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3829
    Statistical analysis title
    		 Second Secondary Endpoint Analysis
    Statistical analysis description
    Difference vs. placebo in adjusted mean percentage change from baseline
    Comparison groups
    DAPA 10 MG + INS v PLA + INS
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.49
         upper limit
    		 -2.99
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3812

    Secondary: Adjusted mean change from baseline in 24-hour continuous glucose monitoring (CGM) mean value at Week 24

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    End point title
    		 Adjusted mean change from baseline in 24-hour continuous glucose monitoring (CGM) mean value at Week 24
    End point description
    To compare the change from baseline in mean value of 24-hour glucose readings obtained from CGM with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
    End point type
    Secondary
    End point timeframe
    Baseline and 24 weeks
    End point values
    		 DAPA 5 MG + INS DAPA 10 MG + INS PLA + INS
    Number of subjects analysed
    252
    255
    257
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -6.46 (-10.04 to -2.87)
    -10.54 (-14.14 to -6.94)
    9.20 (5.57 to 12.83)
    Statistical analysis title
    		 Third Secondary Endpoint Analysis
    Statistical analysis description
    Difference vs. placebo in adjusted mean change from baseline
    Comparison groups
    DAPA 10 MG + INS v PLA + INS
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.34
         upper limit
    		 -15.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.3419
    Statistical analysis title
    		 Third Secondary Endpoint Analysis
    Statistical analysis description
    Difference vs. placebo in adjusted mean change from baseline
    Comparison groups
    DAPA 5 MG + INS v PLA + INS
    Number of subjects included in analysis
    509
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -15.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.26
         upper limit
    		 -11.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.3468

    Secondary: Adjusted mean change from baseline in 24-hour CGM mean amplitude of glycemic excursion (MAGE) value at Week 24

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    End point title
    		 Adjusted mean change from baseline in 24-hour CGM mean amplitude of glycemic excursion (MAGE) value at Week 24
    End point description
    To compare the change from baseline in mean amplitude of glucose excursions (MAGE) of 24-hour glucose readings obtained from CGM with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
    End point type
    Secondary
    End point timeframe
    Baseline and 24 weeks
    End point values
    		 DAPA 5 MG + INS DAPA 10 MG + INS PLA + INS
    Number of subjects analysed
    252
    255
    257
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -10.17 (-13.90 to -6.45)
    -9.68 (-13.44 to -5.93)
    -0.33 (-4.12 to 3.46)
    Statistical analysis title
    		 Fourth Secondary Endpoint Analysis
    Statistical analysis description
    Difference vs. placebo in adjusted mean change from baseline
    Comparison groups
    DAPA 5 MG + INS v PLA + INS
    Number of subjects included in analysis
    509
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.66
         upper limit
    		 -5.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.4519
    Statistical analysis title
    		 Fourth Secondary Endpoint Analysis
    Statistical analysis description
    Difference vs. placebo in adjusted mean change from baseline
    Comparison groups
    DAPA 10 MG + INS v PLA + INS
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.16
         upper limit
    		 -4.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.4487

    Secondary: Change from baseline in the percent of 24-hour glucose readings obtained from CGM that falls within the target range of > 70 mg/dL and <= 180 mg/dL (%) at Week 24

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    End point title
    		 Change from baseline in the percent of 24-hour glucose readings obtained from CGM that falls within the target range of > 70 mg/dL and <= 180 mg/dL (%) at Week 24
    End point description
    To compare the change from baseline in the percent of 24-hour glucose readings obtained from CGM that falls within the target range of >70 mg/dL and <=180 mg/dL with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
    End point type
    Secondary
    End point timeframe
    Baseline and 24 weeks
    End point values
    		 DAPA 5 MG + INS DAPA 10 MG + INS PLA + INS
    Number of subjects analysed
    252
    255
    257
    Units: % of readings
        least squares mean (confidence interval 95%)
    5.92 (4.32 to 7.52)
    7.60 (5.98 to 9.21)
    -3.10 (-4.73 to -1.47)
    Statistical analysis title
    		 Fifth Secondary Endpoint Analysis
    Statistical analysis description
    Difference vs. placebo in adjusted mean change from baseline
    Comparison groups
    DAPA 5 MG + INS v PLA + INS
    Number of subjects included in analysis
    509
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.97
         upper limit
    		 11.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0415
    Statistical analysis title
    		 Fifth Secondary Endpoint Analysis
    Statistical analysis description
    Difference vs. placebo in adjusted mean change from baseline
    Comparison groups
    DAPA 10 MG + INS v PLA + INS
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    10.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.66
         upper limit
    		 12.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0396

    Secondary: Percentage of subjects with HbA1c reduction from baseline to week 24 last observation carried forward (LOCF) >= 0.5% and without severe hypoglycemia events at Week 24

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    End point title
    		 Percentage of subjects with HbA1c reduction from baseline to week 24 last observation carried forward (LOCF) >= 0.5% and without severe hypoglycemia events at Week 24
    End point description
    To compare dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin for the proportion of subjects achieving an HbA1c reduction from baseline to Week 24 visit >=0.5% without severe hypoglycemia events
    End point type
    Secondary
    End point timeframe
    Baseline and 24 weeks
    End point values
    		 DAPA 5 MG + INS DAPA 10 MG + INS PLA + INS
    Number of subjects analysed
    266
    267
    269
    Units: Participants
        Number of Responders
    105
    111
    54
    Statistical analysis title
    		 Sixth Secondary Endpoint Analysis
    Statistical analysis description
    Odds Ratio vs. Placebo
    Comparison groups
    DAPA 5 MG + INS v PLA + INS
    Number of subjects included in analysis
    535
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.81
         upper limit
    		 4.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2058
    Statistical analysis title
    		 Sixth Secondary Endpoint Analysis
    Statistical analysis description
    Odds Ratio vs. Placebo
    Comparison groups
    DAPA 10 MG + INS v PLA + INS
    Number of subjects included in analysis
    536
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.05
         upper limit
    		 4.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2054

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events (AEs), including serious adverse events (SAEs), were collected from the time informed consent was signed throughout the short-term plus long-term treatment period (through week 52).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    DAPA 5 MG + INS
    Reporting group description
    		 Dapagliflozin 5 mg plus insulin

    Reporting group title
    PLA + INS
    Reporting group description
    		 Placebo plus insulin

    Reporting group title
    DAPA 10 MG + INS
    Reporting group description
    		 Dapagliflozin 10 mg plus insulin

    Serious adverse events
    		 DAPA 5 MG + INS PLA + INS DAPA 10 MG + INS
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 271 (11.81%)
    16 / 272 (5.88%)
    19 / 270 (7.04%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thyroid neoplasm
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (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
    Histiocytic necrotising lymphadenitis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
    0 / 270 (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
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Acquired phimosis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (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
    Femur fracture
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (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
    Road traffic accident
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
    Additional description: Humerus fracture
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
    0 / 270 (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
    Intentional overdose
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
    0 / 270 (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
    Upper limb fracture
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
    0 / 270 (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
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
    0 / 270 (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
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic hyperglycaemic coma
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 271 (0.37%)
    1 / 272 (0.37%)
    0 / 270 (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
    Hypoglycaemic coma
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic seizure
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of Encephalic Mass
    Additional description: Loss Of Encephalic Mass (Severe Brain Injury)
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (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
    Cerebral vasoconstriction
    Additional description: Cerebral vasoconstriction
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (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
    Migraine
    Additional description: Migraine with aura
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
    0 / 270 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enteritis
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         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 polyp
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (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
    Additional description: Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
    0 / 270 (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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
    0 / 270 (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
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 271 (0.37%)
    1 / 272 (0.37%)
    0 / 270 (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
    Hepatitis toxic
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
    0 / 270 (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
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         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
    Acute prerenal failure
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder outlet obstruction
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Periarthritis
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         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 / 271 (0.00%)
    1 / 272 (0.37%)
    0 / 270 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 272 (0.00%)
    0 / 270 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (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
    Pneumonia
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (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
    Urinary tract infection
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 271 (0.00%)
    0 / 272 (0.00%)
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 272 (0.00%)
    0 / 270 (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
    Influenza
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (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
    Peritonsillar abscess
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (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
    Wound infection
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (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
    Infection
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
    0 / 270 (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
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    13 / 271 (4.80%)
    1 / 272 (0.37%)
    7 / 270 (2.59%)
         occurrences causally related to treatment / all
    8 / 13
    1 / 1
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycemia
         subjects affected / exposed
    3 / 271 (1.11%)
    2 / 272 (0.74%)
    0 / 270 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ketoacidosis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ketosis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
    0 / 270 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
    0 / 270 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycemia
         subjects affected / exposed
    2 / 271 (0.74%)
    1 / 272 (0.37%)
    0 / 270 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DAPA 5 MG + INS PLA + INS DAPA 10 MG + INS
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    215 / 271 (79.34%)
    202 / 272 (74.26%)
    204 / 270 (75.56%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 271 (6.27%)
    13 / 272 (4.78%)
    18 / 270 (6.67%)
         occurrences all number
    18
    16
    20
    General disorders and administration site conditions
    Thirst
         subjects affected / exposed
    6 / 271 (2.21%)
    2 / 272 (0.74%)
    14 / 270 (5.19%)
         occurrences all number
    7
    2
    14
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    14 / 271 (5.17%)
    8 / 272 (2.94%)
    16 / 270 (5.93%)
         occurrences all number
    20
    11
    24
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    22 / 271 (8.12%)
    7 / 272 (2.57%)
    14 / 270 (5.19%)
         occurrences all number
    23
    7
    15
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    26 / 271 (9.59%)
    15 / 272 (5.51%)
    17 / 270 (6.30%)
         occurrences all number
    34
    19
    20
    Nasopharyngitis
         subjects affected / exposed
    57 / 271 (21.03%)
    69 / 272 (25.37%)
    63 / 270 (23.33%)
         occurrences all number
    79
    97
    91
    Gastroenteritis
         subjects affected / exposed
    14 / 271 (5.17%)
    12 / 272 (4.41%)
    12 / 270 (4.44%)
         occurrences all number
    16
    14
    16
    Urinary tract infection
         subjects affected / exposed
    13 / 271 (4.80%)
    15 / 272 (5.51%)
    11 / 270 (4.07%)
         occurrences all number
    16
    18
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 May 2015
    The primary purpose of the amendment was to modify the Inclusion and Exclusion Criteria based on feedback from the European Medicines Agency (EMA). Specifically, the EMA has endorsed removing the requirement that HbA1c may not drop more than 0.5% during the lead-in phase.
    18 May 2016
    The primary purpose of this amendment is to provide study visit scheduling flexibility by allowing optional phone visits to be done at week -4, week 2 and for the Continuous Glucose Monitoring visits (weeks 10/11 and weeks 22/23) during the 24 week double blinded short term treatment period.

    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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