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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 (DEPICT 1)

    Summary
    EudraCT number
    		 2013-004674-97
    Trial protocol
    		 SE   DK   GB   FI   IT   DE   AT   ES   HU   BE  
    Global end of trial date
    25 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Sep 2018
    First version publication date
    08 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MB102-229
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02268214
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 AZ: D1695C00006
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Pepparedsleden 1, Mölndal, Sweden, 431 83
    Public contact
    Anna Maria Langkilde, AstraZeneca AB, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Anna Maria Langkilde, AstraZeneca AB, 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
    10 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin for the change from baseline in HbA1c after 24 weeks of doubleblinded treatment.
    Protection of trial subjects
    Independent data monitoring committee
    Background therapy
    		 Insulin
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Nov 2014
    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
    Australia: 55
    Country: Number of subjects enrolled
    Austria: 57
    Country: Number of subjects enrolled
    Belgium: 28
    Country: Number of subjects enrolled
    Canada: 61
    Country: Number of subjects enrolled
    Germany: 169
    Country: Number of subjects enrolled
    Denmark: 29
    Country: Number of subjects enrolled
    Spain: 73
    Country: Number of subjects enrolled
    Finland: 43
    Country: Number of subjects enrolled
    France: 32
    Country: Number of subjects enrolled
    United Kingdom: 42
    Country: Number of subjects enrolled
    Hungary: 68
    Country: Number of subjects enrolled
    Israel: 97
    Country: Number of subjects enrolled
    Italy: 55
    Country: Number of subjects enrolled
    Mexico: 180
    Country: Number of subjects enrolled
    Romania: 142
    Country: Number of subjects enrolled
    Sweden: 33
    Country: Number of subjects enrolled
    United States: 440
    Worldwide total number of subjects
    1604
    EEA total number of subjects
    771
    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)
    1512
    From 65 to 84 years
    92
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first subject was enrolled on 11 November 2014. The last subject completed the 24-week short-term treatment period 04 January 2017. This study was conducted at 138 sites in 17 countries.

    Pre-assignment
    Screening details
    		 833 participants were randomized to a treatment group. Of the 771 participants not randomized to a treatment group: 585 No longer met study criteria, 125 withdrew consent, 26 were lost to follow-up, and 35 did not continue for other reasons.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dapagliflozin 5 mg + Insulin
    Arm description
    		 -
    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
    		 Dapagliflozin 10 mg + Insulin
    Arm description
    		 -
    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
    		 Placebo + Insulin
    Arm description
    		 -
    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]
    		Dapagliflozin 5 mg + Insulin Dapagliflozin 10 mg + Insulin Placebo + Insulin
    Started
    277
    296
    260
    Completed
    235
    255
    218
    Not completed
    42
    41
    42
         Subject request to discontinue treatment
    10
    8
    6
         Adverse event, non-fatal
    11
    14
    9
         Pregnancy
    2
    2
    1
         Not entering long-term period
    2
    3
    5
         Other reasons
    7
    3
    3
         Lost to follow-up
    3
    3
    4
         Poor/non-compliance
    2
    1
    2
         Subject no longer meets study criteria
    -
    2
    -
         Lack of efficacy
    1
    -
    2
         Withdrawal by subject
    4
    5
    10
    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: We only summarized data for the patients randomized in the study. Baseline period had all of patients randomized in the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dapagliflozin 5 mg + Insulin
    Reporting group description
    		 -

    Reporting group title
    Dapagliflozin 10 mg + Insulin
    Reporting group description
    		 -

    Reporting group title
    Placebo + Insulin
    Reporting group description
    		 -

    Reporting group values
    		 Dapagliflozin 5 mg + Insulin Dapagliflozin 10 mg + Insulin Placebo + Insulin Total
    Number of subjects
    		 277 296 260 833
    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)
    		 262 279 246 787
        From 65-84 years
    		 15 17 14 46
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.1 ( 13.94 ) 43.4 ( 13.89 ) 42.7 ( 13.57 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 158 144 128 430
        Male
    		 119 152 132 403
    Age categorization
    Units: Subjects
        <65 years
    		 262 279 246 787
        >=65 to <75 years
    		 15 16 14 45
        >= 75 years
    		 0 1 0 1
    Age categorization by tertiles
    Units: Subjects
        < 35 years
    		 97 84 78 259
        >=35 to < 50 years
    		 88 107 91 286
        >= 50 years
    		 92 105 91 288
    Race
    Units: Subjects
        White
    		 264 282 249 795
        Black or African-American
    		 5 7 3 15
        Asian
    		 2 0 1 3
        Other
    		 6 7 7 20
    Ethnicity
    Ethnicity is reported only for US subjects
    Units: Subjects
        Hispanic/Latino
    		 6 5 8 19
        Non-Hispanic/Latino
    		 63 75 53 191
        Not reported
    		 208 216 199 623
    Body mass index categorization
    Units: Subjects
        <=23 Kg/m^2
    		 40 40 32 112
        >23 to <=25 Kg/m^2
    		 37 38 38 113
        >25 to <=27 Kg/m^2
    		 42 57 38 137
        >27 to <=30 Kg/m^2
    		 68 53 63 184
        >30 Kg/m^2
    		 90 108 89 287
    Body weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 81.25 ( 18.053 ) 83.54 ( 17.747 ) 84.36 ( 18.332 ) -
    Body mass index
    Units: Kg/m^2
        arithmetic mean (standard deviation)
    		 28.43 ( 5.711 ) 28.49 ( 5.226 ) 28.62 ( 5.251 ) -
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Randomized subjects that received at least 1 dose of double-blind study medication. The first 55 randomized subjects will be excluded from the full analysis dataset due to the presence of a randomization system error.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety 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 Safety Analysis Set
    Number of subjects
    778
    833
    Age Categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    734
    787
        From 65-84 years
    44
    46
        85 years and over
    0
    0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    42.5 ( 13.91 )
    42.7 ( 13.80 )
    Gender Categorical
    Units: Subjects
        Female
    405
    430
        Male
    373
    403
    Age categorization
    Units: Subjects
        <65 years
    734
    787
        >=65 to <75 years
    43
    45
        >= 75 years
    1
    1
    Age categorization by tertiles
    Units: Subjects
        < 35 years
    250
    259
        >=35 to < 50 years
    262
    286
        >= 50 years
    266
    288
    Race
    Units: Subjects
        White
    744
    795
        Black or African-American
    15
    15
        Asian
    1
    3
        Other
    18
    20
    Ethnicity
    Ethnicity is reported only for US subjects
    Units: Subjects
        Hispanic/Latino
    16
    19
        Non-Hispanic/Latino
    162
    191
        Not reported
    600
    623
    Body mass index categorization
    Units: Subjects
        <=23 Kg/m^2
    111
    112
        >23 to <=25 Kg/m^2
    109
    113
        >25 to <=27 Kg/m^2
    124
    137
        >27 to <=30 Kg/m^2
    174
    184
        >30 Kg/m^2
    260
    287
    Body weight
    Units: Kg
        arithmetic mean (standard deviation)
    82.47 ( 18.078 )
    83.04 ( 18.058 )
    Body mass index
    Units: Kg/m^2
        arithmetic mean (standard deviation)
    28.38 ( 5.406 )
    28.51 ( 5.394 )

    End points

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    End points reporting groups
    Reporting group title
    Dapagliflozin 5 mg + Insulin
    Reporting group description
    		 -

    Reporting group title
    Dapagliflozin 10 mg + Insulin
    Reporting group description
    		 -

    Reporting group title
    Placebo + Insulin
    Reporting group description
    		 -

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Randomized subjects that received at least 1 dose of double-blind study medication. The first 55 randomized subjects will be excluded from the full analysis dataset due to the presence of a randomization system error.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety 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 Hemoglobin A1C (HbA1c) at Week 24 (Repeated Measures Model [RMM])

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    End point title
    		 Adjusted mean change from baseline in Hemoglobin A1C (HbA1c) at Week 24 (Repeated Measures Model [RMM])
    End point description
    HbA1c was measured as percent of hemoglobin by a central laboratory. Baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 4, 8, 12, 18, and 24 in the double-blind period.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Dapagliflozin 5 mg + Insulin Dapagliflozin 10 mg + Insulin Placebo + Insulin
    Number of subjects analysed
    254 [1]
    254 [2]
    257
    Units: Percent
        least squares mean (standard error)
    -0.45 ( 0.0537 )
    -0.47 ( 0.0538 )
    -0.03 ( 0.0540 )
    Notes
    [1] - 18 patients were excluded due to a randomization system error.
    [2] - 37 patients were excluded due to a randomization system error.
    Statistical analysis title
    		 Primary Endpoint Analysis
    Statistical analysis description
    H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
    Comparison groups
    Dapagliflozin 5 mg + Insulin v Placebo + Insulin
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.05 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 -0.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0697
    Notes
    [3] - Dapagliflozin 5 mg + Insulin Vs. Placebo + Insulin
    [4] - [A Dunnett and Tamhane procedure was used to control Type I error across the primary & secondary objectives. Statistical significance for both Dapa doses at 5% if 2-sided p-values from both comparisons <5%. Or the comparison with p-values <2.62%.
    Statistical analysis title
    		 Primary Endpoint Analysis
    Statistical analysis description
    H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
    Comparison groups
    Dapagliflozin 10 mg + Insulin v Placebo + Insulin
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.05 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 -0.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0696
    Notes
    [5] - Dapagliflozin 10 mg + Insulin Vs. Placebo + Insulin
    [6] - A Dunnett and Tamhane procedure was used to control Type I error across the primary & secondary objectives. Statistical significance for both Dapa doses at 5% if 2-sided p-values from both comparisons <5%. Or the comparison with p-values <2.62%.

    Secondary: Adjusted mean percent change from baseline in Total Daily Insulin Dose (IU) at Week 24 (Repeated Measures Model [RMM])

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    End point title
    		 Adjusted mean percent change from baseline in Total Daily Insulin Dose (IU) at Week 24 (Repeated Measures Model [RMM])
    End point description
    Secondary endpoint was tested using a Dunnett and Tamhane procedure according to the pre-specified order. Daily insulin dosing (basal and bolus) were recorded at baseline, Weeks 2, 12 and 24. Baseline was defined as mean of last 7 days assessment on or prior to the date of the first dose of the double-blind study medication.
    End point type
    Secondary
    End point timeframe
    Baseline to 24 Weeks
    End point values
    		 Dapagliflozin 5 mg + Insulin Dapagliflozin 10 mg + Insulin Placebo + Insulin
    Number of subjects analysed
    258 [7]
    254 [8]
    258
    Units: IU
        least squares mean (standard error)
    -7.74 ( 1.4881 )
    -12.16 ( 1.4326 )
    1.16 ( 1.6593 )
    Notes
    [7] - 18 patients were excluded due to a randomization system error.
    [8] - 37 patients were excluded due to a randomization system error.
    Statistical analysis title
    		 First Secondary Endpoint Analysis
    Statistical analysis description
    H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
    Comparison groups
    Dapagliflozin 10 mg + Insulin v Placebo + Insulin
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.05 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -13.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.75
         upper limit
    		 -9.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.8643
    Notes
    [9] - Dapagliflozin 10 mg + Insulin Vs. Placebo + Insulin
    [10] - A Dunnett and Tamhane procedure was used to control Type I error across the primary & secondary objectives. Statistical significance for both Dapa doses at 5% if 2-sided p-values from both comparisons <5%. Or the comparison with p-values <2.62%.
    Statistical analysis title
    		 First Secondary Endpoint Analysis
    Statistical analysis description
    H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
    Comparison groups
    Dapagliflozin 5 mg + Insulin v Placebo + Insulin
    Number of subjects included in analysis
    516
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.05 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -8.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.56
         upper limit
    		 -4.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.9555
    Notes
    [11] - Dapagliflozin 5 mg + Insulin Vs. Placebo + Insulin
    [12] - A Dunnett and Tamhane procedure was used to control Type I error across the primary & secondary objectives. Statistical significance for both Dapa doses at 5% if 2-sided p-values from both comparisons <5%. Or the comparison with p-values <2.62%.

    Secondary: Adjusted mean percent change from baseline in Total Body Weight at Week 24 (Repeated Measures Model [RMM])

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    End point title
    		 Adjusted mean percent change from baseline in Total Body Weight at Week 24 (Repeated Measures Model [RMM])
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 24 weeks
    End point values
    		 Dapagliflozin 5 mg + Insulin Dapagliflozin 10 mg + Insulin Placebo + Insulin
    Number of subjects analysed
    259 [13]
    258 [14]
    259
    Units: Kg
        least squares mean (standard error)
    -3.00 ( 0.2330 )
    -3.67 ( 0.2299 )
    0.05 ( 0.2407 )
    Notes
    [13] - 18 patients were excluded due to a randomization system error.
    [14] - 37 patients were excluded due to a randomization system error.
    Statistical analysis title
    		 Second Secondary Endpoint Analysis
    Statistical analysis description
    H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
    Comparison groups
    Dapagliflozin 5 mg + Insulin v Placebo + Insulin
    Number of subjects included in analysis
    518
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 < 0.05 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.68
         upper limit
    		 -2.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3251
    Notes
    [15] - Dapagliflozin 5 mg + Insulin Vs. Placebo + Insulin
    [16] - A Dunnett and Tamhane procedure was used to control Type I error across the primary & secondary objectives. Statistical significance for both Dapa doses at 5% if 2-sided p-values from both comparisons <5%. Or the comparison with p-values <2.62%.
    Statistical analysis title
    		 Second Secondary Endpoint Analysis
    Statistical analysis description
    H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
    Comparison groups
    Dapagliflozin 10 mg + Insulin v Placebo + Insulin
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 < 0.05 [18]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.34
         upper limit
    		 -3.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3213
    Notes
    [17] - Dapagliflozin 10 mg + Insulin Vs. Placebo + Insulin
    [18] - A Dunnett and Tamhane procedure was used to control Type I error across the primary & secondary objectives. Statistical significance for both Dapa doses at 5% if 2-sided p-values from both comparisons <5%. Or the comparison with p-values <2.62%.

    Secondary: Adjusted mean change from baseline in 24-Hour CGM Mean at Week 24 (Repeated Measures Model [RMM])

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    End point title
    		 Adjusted mean change from baseline in 24-Hour CGM Mean at Week 24 (Repeated Measures Model [RMM])
    End point description
    Secondary endpoint was tested using a Dunnett and Tamhane procedure according to the pre-specified order. Continuous Glucose Monitoring (CGM) measured the subject’s interstitial glucose level using electrodes that measure an electric signal produced by glucose oxidase reaction. 24-hour interstitial glucose levels (at a 5 min interval) were obtained during the lead-in period and at Weeks 12 and 24 of the double-blind period. Baseline was defined as mean of the last 7 days assessment on or prior to the date of the first dose of the double-blind study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Dapagliflozin 5 mg + Insulin Dapagliflozin 10 mg + Insulin Placebo + Insulin
    Number of subjects analysed
    238 [19]
    239 [20]
    234
    Units: mg/dL
        least squares mean (standard error)
    -10.28 ( 1.8862 )
    -12.97 ( 1.9231 )
    5.06 ( 1.9320 )
    Notes
    [19] - 18 patients were excluded due to a randomization system error.
    [20] - 37 patients were excluded due to a randomization system error.
    Statistical analysis title
    		 Third Secondary Endpoint Analysis
    Statistical analysis description
    H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
    Comparison groups
    Dapagliflozin 5 mg + Insulin v Placebo + Insulin
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 < 0.05 [22]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -15.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.22
         upper limit
    		 -10.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.4859
    Notes
    [21] - Dapagliflozin 5 mg + Insulin Vs. Placebo + Insulin
    [22] - A Dunnett and Tamhane procedure was used to control Type I error across the primary & secondary objectives. Statistical significance for both Dapa doses at 5% if 2-sided p-values from both comparisons <5%. Or the comparison with p-values <2.62%.
    Statistical analysis title
    		 Third Secondary Endpoint Analysis
    Statistical analysis description
    H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
    Comparison groups
    Dapagliflozin 10 mg + Insulin v Placebo + Insulin
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 < 0.05 [24]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -18.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.95
         upper limit
    		 -13.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.505
    Notes
    [23] - Dapagliflozin 10 mg + Insulin Vs. Placebo + Insulin
    [24] - A Dunnett and Tamhane procedure was used to control Type I error across the primary & secondary objectives. Statistical significance for both Dapa doses at 5% if 2-sided p-values from both comparisons <5%. Or the comparison with p-values <2.62%.

    Secondary: Adjusted mean change from baseline in 24-Hour Mean Amplified Glucose Excursion (MAGE) at Week 24 (Repeated Measures Model [RMM])

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    End point title
    		 Adjusted mean change from baseline in 24-Hour Mean Amplified Glucose Excursion (MAGE) at Week 24 (Repeated Measures Model [RMM])
    End point description
    Secondary endpoint was tested using a Dunnett and Tamhane procedure according to the pre-specified order. Continuous Glucose Monitoring (CGM) measured the subject’s interstitial glucose level using electrodes that measure an electric signal produced by glucose oxidase reaction. 24-hour interstitial glucose levels (at a 5 min interval) were obtained during the lead-in period and at Weeks 12 and 24 of the double-blind period. Baseline was defined as mean of the last 7 days assessment on or prior to the date of the first dose of the double-blind study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Dapagliflozin 5 mg + Insulin Dapagliflozin 10 mg + Insulin Placebo + Insulin
    Number of subjects analysed
    238 [25]
    239 [26]
    234
    Units: mg/dL
        least squares mean (standard error)
    -14.92 ( 1.9915 )
    -16.55 ( 2.0419 )
    2.38 ( 2.0477 )
    Notes
    [25] - 18 patients were excluded due to a randomization system error.
    [26] - 37 patients were excluded due to a randomization system error.
    Statistical analysis title
    		 Fourth Secondary Endpoint Analysis
    Statistical analysis description
    H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
    Comparison groups
    Dapagliflozin 10 mg + Insulin v Placebo + Insulin
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 < 0.05 [28]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -18.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.13
         upper limit
    		 -13.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.6482
    Notes
    [27] - Dapagliflozin 10 mg + Insulin Vs. Placebo + Insulin
    [28] - A Dunnett and Tamhane procedure was used to control Type I error across the primary & secondary objectives. Statistical significance for both Dapa doses at 5% if 2-sided p-values from both comparisons <5%. Or the comparison with p-values <2.62%.
    Statistical analysis title
    		 Fourth Secondary Endpoint Analysis
    Statistical analysis description
    H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
    Comparison groups
    Dapagliflozin 5 mg + Insulin v Placebo + Insulin
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 < 0.05 [30]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -17.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.46
         upper limit
    		 -12.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.6273
    Notes
    [29] - Dapagliflozin 5 mg + Insulin Vs. Placebo + Insulin
    [30] - A Dunnett and Tamhane procedure was used to control Type I error across the primary & secondary objectives. Statistical significance for both Dapa doses at 5% if 2-sided p-values from both comparisons <5%. Or the comparison with p-values <2.62%.

    Secondary: Adjusted mean change from baseline in 24-hour CGM values > 70 mg/dL and <= 180 mg/dL (%) at Week 24 (Repeated Measures Model [RMM])

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    End point title
    		 Adjusted mean change from baseline in 24-hour CGM values > 70 mg/dL and <= 180 mg/dL (%) at Week 24 (Repeated Measures Model [RMM])
    End point description
    Secondary endpoint was tested using a Dunnett and Tamhane procedure according to the pre-specified order. Continuous Glucose Monitoring (CGM) measured the subject’s interstitial glucose level using electrodes that measure an electric signal produced by glucose oxidase reaction. 24-hour interstitial glucose levels (at a 5 min interval) were obtained during the lead-in period and at Weeks 12 and 24 of the double-blind period. Baseline was defined as mean of the last 7 days assessment on or prior to the date of the first dose of the double-blind study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Dapagliflozin 5 mg + Insulin Dapagliflozin 10 mg + Insulin Placebo + Insulin
    Number of subjects analysed
    238 [31]
    239 [32]
    234
    Units: mg/dL
        least squares mean (standard error)
    6.98 ( 0.8824 )
    8.52 ( 0.9000 )
    -2.13 ( 0.9032 )
    Notes
    [31] - 18 patients were excluded due to a randomization system error.
    [32] - 37 patients were excluded due to a randomization system error.
    Statistical analysis title
    		 Fifth Secondary Endpoint Analysis
    Statistical analysis description
    H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
    Comparison groups
    Dapagliflozin 5 mg + Insulin v Placebo + Insulin
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 < 0.05 [34]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.83
         upper limit
    		 11.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1611
    Notes
    [33] - Dapagliflozin 5 mg + Insulin Vs. Placebo + Insulin
    [34] - A Dunnett and Tamhane procedure was used to control Type I error across the primary & secondary objectives. Statistical significance for both Dapa doses at 5% if 2-sided p-values from both comparisons <5%. Or the comparison with p-values <2.62%.
    Statistical analysis title
    		 Fifth Secondary Endpoint Analysis
    Statistical analysis description
    H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
    Comparison groups
    Dapagliflozin 10 mg + Insulin v Placebo + Insulin
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 < 0.05 [36]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    10.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.35
         upper limit
    		 12.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1689
    Notes
    [35] - Dapagliflozin 10 mg + Insulin Vs. Placebo + Insulin
    [36] - A Dunnett and Tamhane procedure was used to control Type I error across the primary & secondary objectives. Statistical significance for both Dapa doses at 5% if 2-sided p-values from both comparisons <5%. Or the comparison with p-values <2.62%.

    Secondary: Percentage of Subjects with Hemoglobin A1c [HbA1C]) reduction from baseline to Week 24 (Last Observation Carried Forward [LOCF]) >= 0.5% and without severe hypoglycemia events

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    End point title
    		 Percentage of Subjects with Hemoglobin A1c [HbA1C]) reduction from baseline to Week 24 (Last Observation Carried Forward [LOCF]) >= 0.5% and without severe hypoglycemia events
    End point description
    Secondary endpoint was tested using a Dunnett and Tamhane procedure according to the pre-specified order. Percent adjusted for baseline HbA1c and randomization strata. HbA1c was measured as a percent of hemoglobin. Severe hypoglycemia is classified according to recommendations by workgroup on hypoglycemia, American Diabetes Association (2005).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Dapagliflozin 5 mg + Insulin Dapagliflozin 10 mg + Insulin Placebo + Insulin
    Number of subjects analysed
    256 [37]
    254 [38]
    257
    Units: Subjects
        Subjects, reduction in A1c >=0.5% & no severe hypo
    127
    129
    65
    Notes
    [37] - 18 patients were excluded due to a randomization system error.
    [38] - 37 patients were excluded due to a randomization system error.
    Statistical analysis title
    		 Sixth Secondary Endpoint Analysis
    Statistical analysis description
    H0: odds ratio (treat/placebo) = 1 versus the alternative HA: odds ratio (treat/placebo) =/= 1
    Comparison groups
    Dapagliflozin 5 mg + Insulin v Placebo + Insulin
    Number of subjects included in analysis
    513
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 < 0.05 [40]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.1
         upper limit
    		 4.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.198
    Notes
    [39] - Dapagliflozin 5 mg + Insulin Vs. Placebo + Insulin
    [40] - A Dunnett and Tamhane procedure was used to control Type I error across the primary & secondary objectives. Statistical significance for both Dapa doses at 5% if 2-sided p-values from both comparisons <5%. Or the comparison with p-values <2.62%.
    Statistical analysis title
    		 Sixth Secondary Endpoint Analysis
    Statistical analysis description
    H0: odds ratio (treat/placebo) = 1 versus the alternative HA: odds ratio (treat/placebo) =/= 1
    Comparison groups
    Dapagliflozin 10 mg + Insulin v Placebo + Insulin
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 < 0.05 [42]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.23
         upper limit
    		 4.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1979
    Notes
    [41] - Dapagliflozin 10 mg + Insulin Vs. Placebo + Insulin
    [42] - A Dunnett and Tamhane procedure was used to control Type I error across the primary & secondary objectives. Statistical significance for both Dapa doses at 5% if 2-sided p-values from both comparisons <5%. Or the comparison with p-values <2.62%.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Onset on or after the first date of double-blind treatment and on or prior to the last day of treatment 24-week short-term period, 28-week extension period and the 30-day folllow-up period.
    Adverse event reporting additional description
    Participants were questioned at each study visit about the occurrence of any health problems and any examination conducted at a study visit was assessed in comparison to the status at study entry.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Dapagliflozin 5 mg + Insulin
    Reporting group description
    		 Dapagliflozin 5 mg + Insulin

    Reporting group title
    Dapagliflozin 10 mg + Insulin
    Reporting group description
    		 Dapagliflozin 10 mg + Insulin

    Reporting group title
    Placebo + Insulin
    Reporting group description
    		 Placebo + Insulin

    Serious adverse events
    		 Dapagliflozin 5 mg + Insulin Dapagliflozin 10 mg + Insulin Placebo + Insulin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 277 (13.36%)
    40 / 296 (13.51%)
    30 / 260 (11.54%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Bone cancer
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Breast cancer
         subjects affected / exposed
    1 / 277 (0.36%)
    1 / 296 (0.34%)
    0 / 260 (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
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Keratoacanthoma
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Thrombosis
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 277 (0.36%)
    2 / 296 (0.68%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Pyrexia
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         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
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Gynaecomastia
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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 mass
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Liver function test increased
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 277 (0.36%)
    1 / 296 (0.34%)
    0 / 260 (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
    Hand fracture
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Intentional overdose
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Limb injury
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Procedural pain
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Sinus tachycardia
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cubital tunnel syndrome
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic seizure
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Multiple sclerosis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Eye disorders
    Blindness unilateral
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Cataract
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Ophthalmoplegia
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    2 / 277 (0.72%)
    0 / 296 (0.00%)
    0 / 260 (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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Abdominal pain upper
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Cyclic vomiting syndrome
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Diabetic gastroparesis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Gastritis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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 hypomotility
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Oesophagitis
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Oesophagitis haemorrhagic
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Pancreatitis chronic
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic haematoma
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Renal and urinary disorders
    Obstructive uropathy
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Renal colic
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Endocrine disorders
    Hyperparathyroidism primary
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         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
    Foot deformity
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Osteoarthritis
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         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
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Influenza
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Localised infection
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Nasal abscess
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (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
    Pneumonia
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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
    Tooth infection
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 296 (0.00%)
    0 / 260 (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 / 277 (0.36%)
    1 / 296 (0.34%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 296 (0.34%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 296 (0.00%)
    1 / 260 (0.38%)
         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
    Diabetic ketoacidosis
         subjects affected / exposed
    10 / 277 (3.61%)
    7 / 296 (2.36%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    3 / 11
    5 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 277 (0.72%)
    4 / 296 (1.35%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Ketoacidosis
         subjects affected / exposed
    2 / 277 (0.72%)
    4 / 296 (1.35%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ketosis
         subjects affected / exposed
    2 / 277 (0.72%)
    2 / 296 (0.68%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    1 / 277 (0.36%)
    1 / 296 (0.34%)
    0 / 260 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dapagliflozin 5 mg + Insulin Dapagliflozin 10 mg + Insulin Placebo + Insulin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    123 / 277 (44.40%)
    118 / 296 (39.86%)
    99 / 260 (38.08%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 277 (5.05%)
    20 / 296 (6.76%)
    13 / 260 (5.00%)
         occurrences all number
    17
    27
    13
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    11 / 277 (3.97%)
    21 / 296 (7.09%)
    9 / 260 (3.46%)
         occurrences all number
    13
    25
    10
    Nausea
         subjects affected / exposed
    14 / 277 (5.05%)
    15 / 296 (5.07%)
    7 / 260 (2.69%)
         occurrences all number
    18
    20
    7
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    15 / 277 (5.42%)
    10 / 296 (3.38%)
    8 / 260 (3.08%)
         occurrences all number
    16
    13
    10
    Influenza
         subjects affected / exposed
    15 / 277 (5.42%)
    15 / 296 (5.07%)
    17 / 260 (6.54%)
         occurrences all number
    18
    17
    23
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 277 (6.86%)
    28 / 296 (9.46%)
    15 / 260 (5.77%)
         occurrences all number
    26
    36
    28
    Urinary tract infection
         subjects affected / exposed
    27 / 277 (9.75%)
    10 / 296 (3.38%)
    19 / 260 (7.31%)
         occurrences all number
    37
    12
    20
    Viral upper respiratory tract infection
         subjects affected / exposed
    51 / 277 (18.41%)
    46 / 296 (15.54%)
    48 / 260 (18.46%)
         occurrences all number
    67
    65
    66

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 May 2015
    The primary purpose was to modify the Inclusion and Exclusion Criteria, based on feedback from the European Medicines Agency. EMA endorsed removing the requirement that HbA1c may not drop more than 0.5% during the lead-in phase.
    16 May 2016
    The primary purpose of this amendment was to increase the randomization target by 55 to maintain the power for the primary endpoint as the first 55 randomized subjects will be excluded from the primary efficacy analysis due to an IVRS randomization system error.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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