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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Active Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and Efficacy of Add-On Therapy With Saxagliptin and Dapagliflozin Added to Metformin Compared to Add-On Therapy With Saxagliptin in Combination With Metformin or Dapagliflozin in Combination With Metformin in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control on Metformin Alone

    Summary
    EudraCT number
    		 2012-000679-18
    Trial protocol
    		 PL   IT  
    Global end of trial date
    17 Jan 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 May 2016
    First version publication date
    26 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CV181-169
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01606007
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca Pharmaceuticals
    Sponsor organisation address
    Astrazeneca AB, Södertälje, Sweden,
    Public contact
    Eva Johnsson, AstraZeneca Pharmaceuticals, +46 +46 31 7762484, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Eva Johnsson, AstraZeneca Pharmaceuticals, +46 +46 31 7762484, 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 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jan 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Mean change from baseline in HbA1c at Week 24 [ Time Frame: Baseline (Week 0) and at Week 24 ] [ Designated as safety issue: No ]
    Protection of trial subjects
    Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff.
    Background therapy
    		 Metformin
    Evidence for comparator
    		 Drug: Saxagliptin Drug: Metformin XR Drug: Dapagliflozin Drug: Placebo matching with Dapagliflozin Drug: Placebo matching with Saxagliptin
    Actual start date of recruitment
    05 Jun 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 759
    Country: Number of subjects enrolled
    Canada: 51
    Country: Number of subjects enrolled
    Mexico: 173
    Country: Number of subjects enrolled
    Puerto Rico: 32
    Country: Number of subjects enrolled
    Poland: 36
    Country: Number of subjects enrolled
    Romania: 81
    Country: Number of subjects enrolled
    Korea, Republic of: 16
    Country: Number of subjects enrolled
    South Africa: 134
    Worldwide total number of subjects
    1282
    EEA total number of subjects
    117
    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)
    1089
    From 65 to 84 years
    193
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Enrollment: 1282 subjects

    Pre-assignment
    Screening details
    		 Lead-in: 639 subjects

    Period 1
    Period 1 title
    Double-blind Treatment Period (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
    		 Arm 1: Saxagliptin+Metformin XR+Placebo
    Arm description
    		 Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 24 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Saxagliptin+Metformin XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 24 weeks

    Arm title
    		 Arm 2: Dapagliflozin+Metformin XR+Placebo
    Arm description
    		 Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148 Drug: Placebo matching with Saxagliptin Tablets, Oral, 0mg, Once daily, 24 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dapagliflozin+Metformin XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148 Drug: Placebo matching with Saxagliptin Tablets, Oral, 0mg, Once daily, 24 weeks

    Arm title
    		 Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Arm description
    		 Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148
    Arm type
    		 Experimental

    Investigational medicinal product name
    Saxagliptin+Dapagliflozin+Metformin XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks

    Number of subjects in period 1 [1]
    		Arm 1: Saxagliptin+Metformin XR+Placebo Arm 2: Dapagliflozin+Metformin XR+Placebo Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Started
    176
    179
    179
    Completed
    161
    160
    169
    Not completed
    15
    19
    10
         Consent withdrawn by subject
    8
    6
    1
         Reason 'Other' in the protocol
    -
    1
    1
         Adverse event, non-fatal
    -
    1
    1
         Pregnancy
    -
    1
    1
         discontinue study treatment
    -
    2
    1
         Lost to follow-up
    6
    8
    5
         poor or non-compliance
    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: System bug. Enrollment = 1282 subjects Entered "Lead-in" period = 639 subjects Completed "Lead-in" period = 540 subjects Entered "Double-blind treatment" period = 534 subjects Completed "Double-blind treatment" period = 490 subjects

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 1: Saxagliptin+Metformin XR+Placebo
    Reporting group description
    		 Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 24 weeks

    Reporting group title
    Arm 2: Dapagliflozin+Metformin XR+Placebo
    Reporting group description
    		 Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148 Drug: Placebo matching with Saxagliptin Tablets, Oral, 0mg, Once daily, 24 weeks

    Reporting group title
    Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Reporting group description
    		 Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148

    Reporting group values
    		 Arm 1: Saxagliptin+Metformin XR+Placebo Arm 2: Dapagliflozin+Metformin XR+Placebo Arm 3: Saxagliptin+Dapagliflozin+Metformin XR Total
    Number of subjects
    		 176 179 179 534
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 148 158 160 466
        From >= 65 years
    		 28 21 19 68
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.6 ( 9.63 ) 53.5 ( 9.67 ) 53.4 ( 9.84 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 82 90 94 266
        Male
    		 94 89 85 268
    Age, Customized
    Units: Subjects
        <65 years
    		 148 158 160 466
        >=65 years
    		 28 21 19 68
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 121 131 120 372
        Black african/american
    		 22 16 22 60
        Asian
    		 11 10 12 33
        Other
    		 22 22 25 69
    Subject analysis sets

    Subject analysis set title
    Randomized and Treated Subjects Data Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Data from all randomized subjects who took at least one dose of double-blind study medicationduring the double-blind period was included in the Randomized Subjects Data Set. When theRandomized Subjects Data Set is used, subjects are presented in the treatment group to which they were randomized at the start of the double-blind treatment period, even if the treatment they received was different.

    Subject analysis sets values
    		 Randomized and Treated Subjects Data Set
    Number of subjects
    534
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    466
        From >= 65 years
    68
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.8 ( 9.71 )
    Gender, Male/Female
    Units: participants
        Female
    266
        Male
    268
    Age, Customized
    Units: Subjects
        <65 years
    466
        >=65 years
    68
    Race/Ethnicity, Customized
    Units: Subjects
        White
    372
        Black african/american
    60
        Asian
    33
        Other
    69

    End points

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    End points reporting groups
    Reporting group title
    Arm 1: Saxagliptin+Metformin XR+Placebo
    Reporting group description
    		 Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 24 weeks

    Reporting group title
    Arm 2: Dapagliflozin+Metformin XR+Placebo
    Reporting group description
    		 Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148 Drug: Placebo matching with Saxagliptin Tablets, Oral, 0mg, Once daily, 24 weeks

    Reporting group title
    Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Reporting group description
    		 Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148

    Subject analysis set title
    Randomized and Treated Subjects Data Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Data from all randomized subjects who took at least one dose of double-blind study medicationduring the double-blind period was included in the Randomized Subjects Data Set. When theRandomized Subjects Data Set is used, subjects are presented in the treatment group to which they were randomized at the start of the double-blind treatment period, even if the treatment they received was different.

    Primary: Mean change from baseline in HbA1c at Week 24

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    End point title
    		 Mean change from baseline in HbA1c at Week 24
    End point description
    End point type
    Primary
    End point timeframe
    Baseline (Week 0) and at Week 24
    End point values
    		 Arm 1: Saxagliptin+Metformin XR+Placebo Arm 2: Dapagliflozin+Metformin XR+Placebo Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Number of subjects analysed
    143
    151
    158
    Units: % HbA1c
        least squares mean (confidence interval 95%)
    -0.88 (-1.03 to -0.72)
    -1.2 (-1.35 to -1.04)
    -1.47 (-1.62 to -1.31)
    Statistical analysis title
    		 Mean change from baseline in HbA1c
    Statistical analysis description
    Adjusted mean change from baseline in HbA1c at Week 24
    Comparison groups
    Arm 1: Saxagliptin+Metformin XR+Placebo v Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 -0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1112
    Statistical analysis title
    		 Mean change from baseline in HbA1c
    Statistical analysis description
    Adjusted mean change from baseline in HbA1c at Week 24
    Comparison groups
    Arm 2: Dapagliflozin+Metformin XR+Placebo v Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0166
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 -0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1108

    Secondary: Mean change from baseline in 2-hour post-prandial glucose (PPG) during a liquid meal test (2-h MTT)

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    End point title
    		 Mean change from baseline in 2-hour post-prandial glucose (PPG) during a liquid meal test (2-h MTT)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and at Week 24
    End point values
    		 Arm 1: Saxagliptin+Metformin XR+Placebo Arm 2: Dapagliflozin+Metformin XR+Placebo Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Number of subjects analysed
    147
    144
    154
    Units: MG/DL PPG
        least squares mean (confidence interval 95%)
    -35.6 (-42.5 to -28.7)
    -70.4 (-77.4 to -63.5)
    -79.6 (-86.3 to -72.8)
    Statistical analysis title
    		 Mean change from baseline in PPG
    Statistical analysis description
    Adjusted mean change from baseline in 2-hour PPG during a liquid meal test (2-h MTT)
    Comparison groups
    Arm 1: Saxagliptin+Metformin XR+Placebo v Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -53.7
         upper limit
    		 -34.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.914
    Statistical analysis title
    		 Mean change from baseline in PPG
    Statistical analysis description
    Adjusted mean change from baseline in 2-hour PPG during a liquid meal test (2-h MTT)
    Comparison groups
    Arm 2: Dapagliflozin+Metformin XR+Placebo v Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0639
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.8
         upper limit
    		 0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.923

    Secondary: Mean change from baseline in fasting plasma glucose (FPG)

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    End point title
    		 Mean change from baseline in fasting plasma glucose (FPG)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and at Week 24
    End point values
    		 Arm 1: Saxagliptin+Metformin XR+Placebo Arm 2: Dapagliflozin+Metformin XR+Placebo Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Number of subjects analysed
    142
    148
    155
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -14 (-19.6 to -8.4)
    -31.7 (-37.3 to -26.2)
    -37.8 (-43.2 to -32.3)
    Statistical analysis title
    		 Mean change from baseline in FPG
    Statistical analysis description
    Adjusted mean change from baseline in fasting plasma glucose (FPG)
    Comparison groups
    Arm 1: Saxagliptin+Metformin XR+Placebo v Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -23.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.6
         upper limit
    		 -15.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.988
    Statistical analysis title
    		 Mean change from baseline in FPG
    Statistical analysis description
    Adjusted mean change from baseline in fasting plasma glucose (FPG)
    Comparison groups
    Arm 2: Dapagliflozin+Metformin XR+Placebo v Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.8
         upper limit
    		 1.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.957

    Secondary: Number of subjects achieving glycemic response defined as Glycosylated hemoglobin (HbA1c) < 7%

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    End point title
    		 Number of subjects achieving glycemic response defined as Glycosylated hemoglobin (HbA1c) < 7%
    End point description
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    		 Arm 1: Saxagliptin+Metformin XR+Placebo Arm 2: Dapagliflozin+Metformin XR+Placebo Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Number of subjects analysed
    175
    173
    177
    Units: Participants
    29
    40
    74
    Statistical analysis title
    		 Glycemic response HbA1c < 7%
    Statistical analysis description
    Number of subjects achieving glycemic response defined as Glycosylated hemoglobin (HbA1c) < 7%
    Comparison groups
    Arm 1: Saxagliptin+Metformin XR+Placebo v Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    23.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.7
         upper limit
    		 31.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.282
    Statistical analysis title
    		 Glycemic response HbA1c < 7%
    Statistical analysis description
    Number of subjects achieving glycemic response defined as Glycosylated hemoglobin (HbA1c) < 7%
    Comparison groups
    Arm 2: Dapagliflozin+Metformin XR+Placebo v Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    19.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.1
         upper limit
    		 28.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.587

    Secondary: Mean change from baseline in body weight at Week 24 with the addition of Saxagliptin and Dapagliflozin to Metformin vs. the addition of placebo and Saxagliptin to Metformin

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    End point title
    		 Mean change from baseline in body weight at Week 24 with the addition of Saxagliptin and Dapagliflozin to Metformin vs. the addition of placebo and Saxagliptin to Metformin
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and at Week 24
    End point values
    		 Arm 1: Saxagliptin+Metformin XR+Placebo Arm 2: Dapagliflozin+Metformin XR+Placebo Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Number of subjects analysed
    145
    152
    159
    Units: Body weight Kg
        least squares mean (confidence interval 95%)
    0 (-0.48 to 0.49)
    -2.39 (-2.87 to -1.91)
    -2.05 (-2.52 to -1.58)
    Statistical analysis title
    		 Mean change from baseline in body weight
    Statistical analysis description
    Adjust mean change from baseline in body weight at Week 24 with the addition of Saxagliptin and Dapagliflozin to Metformin vs. the addition of placebo and Saxagliptin to Metformin
    Comparison groups
    Arm 1: Saxagliptin+Metformin XR+Placebo v Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.73
         upper limit
    		 -1.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3451

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    24 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    SAXA + MET
    Reporting group description
    		 Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 24 weeks

    Reporting group title
    SAXA + DAPA + MET
    Reporting group description
    		 Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148

    Reporting group title
    DAPA + MET
    Reporting group description
    		 Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148 Drug: Placebo matching with Saxagliptin Tablets, Oral, 0mg, Once daily, 24 weeks

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There are no non-serious adverse events presented due to the 5% cut-off.
    Serious adverse events
    		 SAXA + MET SAXA + DAPA + MET DAPA + MET
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 176 (3.41%)
    2 / 179 (1.12%)
    2 / 179 (1.12%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    GASTRIC NEOPLASM
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 179 (0.56%)
    0 / 179 (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
    PATELLA FRACTURE
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 179 (0.00%)
    0 / 179 (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
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 179 (0.00%)
    0 / 179 (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
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 179 (0.56%)
    0 / 179 (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
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 179 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    1 / 176 (0.57%)
    0 / 179 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    PANCREATITIS CHRONIC
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 179 (0.56%)
    0 / 179 (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
    UMBILICAL HERNIA
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 179 (0.00%)
    0 / 179 (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
    Reproductive system and breast disorders
    BENIGN PROSTATIC HYPERPLASIA
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 179 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 179 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRITIS
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 179 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    TOOTH INFECTION
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 179 (0.00%)
    0 / 179 (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
    Metabolism and nutrition disorders
    HYPERKALAEMIA
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 179 (0.00%)
    0 / 179 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SAXA + MET SAXA + DAPA + MET DAPA + MET
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 179 (0.00%)
    0 / 179 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Apr 2012
    1 Amendment: The objective of this Amendment is to permit the collection and storage of blood samples
    11 Sep 2012
    Amendment 02 is to make clarifications and to correct the

    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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