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    Clinical Trial Results:
    An Exploratory Phase II/III, Randomised, Double-Blind, Placebo Controlled, Parallel Design Study to Evaluate the Efficacy, Safety and Pharmacodynamics of Dapagliflozin and Dapagliflozin in Combination with Saxagliptin in CKD Patients With Type 2 Diabetes Mellitus and Albuminuria Treated with Angiotensin-converting Enzyme Inhibitor (ACEi) or Angiotensin II Receptor Blocker (ARB).

    Summary
    EudraCT number
    		 2015-002676-24
    Trial protocol
    		 ES  
    Global end of trial date
    18 May 2018

    Results information
    Results version number
    		 v1
    This version publication date
    31 May 2019
    First version publication date
    31 May 2019
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    D1690C00023
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02547935
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Pepparedsleden 1, Mölndal, Sweden, SE-431 83
    Public contact
    Global Clinical Lead, AstraZeneca, +1 302 885 1180, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 302 885 1180, 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
    18 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to determine whether dapagliflozin alone or in combination with saxagliptin can decrease albuminuria and improve glycemic control in patients with Type 2 Diabetes Mellitis, albuminuria and renal impairment (Chronic Kidney Disease).
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca policy on Bioethics.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 77
    Country: Number of subjects enrolled
    Korea, Republic of: 53
    Country: Number of subjects enrolled
    Taiwan: 36
    Country: Number of subjects enrolled
    United States: 95
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    Mexico: 79
    Country: Number of subjects enrolled
    South Africa: 42
    Country: Number of subjects enrolled
    Australia: 28
    Country: Number of subjects enrolled
    Spain: 24
    Worldwide total number of subjects
    448
    EEA total number of subjects
    24
    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)
    210
    From 65 to 84 years
    234
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus with micro- or macro-albuminuria and treated with ACEi or ARB were enrolled into an international, multi-centre study from 21 Sep 2015. The last patient's last visit was 18 May 2018.

    Pre-assignment
    Screening details
    		 Enrolled patients were screened during a 4-week single-blind placebo lead-in period. Patients who met all of the inclusion and none of the exclusion criteria in this period were eligible to be randomised into the 24-week double-blind placebo-controlled treatment period.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dapagliflozin 10 mg + Saxagliptin 2.5 mg
    Arm description
    		 Dapagliflozin 10 milligram (mg) and saxagliptin 2.5 mg tablets were taken orally, once daily (in the morning) for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Saxagliptin
    Investigational medicinal product code
    Other name
    Onglyza™
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Saxagliptin 2.5 mg tablet taken orally once a day in the morning for 24 weeks.

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Forxiga™
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dapagliflozin 10 mg tablet taken orally once a day in the morning for 24 weeks.

    Arm title
    		 Dapagliflozin 10 mg
    Arm description
    		 Dapagliflozin 10 mg tablets were taken orally, once daily (in the morning) for 24 weeks. Patients also took placebo tablets to match saxagliptin.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo to match saxagliptin 2.5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Plcaebo tablet taken orally once a day in the morning for 24 weeks.

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Forxiga™
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dapagliflozin 10 mg tablet taken orally once a day in the morning for 24 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablets to match both active products (dapagliflozin and saxagliptin) were taken orally, once daily (in the morning) for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match dapagliflozin 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Plcaebo tablet taken orally once a day in the morning for 24 weeks.

    Investigational medicinal product name
    Placebo to match saxagliptin 2.5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Plcaebo tablet taken orally once a day in the morning for 24 weeks.

    Number of subjects in period 1
    		Dapagliflozin 10 mg + Saxagliptin 2.5 mg Dapagliflozin 10 mg Placebo
    Started
    155
    145
    148
    Received Treatment
    152
    145
    148
    Full Analysis Set
    152
    144
    148
    Safety Analysis Set
    152
    145
    148
    Completed
    150
    137
    143
    Not completed
    5
    8
    5
         Adverse event, serious fatal
    1
    1
    -
         Consent withdrawn by subject
    2
    3
    4
         Physician decision
    -
    1
    -
         Screen Failure
    2
    -
    -
         Not specified
    -
    1
    -
         Lost to follow-up
    -
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dapagliflozin 10 mg + Saxagliptin 2.5 mg
    Reporting group description
    		 Dapagliflozin 10 milligram (mg) and saxagliptin 2.5 mg tablets were taken orally, once daily (in the morning) for 24 weeks.

    Reporting group title
    Dapagliflozin 10 mg
    Reporting group description
    		 Dapagliflozin 10 mg tablets were taken orally, once daily (in the morning) for 24 weeks. Patients also took placebo tablets to match saxagliptin.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets to match both active products (dapagliflozin and saxagliptin) were taken orally, once daily (in the morning) for 24 weeks.

    Reporting group values
    		 Dapagliflozin 10 mg + Saxagliptin 2.5 mg Dapagliflozin 10 mg Placebo Total
    Number of subjects
    		 155 145 148 448
    Age, Customized
    Units: Subjects
        <65 years
    		 78 64 68 210
        >=65 years
    		 77 81 80 238
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.0 ( 9.21 ) 64.7 ( 8.61 ) 64.7 ( 8.53 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 45 43 43 131
        Male
    		 110 102 105 317
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 77 55 64 196
        Black or African American
    		 8 7 11 26
        Asian
    		 57 67 53 177
        Native Hawaiian or other Pacific Islander
    		 1 2 1 4
        American Indian or Alaska Native
    		 0 1 1 2
        Other
    		 12 13 18 43
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 42 32 38 112
        Not Hispanic or Latino
    		 113 113 110 336
        Unknown or Not Reported
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Dapagliflozin 10 mg + Saxagliptin 2.5 mg
    Reporting group description
    		 Dapagliflozin 10 milligram (mg) and saxagliptin 2.5 mg tablets were taken orally, once daily (in the morning) for 24 weeks.

    Reporting group title
    Dapagliflozin 10 mg
    Reporting group description
    		 Dapagliflozin 10 mg tablets were taken orally, once daily (in the morning) for 24 weeks. Patients also took placebo tablets to match saxagliptin.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets to match both active products (dapagliflozin and saxagliptin) were taken orally, once daily (in the morning) for 24 weeks.

    Primary: Adjusted Mean Change from Baseline in Glycosylated Haemoglobin (HbA1c): Comparison of Dapagliflozin 10 mg plus Saxagliptin 2.5 mg and Placebo at Week 24

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    End point title
    		 Adjusted Mean Change from Baseline in Glycosylated Haemoglobin (HbA1c): Comparison of Dapagliflozin 10 mg plus Saxagliptin 2.5 mg and Placebo at Week 24 [1]
    End point description
    HbA1c was analysed at baseline and every 4 weeks during the 24-week treatment period. Only measurements prior to rescue or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a mixed model repeated measures (MMRM) model. Results are presented for patients from the Full Analysis Set (all randomised patients who took at least 1 dose of double-blind study drug and had a non missing baseline value and at least one post-baseline efficacy variable value) and with non-missing baseline and Week 24 values for HbA1c.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This primary endpoint was concerned with comparison of Dapagliflozin 10 mg + Saxagliptin 2.5 mg arm versus placebo only. Comparison of Dapagliflozin 10mg arm to placebo is reported as a secondary endpoint.
    End point values
    		 Dapagliflozin 10 mg + Saxagliptin 2.5 mg Placebo
    Number of subjects analysed
    137
    118
    Units: Percentage
        least squares mean (standard error)
    -0.85 ( 0.09 )
    -0.27 ( 0.09 )
    Statistical analysis title
    		 Longitudinal Repeated Measures Analysis
    Statistical analysis description
    A longitudinal repeated measures analysis included the fixed categorical effects of treatment, week, randomisation stratification factor (i.e. anti-diabetic treatment strata), and treatment-by-week interaction, as well as the continuous fixed covariates of baseline measurement and baseline measurement-by-week interaction.
    Comparison groups
    Placebo v Dapagliflozin 10 mg + Saxagliptin 2.5 mg
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [2]
    Method
    		 MMRM
    Parameter type
    		 Difference in adjusted mean change
    Point estimate
    -0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 -0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [2] - Statistical significance level = 0.025.

    Primary: Adjusted Mean Percent Change from Baseline in Urine Albumin-to-Creatinine Ratio (UACR) at Week 24

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    End point title
    		 Adjusted Mean Percent Change from Baseline in Urine Albumin-to-Creatinine Ratio (UACR) at Week 24
    End point description
    UACR was analysed at baseline and every 4 weeks during the 24-week treatment period. All measurements regardless of rescue medication or treatment discontinuation were analysed. UACR values were first transformed to logarithms and the results were based on exponentiation of model estimates and expressed as adjusted mean percent change from baseline at Week 24. Results are presented for patients from the Full Analysis Set with non-missing baseline and Week 24 values for UACR.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Dapagliflozin 10 mg + Saxagliptin 2.5 mg Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    139
    132
    134
    Units: Percentage
        least squares mean (standard error)
    -39.1 ( 5.1 )
    -22.4 ( 6.6 )
    -1.8 ( 8.3 )
    Statistical analysis title
    		 Longitudinal Repeated Measures Analysis
    Statistical analysis description
    A longitudinal repeated measures model of the logarithms of the post-baseline to baseline ratios included the fixed categorical effects of treatment, week, treatment-by-week interaction, and randomisation stratification factor (i.e. anti-diabetic treatment strata), as well as the continuous fixed covariates of log-baseline UACR value and log-baseline UACR value-by-week interaction.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011 [3]
    Method
    		 MMRM
    Parameter type
    		 Difference in adjusted mean change
    Point estimate
    -21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.1
         upper limit
    		 -5.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.3
    Notes
    [3] - Statistical significance level = 0.025.
    Statistical analysis title
    		 Longitudinal Repeated Measures Analysis
    Statistical analysis description
    A longitudinal repeated measures model of the logarithms of the post-baseline to baseline ratios included the fixed categorical effects of treatment, week, treatment-by-week interaction, and randomisation stratification factor (i.e. anti-diabetic treatment strata), as well as the continuous fixed covariates of log-baseline UACR value and log-baseline UACR value-by-week interaction.
    Comparison groups
    Dapagliflozin 10 mg + Saxagliptin 2.5 mg v Placebo
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [4]
    Method
    		 MMRM
    Parameter type
    		 Difference in adjusted mean change
    Point estimate
    -38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -48.2
         upper limit
    		 -25.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.7
    Notes
    [4] - Statistical significance level = 0.025.

    Secondary: Adjusted Mean Percent Change from Baseline in Total Body Weight at Week 24

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    End point title
    		 Adjusted Mean Percent Change from Baseline in Total Body Weight at Week 24
    End point description
    Total body weight was measured in kilograms (kg) at baseline and at Week 1 then every 4 weeks during the 24-week treatment period. All measurements regardless of rescue medication or treatment discontinuation were analysed. Total body weight values were first transformed to logarithms and the results were based on exponentiation of model estimates and expressed as adjusted mean percent change from baseline at Week 24. Results are presented for patients from the Full Analysis Set with non-missing baseline and Week 24 values for total body weight.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Dapagliflozin 10 mg + Saxagliptin 2.5 mg Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    140
    132
    134
    Units: Percentage
        least squares mean (standard error)
    -0.65 ( 0.55 )
    -1.48 ( 0.56 )
    -0.61 ( 0.56 )
    Statistical analysis title
    		 Longitudinal Repeated Measures Analysis
    Statistical analysis description
    A longitudinal repeated measures model of the logarithms of the post-baseline to baseline ratios included the fixed categorical effects of treatment, week, treatment-by-week interaction, and randomisation stratification factor (i.e. anti-diabetic treatment strata), as well as the continuous fixed covariates of log-baseline total body weight value and log-baseline total body weight value-by-week interaction.
    Comparison groups
    Dapagliflozin 10 mg + Saxagliptin 2.5 mg v Placebo
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.953 [5]
    Method
    		 MMRM
    Parameter type
    		 Difference in adjusted mean change
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.32
         upper limit
    		 1.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.66
    Notes
    [5] - Statistical significance level = 0.025.
    Statistical analysis title
    		 Longitudinal Repeated Measures Analysis
    Statistical analysis description
    A longitudinal repeated measures model of the logarithms of the post-baseline to baseline ratios included the fixed categorical effects of treatment, week, treatment-by-week interaction, and randomisation stratification factor (i.e. anti-diabetic treatment strata), as well as the continuous fixed covariates of log-baseline total body weight value and log-baseline total body weight value-by-week interaction.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.193 [6]
    Method
    		 MMRM
    Parameter type
    		 Difference in adjusted mean change
    Point estimate
    -0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.17
         upper limit
    		 0.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.66
    Notes
    [6] - Statistical significance level = 0.025.

    Secondary: Adjusted Mean Change from Baseline in Fasting Plasma Glucose (FPG) at Week 24

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    End point title
    		 Adjusted Mean Change from Baseline in Fasting Plasma Glucose (FPG) at Week 24
    End point description
    FPG was analysed at baseline and Week 1 then every 4 weeks during the 24-week treatment period. Only measurements prior to rescue or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a MMRM model. Results are presented for patients from the Full Analysis Set with non-missing baseline and Week 24 values for FPG.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Dapagliflozin 10 mg + Saxagliptin 2.5 mg Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    136
    123
    116
    Units: mg/decilitre (dL)
        least squares mean (standard error)
    -17.2 ( 5.2 )
    -13.1 ( 5.4 )
    -11.2 ( 5.5 )
    Statistical analysis title
    		 Longitudinal Repeated Measures Analysis
    Statistical analysis description
    A longitudinal repeated measures analysis included the fixed categorical effects of treatment, week, randomisation stratification factor (i.e.anti-diabetic treatment strata), and treatment-by-week interaction, as well as the continuous fixed covariates of baseline measurement and baseline measurement-by-week interaction.
    Comparison groups
    Dapagliflozin 10 mg + Saxagliptin 2.5 mg v Placebo
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.298 [7]
    Method
    		 MMRM
    Parameter type
    		 Difference in adjusted mean change
    Point estimate
    -6.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.5
         upper limit
    		 5.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.8
    Notes
    [7] - Statistical significance level = 0.025.
    Statistical analysis title
    		 Longitudinal Repeated Measures Analysis
    Statistical analysis description
    A longitudinal repeated measures analysis included the fixed categorical effects of treatment, week, randomisation stratification factor (i.e.anti-diabetic treatment strata), and treatment-by-week interaction, as well as the continuous fixed covariates of baseline measurement and baseline measurement-by-week interaction.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.746 [8]
    Method
    		 MMRM
    Parameter type
    		 Difference in adjusted mean change
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.6
         upper limit
    		 9.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.9
    Notes
    [8] - Statistical significance level = 0.025.

    Secondary: Percentage of Patients Achieving at Least 30% Reduction in UACR at Week 24

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    End point title
    		 Percentage of Patients Achieving at Least 30% Reduction in UACR at Week 24
    End point description
    The proportion of responders (i.e. percentage of patients meeting the criteria of at least a 30% reduction in UACR), was analysed using a logistic regression model. If no measurement was available at Week 24 the last available post-baseline measurement was carried forward (Last Observation Carried Forward [LOCF]). Results are presented for patients from the Full Analysis Set with non-missing baseline and at least one post-baseline UACR value.
    End point type
    Secondary
    End point timeframe
    From baseline up to Week 24
    End point values
    		 Dapagliflozin 10 mg + Saxagliptin 2.5 mg Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    151
    140
    144
    Units: Percentage
        number (not applicable)
    57.0
    45.0
    31.3
    Statistical analysis title
    		 Logistic Regression Model Analysis
    Statistical analysis description
    Logistic regression model analysis with adjustment for baseline UACR and pooled randomisation strata.
    Comparison groups
    Dapagliflozin 10 mg + Saxagliptin 2.5 mg v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [9]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.8
         upper limit
    		 4.8
    Notes
    [9] - Statistical significance level = 0.025.
    Statistical analysis title
    		 Logistic Regression Model Analysis
    Statistical analysis description
    Logistic regression model analysis with adjustment for baseline UACR and pooled randomisation strata.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013 [10]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 3
    Notes
    [10] - Statistical significance level = 0.025.

    Secondary: Percentage of Patients Achieving a Reduction in HbA1c of Less than 7.0% at Week 24

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    End point title
    		 Percentage of Patients Achieving a Reduction in HbA1c of Less than 7.0% at Week 24
    End point description
    The proportion of responders (i.e. percentage of patients meeting the criteria of a less than 7% reduction in HbA1c), was analysed using a logistic regression model. If no measurement was available at Week 24 the last available post-baseline measurement was carried forward (LOCF). Only measurements prior to rescue or treatment discontinuation were analysed. Results are presented for patients from the Full Analysis Set with non-missing baseline and at least one post-baseline HbA1c value.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24
    End point values
    		 Dapagliflozin 10 mg + Saxagliptin 2.5 mg Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    151
    140
    145
    Units: Percentage
        number (not applicable)
    35.1
    15.0
    10.3
    Statistical analysis title
    		 Logistic Regression Model Analysis
    Statistical analysis description
    Logistic regression model analysis with adjustment for baseline HbA1c and pooled randomisation strata.
    Comparison groups
    Dapagliflozin 10 mg + Saxagliptin 2.5 mg v Placebo
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [11]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.6
         upper limit
    		 11.2
    Notes
    [11] - Statistical significance level = 0.025.
    Statistical analysis title
    		 Logistic Regression Model Analysis
    Statistical analysis description
    Logistic regression model analysis with adjustment for baseline HbA1c and pooled randomisation strata.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.167 [12]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 3.8
    Notes
    [12] - Statistical significance level = 0.025.

    Secondary: Adjusted Mean Change from Baseline in Seated Systolic Blood Pressure (SBP) at Week 24

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    End point title
    		 Adjusted Mean Change from Baseline in Seated Systolic Blood Pressure (SBP) at Week 24
    End point description
    Seated SBP was analysed at baseline, Week 1 and every 4 weeks during the 24-week treatment period. All measurements regardless of rescue medication or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a MMRM model. Results are presented for patients from the Full Analysis Set with non-missing baseline and Week 24 values for SBP.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Dapagliflozin 10 mg + Saxagliptin 2.5 mg Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    139
    132
    134
    Units: Millimetre of mercury (mmHg)
        least squares mean (standard error)
    -8.8 ( 1.6 )
    -6.9 ( 1.7 )
    -4.1 ( 1.7 )
    Statistical analysis title
    		 Longitudinal Repeated Measures Analysis
    Statistical analysis description
    A longitudinal repeated measures model of the logarithms of the post-baseline to baseline ratios, included the fixed categorical effects of treatment, week, treatment-by-week interaction, and randomisation strata, as well as the continuous fixed covariates of log-baseline SBP value and log-baseline SBP value-by-week interaction.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.122 [13]
    Method
    		 MMRM
    Parameter type
    		 Difference in adjusted mean change
    Point estimate
    -2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.4
         upper limit
    		 0.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.8
    Notes
    [13] - Statistical significance level = 0.025.
    Statistical analysis title
    		 Longitudinal Repeated Measures Analysis
    Statistical analysis description
    A longitudinal repeated measures model of the logarithms of the post-baseline to baseline ratios, included the fixed categorical effects of treatment, week, treatment-by-week interaction, and randomisation strata, as well as the continuous fixed covariates of log-baseline SBP value and log-baseline SBP value-by-week interaction.
    Comparison groups
    Dapagliflozin 10 mg + Saxagliptin 2.5 mg v Placebo
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009 [14]
    Method
    		 MMRM
    Parameter type
    		 Difference in adjusted mean change
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.3
         upper limit
    		 -1.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.8
    Notes
    [14] - Statistical significance level = 0.025.

    Secondary: Adjusted Mean Change from Baseline in HbA1c: Comparison of Dapagliflozin 10 mg and Placebo at Week 24

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    End point title
    		 Adjusted Mean Change from Baseline in HbA1c: Comparison of Dapagliflozin 10 mg and Placebo at Week 24 [15]
    End point description
    HbA1c was analysed at baseline and every 4 weeks during the 24-week treatment period. Only measurements prior to rescue or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a MMRM model. Results are presented for patients from the Full Analysis Set with non-missing baseline and Week 24 values for HbA1c.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This secondary endpoint was concerned with comparison of Dapagliflozin 10 mg arm versus placebo only. Comparison of Dapagliflozin 10 + Saxagliptin 2.5 mg arm to placebo is reported as a primary endpoint.
    End point values
    		 Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    123
    118
    Units: Percentage
        least squares mean (standard error)
    -0.43 ( 0.09 )
    -0.27 ( 0.09 )
    Statistical analysis title
    		 Longitudinal Repeated Measures Analysis
    Statistical analysis description
    A longitudinal repeated measures analysis included the fixed categorical effects of treatment, week, randomisation stratification factor (i.e. anti-diabetic treatment strata), and treatment-by-week interaction, as well as the continuous fixed covariates of baseline measurement and baseline measurement-by-week interaction.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.142 [16]
    Method
    		 MMRM
    Parameter type
    		 Difference in adjusted mean change
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [16] - Statistical significance level = 0.025.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Non-serious adverse events (AEs) were reported from Day 1 until the last day of double-blind treatment +4 days. Serious AEs were included up to the last day of double-blind treatment + 30 days. A total maximum time frame of 28 weeks.
    Adverse event reporting additional description
    The Safety Analysis Set consisted of all patients who received at least 1 dose of study drug during the 24-week double-blind treatment period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Dapagliflozin 10 mg
    Reporting group description
    		 Dapagliflozin 10 mg tablets were taken orally, once daily (in the morning) for 24 weeks. Patients also took placebo tablets to match saxagliptin.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets to match both active products (dapagliflozin and saxagliptin) were taken orally, once daily (in the morning) for 24 weeks.

    Reporting group title
    Dapagliflozin 10 mg + Saxagliptin 2.5 mg
    Reporting group description
    		 Dapagliflozin 10 mg and saxagliptin 2.5 mg tablets were taken orally, once daily (in the morning) for 24 weeks.

    Serious adverse events
    		 Dapagliflozin 10 mg Placebo Dapagliflozin 10 mg + Saxagliptin 2.5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 145 (8.28%)
    16 / 148 (10.81%)
    12 / 152 (7.89%)
         number of deaths (all causes)
    1
    0
    1
         number of deaths resulting from adverse events
    1
    0
    1
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 148 (0.68%)
    0 / 152 (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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 148 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 148 (0.68%)
    0 / 152 (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
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 148 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 148 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    2 / 148 (1.35%)
    0 / 152 (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
    Humerus fracture
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 148 (0.00%)
    0 / 152 (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 / 145 (0.69%)
    2 / 148 (1.35%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 148 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 148 (0.00%)
    0 / 152 (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
    Cardiogenic shock
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 148 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 145 (0.00%)
    2 / 148 (1.35%)
    0 / 152 (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
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 148 (0.00%)
    0 / 152 (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
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 145 (0.00%)
    2 / 148 (1.35%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 148 (0.00%)
    0 / 152 (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
    Headache
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 148 (0.68%)
    0 / 152 (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
    Presyncope
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 148 (0.68%)
    0 / 152 (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
    Syncope
         subjects affected / exposed
    2 / 145 (1.38%)
    0 / 148 (0.00%)
    0 / 152 (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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 148 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 148 (0.68%)
    0 / 152 (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
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 148 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenomegaly
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 148 (0.68%)
    0 / 152 (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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 148 (0.68%)
    0 / 152 (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
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 148 (0.00%)
    0 / 152 (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
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 148 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 148 (0.00%)
    0 / 152 (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 / 145 (0.00%)
    0 / 148 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 145 (0.00%)
    2 / 148 (1.35%)
    0 / 152 (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
    Glomerulonephritis rapidly progressive
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 148 (0.68%)
    0 / 152 (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
    Urinary retention
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 148 (0.68%)
    0 / 152 (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
    Musculoskeletal and connective tissue disorders
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 148 (0.00%)
    0 / 152 (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
    Diabetic foot infection
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 148 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Emphysematous pyelonephritis
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 148 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Genital infection
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 148 (0.00%)
    0 / 152 (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
    Groin abscess
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 148 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 148 (0.00%)
    0 / 152 (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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 148 (0.68%)
    0 / 152 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 148 (0.68%)
    0 / 152 (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
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 148 (0.00%)
    0 / 152 (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
    Hypoglycaemia
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 148 (0.68%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         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 10 mg Placebo Dapagliflozin 10 mg + Saxagliptin 2.5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 145 (12.41%)
    8 / 148 (5.41%)
    12 / 152 (7.89%)
    Infections and infestations
    Influenza
         subjects affected / exposed
    8 / 145 (5.52%)
    2 / 148 (1.35%)
    2 / 152 (1.32%)
         occurrences all number
    8
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    10 / 145 (6.90%)
    6 / 148 (4.05%)
    10 / 152 (6.58%)
         occurrences all number
    11
    6
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Nov 2015
    Major changes included: Benefit/risk and overdose text revised to align with new Investigator Brochure. Added additional 24 hour laboratory assessments. Revised allowed concomitant medication text to specify that doses should remain constant throughout both the 24-week treatment period and the 3 week follow-up period. Increased upper Body Mass Index limit in inclusion criteria from 40 kg/m2 to 45 kg/m2. 24 hour urine assessments were removed from Visits 5 and 7.
    08 Jan 2016
    Major changes included: added measurement of arterial stiffness in Canada, Spain & US to Exploratory Objectives listed for both the Saxagliptin/Dapagliflozin and Dapagliflozin treatment arms. Exclusion criteria section was changed to patients with Type 1 Diabetes Mellitus, history of pancreatitis or pancreatic surgery. Benefit/risk section was modified to add new text regarding risk of ketoacidosis.
    01 Apr 2016
    Major changes included: AEs of special interest section was updated to include regulatory requirements. The HbA1c and estimated glomerular filtration rate (eGFR) limits and the insulin regimen were updated due to modification of inclusion criteria. Lost to follow-up was added as one of the withdrawal criteria from the study due to comment from FDA. The concomitant and other treatments section was updated to allow use of erythropoiesis stimulating agents with restrictions due to modification of exclusion criteria. Analysis of the secondary variables and Exploratory analysis updated to replace current methodologoy with a logistic regression model.
    17 Nov 2016
    Major changes included: eGFR limits were updated. The target patient population has been changed to Chronic Kidney Disease patients with Type 2 Diabetes Mellitus and albuminuria, due to modification of eGFR inclusion criteria. Concomitant and other treatments section modified to remove the aneamia treatment from the list of prohibited medication. AEs of special interest section removed.
    18 Sep 2017
    Major changes included: information related to the reporting and adjudication of diabetic ketoacidosis events in the study. New section added to describe collection of specific information related to AEs leading to amputation and AEs leading to a risk for lower limb amputations in globally sponsored dapagliflozin studies.

    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.
    Anomalous data at 1 site was identified following completion of the study. All data from this site were excluded from the full analysis following an audit; the findings led the sponsor to believe the site did not comply with the principles of GCP.
    For support, Contact us.
    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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