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    Clinical Trial Results:
    A 24-week International, Multicenter, Randomized, Open-Label, Active-Controlled, Parallel Group, Phase 3b Trial with a 28-week Extension to Evaluate the Efficacy and Safety of Saxagliptin Co-administered with Dapagliflozin Compared to Insulin Glargine in Subjects with Type 2 Diabetes who have Inadequate Glycemic Control on Metformin with or without Sulfonylurea Therapy

    Summary
    EudraCT number
    		 2015-001702-33
    Trial protocol
    		 HU   CZ   ES   SE   DK   DE  
    Global end of trial date
    10 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Nov 2018
    First version publication date
    07 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CV181-369
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02551874
    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, +46 031 7761000, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +46 031 7761000, ClinicalTrialTransparency@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to examine whether the mean change from baseline in hemoglobin A1c (HbA1c) with co-administered saxagliptin 5 milligrams (mg) once daily (QD) and dapagliflozin 10 mg QD plus metformin with or without sulfonylurea (SU) is noninferior to titrated insulin glargine plus metformin with or without SU after 24 weeks of open-label treatment.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements, and the AstraZeneca policy on Bioethics.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Oct 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
    United States: 336
    Country: Number of subjects enrolled
    Mexico: 79
    Country: Number of subjects enrolled
    South Africa: 43
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Poland: 53
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    Hungary: 53
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Romania: 27
    Worldwide total number of subjects
    643
    EEA total number of subjects
    185
    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)
    525
    From 65 to 84 years
    118
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 112 centers in 11 countries from 20 Oct 2015 to 10 Nov 2017. There were 2 data cut-offs for this study: 8 May 2017 for analyses of the short-term study period (after 24 weeks of open-label treatment) and 10 Nov 2017 for analyses of the short-term plus long-term study period (after 52 weeks of open-label treatment).

    Pre-assignment
    Screening details
    		 The study duration was up to 56 weeks, consisting of a 2-week screening period, 2-week lead-in period, 24-week short-term treatment period, and 28-week long-term treatment period.

    Pre-assignment period milestones
    Number of subjects started
    		 650 [1]
    Number of subjects completed
    		 643

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Did not receive randomised treatment: 7
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 650 subjects were randomized overall, and number Started for Pre-assignment period reflects this value. A total of 7 of the 650 randomized subjects did not receive treatment. The randomized subject data set consisted of all randomized subjects who received at least 1 dose of study medication and therefore number in this subject population was 643. Demographic characteristics, including subject enrollment per country, was summarized for the randomized subject data set (ie, 643).
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dapagliflozin + Saxagliptin + Metformin
    Arm description
    		 Subjects received dapagliflozin 10 mg and saxagliptin 5 mg, administered orally QD in the morning for the 52-week treatment period (24-week short-term period and 28-week long term period). Subjects continued to receive their stable dose of metformin with or without SU throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Farxiga, BMS-512148
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dapagliflozin 10 mg tablets were administered orally QD in the morning for the 52-week treatment period.

    Investigational medicinal product name
    Saxagliptin
    Investigational medicinal product code
    Other name
    Onglyza
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Saxagliptin 5 mg tablets were administered orally QD in the morning for the 52-week treatment period.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Glucophage XR
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin 500 mg tablets were administered orally per investigator discretion at a dose of no less than 1500 mg per day and not to exceed 2500 mg per day (or maximum locally approved dose) based on the subject’s qualifying dose at screening.

    Arm title
    		 Titrated Insulin + Metformin
    Arm description
    		 Subjects were to administer insulin glargine subcutaneously QD at the same time every day for the 52-week treatment period (24-week short-term period and 28-week long term period), following investigator instructions and training. All subjects started with an initial dose of 0.2 units/kg body weight or at least 10 units of insulin per day. Subjects self-titrated the dose of insulin glargine over the first 8 weeks of the study based on daily glucose monitoring. The investigator had the discretion to modify insulin dose based on his/her assessment between Week 8 and Week 12 with the goal to reach an acceptable and stable insulin dose by Week 12. Subjects continued to receive their stable dose of metformin with or without SU throughout the study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    Lantus
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All subjects started with an initial dose of 0.2 units/kilogram (kg) body weight or at least 10 units of insulin per day. Subjects self-titrated the dose of insulin glargine over the first 8 weeks of the study based on daily glucose monitoring. Insulin was administered as 100 units/millilitre solution for injection.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Glucophage XR
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin 500 mg tablets were administered orally per investigator discretion at a dose of no less than 1500 mg per day and not to exceed 2500 mg per day (or maximum locally approved dose) based on the subject’s qualifying dose at screening.

    Number of subjects in period 1
    		Dapagliflozin + Saxagliptin + Metformin Titrated Insulin + Metformin
    Started
    324
    319
    Entered long-term study
    306
    294
    Received treatment in long-term study
    295 [2]
    284 [3]
    Completed
    296
    287
    Not completed
    28
    32
         Reason not reported
    10
    4
         Pregnancy
    -
    1
         Did not enter long-term study
    18
    25
         Lost to follow-up
    -
    2
    Notes
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Started = subjects randomized to Dapagliflozin + Saxagliptin + Metformin arm who received treatment in short-term study (324). Intermediate milestones: subjects entering long-term study (306) and subjects receiving treatment in long-term study (295). Completed = subjects completing long-term study (296). Since Started - Completed = Not Completed and Subject Disposition is presented for the overall study, those subjects not entering the long-term study (18) are indicated as non-completers.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Started = subjects randomized to Dapagliflozin + Saxagliptin + Metformin arm who received treatment in short-term study (319). Intermediate milestones: subjects entering long-term study (294) and subjects receiving treatment in long-term study (284). Completed = subjects completing long-term study (287). Since Started - Completed = Not Completed and Subject Disposition is presented for the overall study, those subjects not entering the long-term study (25) are indicated as non-completers.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dapagliflozin + Saxagliptin + Metformin
    Reporting group description
    		 Subjects received dapagliflozin 10 mg and saxagliptin 5 mg, administered orally QD in the morning for the 52-week treatment period (24-week short-term period and 28-week long term period). Subjects continued to receive their stable dose of metformin with or without SU throughout the study.

    Reporting group title
    Titrated Insulin + Metformin
    Reporting group description
    		 Subjects were to administer insulin glargine subcutaneously QD at the same time every day for the 52-week treatment period (24-week short-term period and 28-week long term period), following investigator instructions and training. All subjects started with an initial dose of 0.2 units/kg body weight or at least 10 units of insulin per day. Subjects self-titrated the dose of insulin glargine over the first 8 weeks of the study based on daily glucose monitoring. The investigator had the discretion to modify insulin dose based on his/her assessment between Week 8 and Week 12 with the goal to reach an acceptable and stable insulin dose by Week 12. Subjects continued to receive their stable dose of metformin with or without SU throughout the study.

    Reporting group values
    		 Dapagliflozin + Saxagliptin + Metformin Titrated Insulin + Metformin Total
    Number of subjects
    		 324 319 643
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 265 260 525
        From 65-84 years
    		 59 59 118
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.7 ( 9.52 ) 55.3 ( 9.63 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 148 148 296
        Male
    		 176 171 347
    Race, Customized
    Units: Subjects
        American Indian Or Alaska Native|
    		 12 6 18
        Asian|
    		 12 12 24
        Black Or African American|
    		 28 35 63
        Native Hawaiian Or Other Pacific Islander|
    		 0 1 1
        Other|
    		 9 11 20
        White|
    		 263 254 517

    End points

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    End points reporting groups
    Reporting group title
    Dapagliflozin + Saxagliptin + Metformin
    Reporting group description
    		 Subjects received dapagliflozin 10 mg and saxagliptin 5 mg, administered orally QD in the morning for the 52-week treatment period (24-week short-term period and 28-week long term period). Subjects continued to receive their stable dose of metformin with or without SU throughout the study.

    Reporting group title
    Titrated Insulin + Metformin
    Reporting group description
    		 Subjects were to administer insulin glargine subcutaneously QD at the same time every day for the 52-week treatment period (24-week short-term period and 28-week long term period), following investigator instructions and training. All subjects started with an initial dose of 0.2 units/kg body weight or at least 10 units of insulin per day. Subjects self-titrated the dose of insulin glargine over the first 8 weeks of the study based on daily glucose monitoring. The investigator had the discretion to modify insulin dose based on his/her assessment between Week 8 and Week 12 with the goal to reach an acceptable and stable insulin dose by Week 12. Subjects continued to receive their stable dose of metformin with or without SU throughout the study.

    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
    To examine whether the mean change from baseline in HbA1c with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU is noninferior (noninferiority margin of 0.3%) to titrated insulin glargine plus metformin with or without SU after 24 weeks of open-label treatment. Analysis performed on the randomized subjects data set, consisting of all randomized subjects who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Dapagliflozin + Saxagliptin + Metformin Titrated Insulin + Metformin
    Number of subjects analysed
    319
    312
    Units: % HbA1c
        least squares mean (confidence interval 95%)
    -1.67 (-1.79 to -1.55)
    -1.54 (-1.66 to -1.42)
    Statistical analysis title
    		 Change in HbA1c
    Comparison groups
    Dapagliflozin + Saxagliptin + Metformin v Titrated Insulin + Metformin
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.118 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.085
    Notes
    [1] - Non-inferiority was defined by upper bound of 95% CI <0.3%
    [2] - Superiority

    Secondary: Mean change from baseline in total body weight at Week 24

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    End point title
    		 Mean change from baseline in total body weight at Week 24
    End point description
    To compare the mean change from baseline in total body weight with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU versus titrated insulin glargine plus metformin with or without SU after 24 weeks of open-label treatment. Analysis performed on subjects in the randomized subject data set with non-missing baseline assessments and at least one post-baseline assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Dapagliflozin + Saxagliptin + Metformin Titrated Insulin + Metformin
    Number of subjects analysed
    319
    313
    Units: kg
        least squares mean (confidence interval 95%)
    -1.50 (-1.89 to -1.11)
    2.14 (1.75 to 2.54)
    Statistical analysis title
    		 Change in total body weight
    Comparison groups
    Dapagliflozin + Saxagliptin + Metformin v Titrated Insulin + Metformin
    Number of subjects included in analysis
    632
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.2
         upper limit
    		 -3.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.282

    Secondary: Percentage of subjects with confirmed hypoglycemia at Week 24

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    End point title
    		 Percentage of subjects with confirmed hypoglycemia at Week 24
    End point description
    Hypoglycemia defined as plasma glucose ≤70 mg/dL (3.9 mmol/L). Analysis performed on the randomized subjects data set, consisting of all randomized subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Dapagliflozin + Saxagliptin + Metformin Titrated Insulin + Metformin
    Number of subjects analysed
    324
    319
    Units: Adjusted % Participants
        number (confidence interval 95%)
    21.3 (17.03 to 26.22)
    38.4 (32.94 to 44.07)
    Statistical analysis title
    		 Confirmed hypoglycemia
    Comparison groups
    Dapagliflozin + Saxagliptin + Metformin v Titrated Insulin + Metformin
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.62

    Secondary: Percentage of subjects achieving a therapeutic glycemic response, without hypoglycaemia, at Week 24

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    End point title
    		 Percentage of subjects achieving a therapeutic glycemic response, without hypoglycaemia, at Week 24
    End point description
    To compare the percentage of subjects achieving a therapeutic glycemic response, defined as HbA1c <7.0%, without any reported hypoglycemia, with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU versus titrated insulin glargine plus metformin with or without SU after 24 weeks of open-label treatment. Analysis performed on the randomized subjects data set, consisting of all randomized subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Dapagliflozin + Saxagliptin + Metformin Titrated Insulin + Metformin
    Number of subjects analysed
    324
    319
    Units: Adjusted % Participants
        number (confidence interval 95%)
    20.9 (16.69 to 25.83)
    13.1 (9.72 to 17.33)
    Statistical analysis title
    		 Glycemic response/no hypoglycemia
    Comparison groups
    Dapagliflozin + Saxagliptin + Metformin v Titrated Insulin + Metformin
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.16
         upper limit
    		 2.67

    Secondary: Percentage of subjects achieving a therapeutic glycemic response at Week 24

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    End point title
    		 Percentage of subjects achieving a therapeutic glycemic response at Week 24
    End point description
    To examine whether the percentage of subjects achieving a therapeutic glycemic response, defined as HbA1c <7.0%, with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU is noninferior (noninferiority margin of 10%) to titrated insulin glargine plus metformin with or without SU after 24 weeks of open-label treatment. Analysis performed on the randomized subjects data set, consisting of all randomized subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Dapagliflozin + Saxagliptin + Metformin Titrated Insulin + Metformin
    Number of subjects analysed
    324
    319
    Units: Adjusted % Participants
        number (confidence interval 95%)
    33.2 (28.00 to 38.79)
    33.5 (28.28 to 39.26)
    Statistical analysis title
    		 Therapeutic glycemic response
    Comparison groups
    Dapagliflozin + Saxagliptin + Metformin v Titrated Insulin + Metformin
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Adjusted Percent Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.42
         upper limit
    		 6.54
    Notes
    [3] - Non-inferiority was defined by lower bound of 95% CI >-10%.

    Secondary: Change from baseline in the mean value of 24-hour glucose at Week 2

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    End point title
    		 Change from baseline in the mean value of 24-hour glucose at Week 2
    End point description
    Change from baseline in the mean value of 24-hour glucose readings measured by Continuous Glucose Monitoring with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU is noninferior to titrated insulin glargine plus metformin with or without SU after 2 weeks of open-label treatment. Analysis performed on the randomized subjects data set, consisting of all randomized subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 2
    End point values
    		 Dapagliflozin + Saxagliptin + Metformin Titrated Insulin + Metformin
    Number of subjects analysed
    133
    133
    Units: mg/deciliter (dL)
        least squares mean (confidence interval 95%)
    -48.53 (-53.47 to -43.59)
    -28.54 (-33.47 to -23.61)
    Statistical analysis title
    		 Change in 24-h glucose
    Comparison groups
    Dapagliflozin + Saxagliptin + Metformin v Titrated Insulin + Metformin
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.98
         upper limit
    		 -13
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.55
    Notes
    [4] - Non-inferiority was defined by upper bound of 95% CI <12 mg/dL.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline (Day 1) up to Week 52 (24-week short-term treatment period + 28-week long-term treatment period).
    Adverse event reporting additional description
    Adverse event (AE) data is reported for the treated subject data set, and included AEs with an onset date on or after the date of first dose of short-term study treatment and up to and including 30 days following the date of last dose of short-term + long-term study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Dapagliflozin + Saxagliptin + Metformin
    Reporting group description
    		 Subjects received dapagliflozin 10 mg and saxagliptin 5 mg, administered orally QD in the morning for the 52-week treatment period (24-week short-term period and 28-week long term period). Subjects continued to receive their stable dose of metformin with or without sulfonylurea throughout the study.

    Reporting group title
    Titrated Insulin + Metformin
    Reporting group description
    		 Subjects were to administer insulin glargine subcutaneously QD at the same time every day for the 52-week treatment period (24-week short-term period and 28-week long term period), following investigator instructions and training. All subjects started with an initial dose of 0.2 units/kilogram (kg) body weight or at least 10 units of insulin per day. Subjects self-titrated the dose of insulin glargine over the first 8 weeks of the study based on daily glucose monitoring. The investigator had the discretion to modify insulin dose based on his/her assessment between Week 8 and Week 12 with the goal to reach an acceptable and stable insulin dose by Week 12. Subjects continued to receive their stable dose of metformin with or without SU throughout the study.

    Serious adverse events
    		 Dapagliflozin + Saxagliptin + Metformin Titrated Insulin + Metformin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 324 (6.17%)
    13 / 319 (4.08%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Fibroadenoma of breast
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer female
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Inflammation
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatomegaly
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post-traumatic stress disorder
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative hernia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lisfranc fracture
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 319 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    3 / 324 (0.93%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Femoral hernia incarcerated
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Hidradenitis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary bladder polyp
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gangrene
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dapagliflozin + Saxagliptin + Metformin Titrated Insulin + Metformin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 324 (16.98%)
    73 / 319 (22.88%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 324 (3.70%)
    22 / 319 (6.90%)
         occurrences all number
    15
    24
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 324 (5.25%)
    23 / 319 (7.21%)
         occurrences all number
    24
    26
    Viral upper respiratory tract infection
         subjects affected / exposed
    25 / 324 (7.72%)
    19 / 319 (5.96%)
         occurrences all number
    28
    24
    Influenza
         subjects affected / exposed
    8 / 324 (2.47%)
    16 / 319 (5.02%)
         occurrences all number
    8
    16

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Mar 2016
    Addition of discontinuation guidelines due to ketoacidosis, clarification of starting insulin dose to 0.2 units/kg body weight or at least 10 units of insulin per day and addition of language describing investigator modification of insulin-dose titration, and removal of details about discontinuation due to hypoglycemia during the lead-in period.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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