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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Double-Blind, Active-Comparator Controlled Clinical Trial to Study the Safety and Efficacy of the Addition of Sitagliptin Compared with the Addition of Dapagliflozin in Subjects with Type 2 Diabetes Mellitus and Mild Renal Impairment Who Have Inadequate Glycemic Control on Metformin With or Without a Sulfonylurea

    Summary
    EudraCT number
    		 2014-005525-13
    Trial protocol
    		 LT   LV   FI   IE   EE   HU   ES   GB  
    Global end of trial date
    10 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Oct 2018
    First version publication date
    04 Oct 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    0431-838
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02532855
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Protocol Number: MK-0431-838
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the study is to assess the effect of the addition of sitagliptin to metformin with or without a sulfonylurea compared with the addition of dapagliflozin to metformin with or without a sulfonylurea on hemoglobin A1c (A1C) over 24 weeks of treatment as well as the overall safety and tolerability of sitagliptin in comparison to that of dapagliflozin after 24 weeks of treatment. The primary hypothesis is that the change from baseline in A1C in participants treated with the addition of sitagliptin is non-inferior compared to that in participants treated with the addition of dapagliflozin after 24 weeks of treatment.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    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
    Argentina: 32
    Country: Number of subjects enrolled
    Brazil: 23
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Colombia: 27
    Country: Number of subjects enrolled
    Estonia: 16
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Hungary: 36
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Latvia: 17
    Country: Number of subjects enrolled
    Lithuania: 21
    Country: Number of subjects enrolled
    Mexico: 51
    Country: Number of subjects enrolled
    New Zealand: 19
    Country: Number of subjects enrolled
    Norway: 18
    Country: Number of subjects enrolled
    Peru: 11
    Country: Number of subjects enrolled
    Romania: 27
    Country: Number of subjects enrolled
    Russian Federation: 68
    Country: Number of subjects enrolled
    South Africa: 22
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 150
    Worldwide total number of subjects
    614
    EEA total number of subjects
    179
    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)
    203
    From 65 to 84 years
    407
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 183 medical centers in 24 countries.

    Pre-assignment
    Screening details
    		 Male and female participants, 25 years or older, with Type 2 diabetes mellitus (T2DM) and mild renal impairment on metformin alone or in combination with a sulfonylurea (SU) agent were enrolled in this trial.

    Period 1
    Period 1 title
    Pre-Treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sitagliptin
    Arm description
    		 Participants receive sitagliptin 100 mg once daily plus matching placebo for dapagliflozin 5 mg once daily for 4 weeks followed by sitagliptin 100 mg once daily plus matching placebo for dapagliflozin 10 mg once daily for 20 weeks. Participants continue pre-study metformin (at least 1500 mg daily) alone or in combination with a sulfonylurea agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) throughout the duration of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    MK-0431
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin, 100 mg, once daily (q.d.), oral, for 24 weeks

    Investigational medicinal product name
    Matching placebo for dapagliflozin 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, q.d. for 4 weeks (Day 1 to Week 4)

    Investigational medicinal product name
    Matching placebo for dapagliflozin 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, q.d. for 20 weeks (Week 4 to Week 24)

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin, oral tablet(s), at least 1500 mg daily

    Investigational medicinal product name
    Sulfonylurea agent
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sulfonylurea agent, dose required to be at least 50% of maximum labeled dose, consistent with near maximum efficacy of the sulfonylurea agent.

    Arm title
    		 Dapagliflozin
    Arm description
    		 Participants receive dapagliflozin 5 mg once daily plus matching placebo for sitagliptin 100 mg once daily for 4 weeks followed by dapagliflozin 10 mg once daily plus matching placebo for sitagliptin 100 mg once daily for 20 weeks. Participants continue pre-study metformin (at least 1500 mg daily) alone or in combination with a sulfonylurea agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) throughout the duration of the study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dapagliflozin 10 mg group
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dapagliflozin, 5 mg, q.d., for 4 weeks (Day 1 to Week 4)

    Investigational medicinal product name
    Dapagliflozin 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dapagliflozin 10 mg, oral, q.d. for 20 weeks (Week 4 to Week 24)

    Investigational medicinal product name
    Matching placebo for sitagliptin 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, q.d. for 24 weeks

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin, oral tablet(s), at least 1500 mg daily

    Investigational medicinal product name
    Sulfonylurea agent
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sulfonylurea agent, dose required to be at least 50% of maximum labeled dose, consistent with near maximum efficacy of the sulfonylurea agent.

    Number of subjects in period 1
    		Sitagliptin Dapagliflozin
    Started
    307
    307
    Completed
    307
    306
    Not completed
    0
    1
         One participant was randomized but not treated
    -
    1
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sitagliptin
    Arm description
    		 Participants receive sitagliptin 100 mg once daily plus matching placebo for dapagliflozin 5 mg once daily for 4 weeks followed by sitagliptin 100 mg once daily plus matching placebo for dapagliflozin 10 mg once daily for 20 weeks. Participants continue pre-study metformin (at least 1500 mg daily) alone or in combination with a sulfonylurea agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) throughout the duration of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    MK-0431
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin, 100 mg once daily (q.d.), oral, for 24 weeks

    Investigational medicinal product name
    Matching placebo for dapagliflozin 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, q.d. for 4 weeks (Day 1 to Week 4)

    Investigational medicinal product name
    Matching placebo for dapagliflozin 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, q.d. for 20 weeks (Week 4 to Week 24)

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin, oral tablet(s), at least 1500 mg daily

    Investigational medicinal product name
    Sulfonylurea agent
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sulfonylurea agent, dose required to be at least 50% of maximum labeled dose, consistent with near maximum efficacy of the sulfonylurea agent.

    Arm title
    		 Dapagliflozin
    Arm description
    		 Participants receive dapagliflozin 5 mg once daily plus matching placebo for sitagliptin 100 mg once daily for 4 weeks followed by dapagliflozin 10 mg once daily plus matching placebo for sitagliptin 100 mg once daily for 20 weeks. Participants continue pre-study metformin (at least 1500 mg daily) alone or in combination with a sulfonylurea agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) throughout the duration of the study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dapagliflozin 10 mg group
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dapagliflozin 5 mg, q.d., for 4 weeks (Day 1 to Week 4)

    Investigational medicinal product name
    Dapagliflozin 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dapagliflozin 10 mg, oral, q.d. for 20 weeks (Week 4 to Week 24)

    Investigational medicinal product name
    Matching placebo for sitagliptin 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, q.d. for 24 weeks

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin, oral tablet(s), at least 1500 mg daily

    Investigational medicinal product name
    Sulfonylurea agent
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sulfonylurea agent, dose required to be at least 50% of maximum labeled dose, consistent with near maximum efficacy of the sulfonylurea agent.

    Number of subjects in period 2
    		Sitagliptin Dapagliflozin
    Started
    307
    306
    Completed
    299
    295
    Not completed
    8
    11
         Consent withdrawn by subject
    4
    8
         Lost to follow-up
    4
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sitagliptin
    Reporting group description
    		 Participants receive sitagliptin 100 mg once daily plus matching placebo for dapagliflozin 5 mg once daily for 4 weeks followed by sitagliptin 100 mg once daily plus matching placebo for dapagliflozin 10 mg once daily for 20 weeks. Participants continue pre-study metformin (at least 1500 mg daily) alone or in combination with a sulfonylurea agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) throughout the duration of the study.

    Reporting group title
    Dapagliflozin
    Reporting group description
    		 Participants receive dapagliflozin 5 mg once daily plus matching placebo for sitagliptin 100 mg once daily for 4 weeks followed by dapagliflozin 10 mg once daily plus matching placebo for sitagliptin 100 mg once daily for 20 weeks. Participants continue pre-study metformin (at least 1500 mg daily) alone or in combination with a sulfonylurea agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) throughout the duration of the study.

    Reporting group values
    		 Sitagliptin Dapagliflozin Total
    Number of subjects
    		 307 307 614
    Age categorical
    All randomized participants
    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)
    		 97 106 203
        From 65-84 years
    		 206 201 407
        85 years and over
    		 4 0 4
    Age Continuous
    All randomized participants
    Units: years
        arithmetic mean (standard deviation)
    		 67.7 ( 8.5 ) 66.6 ( 8.6 ) -
    Sex: Female, Male
    All randomized participants
    Units: Subjects
        Female
    		 138 120 258
        Male
    		 169 187 356
    Background Antihyperglycemic Agent (AHA)
    All randomized participants
    Units: Subjects
        Metformin Alone
    		 212 225 437
        Metformin and Sulfonylurea
    		 95 81 176
        Unknown
    		 0 1 1
    Race (NIH/OMB)
    All randomized participants
    Units: Subjects
        American Indian or Alaska Native
    		 18 14 32
        Asian
    		 11 7 18
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 8 11 19
        White
    		 240 235 475
        More than one race
    		 30 39 69
        Unknown or Not Reported
    		 0 0 0
    Hemoglobin A1C
    All randomized and treated participants. N=307, 306
    Units: Percentage
        arithmetic mean (standard deviation)
    		 7.7 ( 0.7 ) 7.8 ( 0.7 ) -
    Fasting Plasma Glucose (FPG)
    All randomized and treated participants. N=307, 306
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 162.3 ( 40.4 ) 165.2 ( 40.6 ) -
    Incremental 2-hour Postprandial Glucose Excursion (PPGE)
    All randomized and treated participants who underwent MMTT analysis and had a baseline measurement for this endpoint. N=295, 290
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 96.2 ( 55.3 ) 95.7 ( 47.1 ) -
    2-hr Postprandial Glucose
    All randomized and treated participants who underwent MMTT analysis and had a baseline measurement for this endpoint. N=296, 292
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 257.7 ( 67.1 ) 259.9 ( 64.4 ) -
    Glucagon Area Under the Curve (AUC0-120 minutes)
    All randomized and treated participants who underwent MMTT analysis and had a baseline measurement for this endpoint. N=108, 109
    Units: pmol.hr/L
        arithmetic mean (standard deviation)
    		 49.6 ( 44.7 ) 51.8 ( 45.1 ) -
    Insulin AUC0-120 minutes
    All randomized and treated participants who underwent MMTT analysis and had a baseline measurement for this endpoint. N=113, 112
    Units: mIU.hr/L
        arithmetic mean (standard deviation)
    		 155.0 ( 121.8 ) 139.9 ( 93.5 ) -
    Insulin AUC0-120 minutes to Glucagon AUC0-120 minutes Ratio
    All randomized and treated participants who underwent MMTT analysis and had a baseline measurement for this endpoint. N=104, 102
    Units: Ratio
        arithmetic mean (standard deviation)
    		 4.0 ( 3.7 ) 3.5 ( 3.0 ) -

    End points

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    End points reporting groups
    Reporting group title
    Sitagliptin
    Reporting group description
    		 Participants receive sitagliptin 100 mg once daily plus matching placebo for dapagliflozin 5 mg once daily for 4 weeks followed by sitagliptin 100 mg once daily plus matching placebo for dapagliflozin 10 mg once daily for 20 weeks. Participants continue pre-study metformin (at least 1500 mg daily) alone or in combination with a sulfonylurea agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) throughout the duration of the study.

    Reporting group title
    Dapagliflozin
    Reporting group description
    		 Participants receive dapagliflozin 5 mg once daily plus matching placebo for sitagliptin 100 mg once daily for 4 weeks followed by dapagliflozin 10 mg once daily plus matching placebo for sitagliptin 100 mg once daily for 20 weeks. Participants continue pre-study metformin (at least 1500 mg daily) alone or in combination with a sulfonylurea agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) throughout the duration of the study.
    Reporting group title
    Sitagliptin
    Reporting group description
    		 Participants receive sitagliptin 100 mg once daily plus matching placebo for dapagliflozin 5 mg once daily for 4 weeks followed by sitagliptin 100 mg once daily plus matching placebo for dapagliflozin 10 mg once daily for 20 weeks. Participants continue pre-study metformin (at least 1500 mg daily) alone or in combination with a sulfonylurea agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) throughout the duration of the study.

    Reporting group title
    Dapagliflozin
    Reporting group description
    		 Participants receive dapagliflozin 5 mg once daily plus matching placebo for sitagliptin 100 mg once daily for 4 weeks followed by dapagliflozin 10 mg once daily plus matching placebo for sitagliptin 100 mg once daily for 20 weeks. Participants continue pre-study metformin (at least 1500 mg daily) alone or in combination with a sulfonylurea agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) throughout the duration of the study.

    Primary: Change from Baseline in A1C at Week 24

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    End point title
    		 Change from Baseline in A1C at Week 24
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Thus, this change from baseline reflects the Week 24 A1C minus the Week 0 A1C. The analysis population included all randomized and treated participants who had at least one observation for the analysis endpoint, at baseline or subsequent to at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Sitagliptin Dapagliflozin
    Number of subjects analysed
    307
    306
    Units: Percentage
        least squares mean (confidence interval 95%)
    -0.51 (-0.60 to -0.43)
    -0.36 (-0.45 to -0.27)
    Statistical analysis title
    		 Difference in the LSM (sitagliptin-dapagliflozin)
    Statistical analysis description
    Based on a Longitudinal Data Analysis (LDA) model including terms for treatment, time, background antihyperglycemic agent (AHA), the interaction of time and background AHA, and the interaction of time by treatment. Least squares means (LSM)
    Comparison groups
    Sitagliptin v Dapagliflozin
    Number of subjects included in analysis
    613
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference in the LSM (Sit.-Dap.)
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 -0.04
    Notes
    [1] - For the primary hypothesis, sitagliptin will be considered non-inferior to dapagliflozin if the upper bound of the two-sided 95% confidence interval (CI) of the between-group difference in least squares mean change from baseline in A1C (sitagliptin minus dapagliflozin) is less than 0.3% (the non-inferiority margin).
    Statistical analysis title
    		 Difference in the LSM (Sit. - Dap.)
    Statistical analysis description
    Based on a LDA model including terms for treatment, time, background AHA, the interaction of time and background AHA, and the interaction of time by treatment.
    Comparison groups
    Sitagliptin v Dapagliflozin
    Number of subjects included in analysis
    613
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in the LSM (Sit. - Dap.)
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 -0.04

    Primary: Percentage of Participants Who Experienced One or More Adverse Events

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    End point title
    		 Percentage of Participants Who Experienced One or More Adverse Events
    End point description
    An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product. The AE does not have to have a causal relationship with this treatment. The AE can include any unfavourable and unintended sign, symptom, or disease or any worsening (change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the pharmaceutical product. The population analyzed included all randomized and treated participants.
    End point type
    Primary
    End point timeframe
    Up to 26 weeks
    End point values
    		 Sitagliptin Dapagliflozin
    Number of subjects analysed
    307
    306
    Units: Percentage of participants
        number (not applicable)
    48.9
    51.6
    Statistical analysis title
    		 Difference in % (Sit. - Dap.)
    Statistical analysis description
    Based on Miettinen & Nurminen method.
    Comparison groups
    Sitagliptin v Dapagliflozin
    Number of subjects included in analysis
    613
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in % (Sit. - Dap.)
    Point estimate
    -2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.7
         upper limit
    		 5.1

    Primary: Percentage of Participants Who Discontinued Study Drug Due to an AE

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    End point title
    		 Percentage of Participants Who Discontinued Study Drug Due to an AE
    End point description
    An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product. The AE does not have to have a causal relationship with this treatment. The AE can include any unfavourable and unintended sign, symptom, or disease or any worsening (change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the pharmaceutical product. The analysis population included all randomized and treated participants.
    End point type
    Primary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Sitagliptin Dapagliflozin
    Number of subjects analysed
    307
    306
    Units: Percentage of participants
        number (not applicable)
    3.3
    3.3
    Statistical analysis title
    		 Difference in % (Sit. - Dap.)
    Statistical analysis description
    Based on Miettinen & Nurminen method.
    Comparison groups
    Sitagliptin v Dapagliflozin
    Number of subjects included in analysis
    613
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in % (Sit. - Dap.)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 3

    Secondary: Change from Baseline in Incremental 2-hour (2-hr) Postprandial Glucose Excursion (PPGE) at Week 24

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    End point title
    		 Change from Baseline in Incremental 2-hour (2-hr) Postprandial Glucose Excursion (PPGE) at Week 24
    End point description
    The 2hr PPGE is defined as T-120 minus T-0 for each participant: change from baseline PPGE = Week 24 mean (T-120 minus T-0) minus Baseline mean (T-120 minus T-0). The 2-point MMTT measured values at T-0 and T-120 while the 3-point MMTT measured values at T-0, T-60, and T-120: although only a subset of participants had the 3-point MMTT performed, all participants had a T-0 and T-120 time point. A negative (-) change from baseline to Week 24 indicates better control of postprandial glucose. The analysis population consisted of all randomized and treated participants who underwent MMTT for the analysis endpoint, had both baseline and Week 24 endpoint measurements, without: drug compliance <75%, use of prohibited AHA medications or pharmacologic doses of corticosteroids or incorrect double-blind study drug or a change in metformin or sulfonylurea dose.
    End point type
    Secondary
    End point timeframe
    Immediately before and 120 minutes after the standard meal at Baseline and Week 24
    End point values
    		 Sitagliptin Dapagliflozin
    Number of subjects analysed
    298
    296
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -24.2 (-30.4 to -18.0)
    -18.5 (-24.9 to -12.1)
    Statistical analysis title
    		 Difference in the LSM Change from Baseline (CFB)
    Statistical analysis description
    Based on a LDA model including terms for treatment, time, background AHA, the interaction of time and background AHA, and the interaction of time by treatment.
    Comparison groups
    Sitagliptin v Dapagliflozin
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.138
    Method
    		 LDA
    Parameter type
    		 Difference in LSM (Sit. - Dap.)
    Point estimate
    -5.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.3
         upper limit
    		 1.8

    Secondary: Change from Baseline in 2-hr Postprandial Glucose (PPG) at Week 24

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    End point title
    		 Change from Baseline in 2-hr Postprandial Glucose (PPG) at Week 24
    End point description
    The 2hr change from baseline in mean PPG = Week 24 mean T-120 glucose minus Baseline mean T-120 glucose) and shows each drugs impact on PPG. The 2-point MMTT measured values at T-0 and T-120 while the 3-point MMTT measured values at T-0, T-60, and T-120: although only a subset of the study had the 3-point MMTT performed, all participants had a T-0 and T-120 time point. A negative (-) change from baseline to Week 24 indicates better control of postprandial glucose. The analysis population consisted of all randomized and treated participants who underwent MMTT for the analysis endpoint, had both baseline and Week 24 endpoint measurements, without: drug compliance <75%, use of prohibited AHA medications or pharmacologic doses of corticosteroids or incorrect double blind study drug or a change in metformin or sulfonylurea dose.
    End point type
    Secondary
    End point timeframe
    Immediately before and 120 minutes after the standard meal at Baseline and Week 24
    End point values
    		 Sitagliptin Dapagliflozin
    Number of subjects analysed
    258
    248
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -40.4 (-46.9 to -33.9)
    -37.0 (-43.7 to -30.3)
    Statistical analysis title
    		 Difference in the LSM CFB at Week 24
    Statistical analysis description
    The ANCOVA model included terms for treatment, background AHA, and the baseline 2-hour PPG value as a covariate.
    Comparison groups
    Sitagliptin v Dapagliflozin
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in the LSM (Sit. - Dap.)
    Point estimate
    -3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.1
         upper limit
    		 5.3

    Secondary: Change from Baseline in Glucagon Area Under the Curve (AUC0-120 minutes) at Week 24

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    End point title
    		 Change from Baseline in Glucagon Area Under the Curve (AUC0-120 minutes) at Week 24
    End point description
    Participants who underwent the 3-point MMTT had a first blood sample (T=0 minutes) drawn immediately prior to a standard meal and 60 and 120 minutes after the standard meal. The AUC curve was generated with the 3 time points. Change in postprandial glucagon AUC was calculated from the glucagon AUC over the first 120 minutes following the morning meal at baseline minus glucagon AUC over the first 120 minutes following the morning meal at Week 24. A negative (-) change from baseline to Week 24 indicates better control of postprandial glucose. All randomized and treated participants who underwent MMTT for the analysis endpoint, had both baseline and Week 24 endpoint measurements, without: drug compliance <75%, use of prohibited AHA medications or pharmacologic doses of corticosteroids or incorrect double-blind study drug or a change in metformin or sulfonylurea dose.
    End point type
    Secondary
    End point timeframe
    Immediately before and 60 and 120 minutes after the standard meal at Baseline and Week 24
    End point values
    		 Sitagliptin Dapagliflozin
    Number of subjects analysed
    85
    88
    Units: pmol.hr/L
        least squares mean (confidence interval 95%)
    -4.2 (-8.8 to 0.4)
    0.2 (-4.4 to 4.8)
    Statistical analysis title
    		 Difference in LSM (Sit. - Dap.)
    Statistical analysis description
    The ANCOVA model included terms for treatment, background AHA, and the baseline glucagon AUC value as a covariate.
    Comparison groups
    Sitagliptin v Dapagliflozin
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in the LSM (Sit. - Dap.)
    Point estimate
    -4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.1
         upper limit
    		 1.4

    Secondary: Change from Baseline in Insulin AUC0-120 minutes at Week 24

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    End point title
    		 Change from Baseline in Insulin AUC0-120 minutes at Week 24
    End point description
    Participants who underwent the 3-point MMTT had a first blood sample (T=0 minutes) drawn immediately prior to a standard meal and 60 and 120 minutes after the standard meal. The AUC curve was generated with the 3 time points. Change in postprandial insulin AUC was calculated from the insulin AUC over the first 120 minutes following the morning meal at baseline minus insulin AUC over the first 120 minutes following the morning meal at Week 24. A negative (-) change from baseline to Week 24 indicates better control of postprandial glucose. The analysis population included all randomized and treated participants who underwent MMTT for the analysis endpoint, had both baseline and Week 24 endpoint measurements, without: drug compliance <75%, use of prohibited AHA medications or pharmacologic doses of corticosteroids or incorrect double-blind study drug or a change in metformin or sulfonylurea dose.
    End point type
    Secondary
    End point timeframe
    Immediately before and 60 and 120 minutes after the standard meal at Baseline and Week 24
    End point values
    		 Sitagliptin Dapagliflozin
    Number of subjects analysed
    96
    94
    Units: mIU.hr/L
        least squares mean (confidence interval 95%)
    -23.4 (-36.8 to -9.9)
    -28.2 (-42.1 to -14.4)
    Statistical analysis title
    		 Difference in the LSM (Sit. - Dap.)
    Statistical analysis description
    The ANCOVA model included terms for treatment, background AHA, and the baseline insulin AUC value as a covariate.
    Comparison groups
    Sitagliptin v Dapagliflozin
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in the LSM (Sit. - Dap.)
    Point estimate
    4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.2
         upper limit
    		 22

    Secondary: Change from Baseline in Postprandial Insulin AUC0-120 minutes to Glucagon AUC0-120 minutes Ratio at Week 24

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    End point title
    		 Change from Baseline in Postprandial Insulin AUC0-120 minutes to Glucagon AUC0-120 minutes Ratio at Week 24
    End point description
    Participants who underwent the 3-point MMTT had a first blood sample (T=0 minutes) drawn immediately prior to a standard meal and 60 and 120 minutes after the standard meal. The AUC curve was generated with the 3 time points. The endpoint was calculated from the ratio of (insulin AUC / glucagon AUC) over the first 120 minutes following the morning meal at baseline minus AUC over the first 120 minutes following the morning meal at Week 24. A negative (-) change from baseline to Week 24 indicates better control of postprandial glucose. The analysis population consisted of all randomized and treated participants who underwent MMTT for the analysis endpoint, had both baseline and Week 24 endpoint measurements, without: drug compliance <75%, use of prohibited AHA medications or pharmacologic doses of corticosteroids or incorrect double-blind study drug or a change in metformin or sulfonylurea dose.
    End point type
    Secondary
    End point timeframe
    Immediately before and 60 and 120 minutes after the standard meal at Baseline and Week 24
    End point values
    		 Sitagliptin Dapagliflozin
    Number of subjects analysed
    83
    81
    Units: Ratio
        least squares mean (confidence interval 95%)
    -0.6 (-1.1 to -0.0)
    -1.2 (-1.8 to -0.7)
    Statistical analysis title
    		 Difference in LSM (Sit. - Dap.)
    Statistical analysis description
    The ANCOVA model included terms for treatment, background AHA, and the baseline insulin AUC to glucagon AUC ratio value as a covariate.
    Comparison groups
    Sitagliptin v Dapagliflozin
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in the LSM (Sit. - Dap.)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 1.3

    Secondary: Percentage of Participants with A1C <7% (53 mmol/mol) at Week 24.

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    End point title
    		 Percentage of Participants with A1C <7% (53 mmol/mol) at Week 24.
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. The percentage of participants was estimated using standard multiple imputation techniques from cLDA model including terms for treatment, time, background AHA, the interaction of time and background AHA, and the interaction of time by treatment with the constraint that the mean baseline is the same for all treatment groups. The analysis population included all randomized and treated participants who had at least one observation for the analysis endpoint, at baseline or subsequent to at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Sitagliptin Dapagliflozin
    Number of subjects analysed
    307
    306
    Units: Percentage of Participants
        number (not applicable)
    42.6
    27.0
    Statistical analysis title
    		 Difference in % (Sitagliptin - Dapagliflozin)
    Statistical analysis description
    Miettinen and Nurminen (M&N) method with multiple imputation from a LDA Model. The percentage of participants was estimated using standard multiple imputation techniques from LDA model including terms for treatment, time, background AHA, the interaction of time and background AHA, and the interaction of time by treatment.
    Comparison groups
    Sitagliptin v Dapagliflozin
    Number of subjects included in analysis
    613
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in % (Sit. - Dap.)
    Point estimate
    15.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.7
         upper limit
    		 23.2

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

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    End point title
    		 Change from Baseline in Fasting Plasma Glucose (FPG) at Week 24
    End point description
    Blood glucose was measured on a fasting basis. Blood was drawn at predose on Day 1 and after 24 weeks of treatment to determine change in plasma glucose levels (i.e., FPG at Week 24 minus FPG at Week 0). The analysis population included all randomized and treated participants who had at least one observation for the analysis endpoint, at baseline or subsequent to at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Sitagliptin Dapagliflozin
    Number of subjects analysed
    307
    306
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -16.5 (-20.6 to -12.5)
    -20.1 (-24.3 to -15.9)
    Statistical analysis title
    		 Difference in the LSM CFB at Week 24
    Statistical analysis description
    Difference in LSM (Sitagliptin - Dapagliflozin) change from Baseline at Week 24 are compared. Based on a LDA model including terms for treatment, time, background AHA, the interaction of time and background AHA, and the interaction of time by treatment.
    Comparison groups
    Sitagliptin v Dapagliflozin
    Number of subjects included in analysis
    613
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the LSM (Sit. - Dap.)
    Point estimate
    3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 8.3

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 26 weeks
    Adverse event reporting additional description
    The population analyzed included all randomized and treated participants.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Dapagliflozin
    Reporting group description
    		 -

    Reporting group title
    Sitagliptin
    Reporting group description
    		 -

    Serious adverse events
    		 Dapagliflozin Sitagliptin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 306 (4.25%)
    10 / 307 (3.26%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (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 / 306 (0.33%)
    0 / 307 (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
    Epiphyseal fracture
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 306 (0.33%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 307 (0.33%)
         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 / 306 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (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
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enterocolitis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reflux gastritis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (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
    Atypical pneumonia
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dapagliflozin Sitagliptin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 306 (6.86%)
    22 / 307 (7.17%)
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    21 / 306 (6.86%)
    22 / 307 (7.17%)
         occurrences all number
    64
    51

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Mar 2016
    Amendment 02: The primary reason for amendment was to increase participant enrollment by expansion of background AHAs to include patients on either metformin monotherapy or metformin in dual combination with a sulfonylurea agent and the A1C upper limit to 9.5%.

    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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