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    Clinical Trial Results:
    A Randomized, Multi-Center, Parallel Group, Single-Dose, Pharmacokinetics and Pharmacodynamics Study of Dapagliflozin in Children and Adolescents Aged 10 to 17 Years with Type 2 Diabetes Mellitus

    Summary
    EudraCT number
    		 2011-005225-40
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    13 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Oct 2016
    First version publication date
    15 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MB102-091
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01525238
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb International, ctt.group@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb International, ctt.group@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000694-PIP01-09
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary purpose of this study is to evaluate the pharmacokinetics of dapagliflozin in pediatric subjects with T2DM
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Jul 2012
    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: 44
    Country: Number of subjects enrolled
    Mexico: 9
    Worldwide total number of subjects
    53
    EEA total number of subjects
    0
    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)
    5
    Adolescents (12-17 years)
    48
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 53 participants enrolled; 24 randomized; 24 treated with study drug. 29 participants were not randomized due to no longer meeting study criteria (25), withdrawal of consent (2), or other reasons (2).

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open-label study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dapagliflozin 2.5 mg
    Arm description
    		 Dapagliflozin: Tablet, Oral, 2.5 mg, Single-dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Farxiga, Forxiga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dapagliflozin was administered to each subject at the clinical facility on the morning of Day 1. Subjects were required to fast for at least 8 hours prior to study drug administration and until 2 hours after study drug administration.

    Arm title
    		 Dapagliflozin 5 mg
    Arm description
    		 Dapagliflozin: Tablet, Oral, 5 mg, Single-dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Farxiga, Forxiga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dapagliflozin was administered to each subject at the clinical facility on the morning of Day 1. Subjects were required to fast for at least 8 hours prior to study drug administration and until 2 hours after study drug administration.

    Arm title
    		 Dapagliflozin 10 mg
    Arm description
    		 Dapagliflozin: Tablet, Oral, 10 mg, Single-dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Farxiga, Forxiga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dapagliflozin was administered to each subject at the clinical facility on the morning of Day 1. Subjects were required to fast for at least 8 hours prior to study drug administration and until 2 hours after study drug administration.

    Number of subjects in period 1 [1]
    		Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Started
    8
    8
    8
    Completed
    7
    8
    8
    Not completed
    1
    0
    0
         Subject withdrew from study for personal reasons
    1
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of the 53 participants enrolled, only 24 continued to the treatment period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dapagliflozin 2.5 mg
    Reporting group description
    		 Dapagliflozin: Tablet, Oral, 2.5 mg, Single-dose

    Reporting group title
    Dapagliflozin 5 mg
    Reporting group description
    		 Dapagliflozin: Tablet, Oral, 5 mg, Single-dose

    Reporting group title
    Dapagliflozin 10 mg
    Reporting group description
    		 Dapagliflozin: Tablet, Oral, 10 mg, Single-dose

    Reporting group values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg Total
    Number of subjects
    		 8 8 8 24
    Age categorical
    All treated participants
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 1 1 2
        Adolescents (12-17 years)
    		 8 7 7 22
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 5 5 5 15
        Male
    		 3 3 3 9

    End points

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    End points reporting groups
    Reporting group title
    Dapagliflozin 2.5 mg
    Reporting group description
    		 Dapagliflozin: Tablet, Oral, 2.5 mg, Single-dose

    Reporting group title
    Dapagliflozin 5 mg
    Reporting group description
    		 Dapagliflozin: Tablet, Oral, 5 mg, Single-dose

    Reporting group title
    Dapagliflozin 10 mg
    Reporting group description
    		 Dapagliflozin: Tablet, Oral, 10 mg, Single-dose

    Primary: Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin

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    End point title
    		 Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin [1]
    End point description
    Maximum observed plasma concentration (Cmax) was measured by plasma concentration of Dapagliflozin over time. The geometric means are reported in nanograms per milliliter (ng/mL). All treated subjects with evaluable PK profiles were analyzed.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 3
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    7
    8
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    24.8 ± 34
    48.4 ± 41
    118 ± 35
    No statistical analyses for this end point

    Primary: Median Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin

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    End point title
    		 Median Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin [2]
    End point description
    Time of maximum observed plasma concentration (Tmax) for Dapagliflozin was derived from plasma concentrations versus time data. Medians were reported in hours (h). All treated subjects with evaluable PK profiles were analyzed.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 3
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    7
    8
    8
    Units: hours
        median (full range (min-max))
    1.5 (0.75 to 2)
    0.96 (0.58 to 1.53)
    0.875 (0.75 to 4)
    No statistical analyses for this end point

    Primary: Geometric Mean of AUC(INF) of Dapagliflozin

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    End point title
    		 Geometric Mean of AUC(INF) of Dapagliflozin [3]
    End point description
    Area under the plasma concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] was derived from concentration versus time data. Geometric means are reported in nanogram hours per milliliter (ng*hr/mL). All treated subjects with evaluable PK profiles were analyzed.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 3
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    7
    8
    8
    Units: ng*hr/mL
        geometric mean (geometric coefficient of variation)
    101 ± 23
    199 ± 29
    427 ± 31
    No statistical analyses for this end point

    Primary: Geometric Mean of AUC(0-T) of Dapagliflozin

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    End point title
    		 Geometric Mean of AUC(0-T) of Dapagliflozin [4]
    End point description
    Area under the concentration-time curve from time zero to time of the last quantifiable concentration [AUC(0-T)] was measured by plasma concentration of Dapagliflozin over time. The geometric means are reported in nanogram hours per milliliter (ng*h/mL). All treated subjects with evaluable PK profiles were analyzed.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 3
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    7
    8
    8
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    92.3 ± 27
    189 ± 31
    418 ± 31
    No statistical analyses for this end point

    Primary: Mean Plasma Half-life (T-HALF) of Dapagliflozin

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    End point title
    		 Mean Plasma Half-life (T-HALF) of Dapagliflozin [5]
    End point description
    Plasma half-life (T-Half) for Dapagliflozin was derived from plasma concentrations versus time data. Means are reported in hours. All treated subjects with evaluable PK profiles were analyzed.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 3
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    7
    8
    8
    Units: hours
        arithmetic mean (standard deviation)
    14.1 ± 5.59
    10.3 ± 3.72
    10.7 ± 2.16
    No statistical analyses for this end point

    Primary: Geometric Mean of Apparent Clearance After Extravascular Administration (CL/F) of Dapagliflozin

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    End point title
    		 Geometric Mean of Apparent Clearance After Extravascular Administration (CL/F) of Dapagliflozin [6]
    End point description
    Apparent clearance after extravascular administration (CL/F) of Dapagliflozin was derived from plasma concentrations versus time data. Geometric means are reported in milliliters per minute (mL/min). All treated subjects with evaluable PK profiles were analyzed.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 3
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    7
    8
    8
    Units: mL/min
        geometric mean (geometric coefficient of variation)
    413 ± 26
    418 ± 27
    391 ± 25
    No statistical analyses for this end point

    Primary: Geometric Mean of Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F)

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    End point title
    		 Geometric Mean of Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F) [7]
    End point description
    Geometric mean of apparent volume of distribution at terminal phase after extravascular administration (Vz/F) of Dapagliflozin was derived from plasma concentration versus time data. Geometric means are reported in Liters (L). All treated subjects with evaluable PK profiles were analyzed.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 3
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    7
    8
    8
    Units: Liters
        geometric mean (geometric coefficient of variation)
    468 ± 34
    343 ± 45
    355 ± 34
    No statistical analyses for this end point

    Secondary: Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin 3-O-Glucuronide

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    End point title
    		 Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin 3-O-Glucuronide
    End point description
    Maximum observed plasma concentration (Cmax) was measured by plasma concentration of Dapagliflozin 3-O-Glucuronide over time. The geometric means are reported in nanograms per milliliter (ng/mL). All treated subjects with evaluable PK profiles were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 3
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    7
    8
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    24.6 ± 45
    49 ± 50
    154 ± 27
    No statistical analyses for this end point

    Secondary: Median Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin 3-O-Glucuronide

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    End point title
    		 Median Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin 3-O-Glucuronide
    End point description
    Time of maximum observed plasma concentration (Tmax) for Dapagliflozin 3-O-Glucuronide was derived from plasma concentrations versus time data. Medians were reported in hours (h). All treated subjects with evaluable PK profiles were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 3
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    7
    8
    8
    Units: hours
        median (full range (min-max))
    1.5 (1 to 4)
    1.5 (0.83 to 4)
    1.5 (1.47 to 4)
    No statistical analyses for this end point

    Secondary: Geometric Mean of AUC(INF) of Dapagliflozin 3-O-Glucuronide

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    End point title
    		 Geometric Mean of AUC(INF) of Dapagliflozin 3-O-Glucuronide
    End point description
    Area under the plasma concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] was derived from concentration versus time data. Geometric means are reported in nanogram hours per milliliter (ng*hr/mL). All treated subjects with evaluable PK profiles were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 3
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    7
    8
    8
    Units: ng*hr/mL
        geometric mean (geometric coefficient of variation)
    105 ± 23
    232 ± 30
    658 ± 21
    No statistical analyses for this end point

    Secondary: Geometric Mean of AUC(0-T) of Dapagliflozin 3-O-Glucuronide

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    End point title
    		 Geometric Mean of AUC(0-T) of Dapagliflozin 3-O-Glucuronide
    End point description
    Area under the concentration-time curve from time zero to time of the last quantifiable concentration [AUC(0-T)] was measured by plasma concentration of Dapagliflozin 3-O-Glucuronide over time. The geometric means are reported in nanogram hours per milliliter (ng*h/mL). All treated subjects with evaluable PK profiles were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 3
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    7
    8
    8
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    95.8 ± 20
    208 ± 32
    612 ± 24
    No statistical analyses for this end point

    Secondary: Mean Plasma Half-life (T-HALF) of Dapagliflozin 3-O-Glucuronide

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    End point title
    		 Mean Plasma Half-life (T-HALF) of Dapagliflozin 3-O-Glucuronide
    End point description
    Plasma half-life (T-Half) for Dapagliflozin was derived from plasma concentration versus time data. Means are reported in hours. All treated subjects with evaluable PK profiles were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 3
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    7
    8
    8
    Units: hours
        arithmetic mean (standard deviation)
    4.62 ± 3.09
    8.71 ± 2.02
    8.37 ± 3.33
    No statistical analyses for this end point

    Secondary: Mean Fasting Plasma Glucose Concentrations at Pre-dose on Day 1 and on Day 2 After an 8-hr Fast

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    End point title
    		 Mean Fasting Plasma Glucose Concentrations at Pre-dose on Day 1 and on Day 2 After an 8-hr Fast
    End point description
    Plasma glucose concentrations were evaluated in all treated subjects at Day 1 pre-dose and at Day 2 after fasting for 8 hours. Means are reported in milligrams per deciliter (mg/dL). All treated subjects with evaluable PD profiles were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 (Pre-dose) to Day 2
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    6
    8
    8
    Units: mg/dL
    arithmetic mean (standard deviation)
        Day 1 (Pre-Dose) (n= 6, 8, 8)
    146.2 ± 72.56
    152.1 ± 49.06
    139.8 ± 39.63
        Day 2 after 8 hour fast (n= 3, 8, 7)
    124 ± 45.21
    119.4 ± 17.18
    119 ± 29.15
    No statistical analyses for this end point

    Secondary: Mean Change in Fasting Plasma Glucose From Baseline Until Day 2

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    End point title
    		 Mean Change in Fasting Plasma Glucose From Baseline Until Day 2
    End point description
    Plasma glucose concentrations were evaluated in all treated subjects at Day 1 pre-dose and at Day 2 after fasting for 8 hours. Mean change from baseline to Day 2 is reported in milligrams per deciliter (mg/dL). All treated subjects with evaluable PD profiles were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 (Pre-dose) to Day 2
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    3
    8
    7
    Units: mg/dL
        arithmetic mean (standard deviation)
    -46.7 ± 60.08
    -32.8 ± 42.41
    -22 ± 27.32
    No statistical analyses for this end point

    Secondary: Mean Total Amount of Glucose Excreted in Urine Over 24 Hours

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    End point title
    		 Mean Total Amount of Glucose Excreted in Urine Over 24 Hours
    End point description
    The total amount of glucose excreted in urine was measured for 24 hours following administration of Dapagliflozin. Means are reported in grams. All treated subjects with evaluable PD profiles were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 2
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    5
    8
    7
    Units: grams
        arithmetic mean (standard deviation)
    52.84 ± 27.18
    62.39 ± 26.55
    89.04 ± 41.25
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormalities in Vital Signs, Electrocardiograms (ECG), or Physical Examinations

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    End point title
    		 Number of Participants With Abnormalities in Vital Signs, Electrocardiograms (ECG), or Physical Examinations
    End point description
    Participants were followed from dosing on Day 1 until study discharge on Day 3. The number of participants with investigator-assessed clinically-important abnormalities in vital sign measurements, ECGs or physical examinations was reported. All treated participants were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 3
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    8
    8
    8
    Units: participants
        Vital sign abnormalities
    0
    0
    0
        ECG abnormalities
    0
    0
    0
        Physical exam abnormalities
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Marked Hematology Laboratory Abnormalities

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    End point title
    		 Number of Participants With Marked Hematology Laboratory Abnormalities
    End point description
    LLN=Lower Limit of Normal, ULN=Upper Limit of Normal, Pre-Rx=Value before first dose (Day -1). All treated participants were analyzed. Lab values that met the following criteria were marked as abnormalities: Hemoglobin (grams per deciliter:g/dL): <0.85*Pre-Rx. Hematocrit (%): <0.85*Pre-Rx. Platelet Count (x10^9 cells per liter:c/L): <0.85*LLN or >1.5*ULN (if Pre-Rx<LLN, use <0.85*Pre-Rx). Leukocytes (x10^3 cells per microliter: c/uL): <0.9*LLN, >1.2*ULN (if Pre-Rx<LLN, use <0.85*Pre-Rx or >ULN, if Pre-Rx>ULN, use >1.15*Pre-Rx or <LLN). Neutrophils (Absolute) (x10^3 c/uL): <=1.5. Lymphocytes (Absolute) (x10^3 c/ uL): <0.75 or >7.5. Monocytes (Absolute) (x10^3 c/uL): >2.000. Basophils (x10^3 c/uL): >0.4. Eosinophils (Absolute) (x10^3 c/uL): >0.75. Blasts (Absolute) (x10^9 c/L) > 0.
    End point type
    Secondary
    End point timeframe
    Day 1 (Pre-dose) to Day 3
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    8
    8
    8
    Units: participants
        Hemoglobin, low (n=8, 8, 8)
    0
    0
    0
        Hematocrit, low (n=8, 7, 8)
    0
    0
    0
        Platelet count, low (n=8, 8, 7)
    0
    0
    0
        Platelet count, high (n=8, 8, 7)
    0
    0
    0
        Leukocytes, low (n=8, 8, 8)
    1
    0
    1
        Leukocytes, high (n=8, 8, 8)
    0
    0
    0
        Basophils, high (n=8, 8, 8)
    0
    0
    0
        Blasts, high (n=0, 0, 0)
    0
    0
    0
        Eosinophils, high (n=8, 8, 8)
    0
    0
    0
        Lymphocytes, low (n=8, 8, 8)
    0
    0
    0
        Monocytes, high (n=8, 8, 8)
    0
    0
    0
        Neutrophils, low (n=8, 8, 8)
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Marked Serum Chemistry Abnormalities

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    End point title
    		 Number of Participants With Marked Serum Chemistry Abnormalities
    End point description
    All treated participants were analyzed. Lab values that met the following criteria were marked as abnormalities: Alkaline Phosphatase (units per liter: U/L), Aspartate Aminotransferase (U/L), Alanine Aminotransferase (U/L): >1.25*ULN (if Pre-Rx>ULN, use >1.25*Pre-Rx). Bilirubin (milligrams per deciliter: mg/dL): >1.1*ULN (if Pre-Rx>ULN, use >1.25*Pre-Rx). Blood Urea Nitrogen (mg/dL): >1.1*ULN (if Pre-Rx>ULN, use >1.2*Pre-Rx). Creatinine (micromoles per Liter (umol/ L)): >1.5*ULN if Pre-Rx missing or <= ULN, >1.33*Pre-Rx if PreRx > ULN. Sodium (mmol/L): >1.05*ULN, 1.05*Pre-Rx if Pre-Rx>ULN: <0.95*Pre-Rx, >ULN. If Pre-Rx>ULN: >1.05*Pre-Rx, <LLN). Potassium(mmol/L), Chloride (mmol/L), Calcium(mmol/L): <0.9*LLN, >1.1*ULN (if Pre-Rx<LLN: <0.9*Pre-Rx, >ULN. If Pre-Rx>ULN: >1.1*Pre-Rx, <LLN). Phosphorus (mg/dL): <0.85*LLN, >1.25*ULN (if Pre-Rx<LLN, <0.85*Pre-Rx, >ULN. if Pre-Rx>ULN: >1.25*Pre-Rx, <LLN).
    End point type
    Secondary
    End point timeframe
    Day 1 (Pre-dose) to Day 3
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    8
    8
    8
    Units: participants
        ALP, high (n=8, 8, 8)
    0
    0
    0
        ALT, high (8, 8, 8)
    1
    0
    0
        AST, high (n=8, 8, 8)
    1
    0
    0
        Bilirubin, high (n=8, 8, 8)
    0
    0
    0
        Blood Urea Nitrogen, high (n=8, 8, 8)
    0
    0
    0
        Calcium, low (n=8, 8, 8)
    0
    0
    0
        Creatinine, high (n=8, 8, 8)
    0
    0
    0
        Chloride, low (n=8, 8, 8)
    0
    0
    0
        Calcium, high (n=8, 8, 8)
    0
    0
    0
        Potassium, low (n=8, 8, 8)
    0
    0
    0
        Potassium, high (n=8, 8, 8)
    0
    0
    0
        Sodium, low (n=8, 8, 8)
    0
    0
    0
        Sodium, high (n=8, 8, 8)
    0
    0
    0
        Phosphorus, Inorganic, low (n=8, 8, 8)
    0
    0
    0
        Phosphorus, Inorganic, high (n=8, 8, 8)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Marked Abnormalities in Other Chemistry Testing

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    End point title
    		 Number of Participants With Marked Abnormalities in Other Chemistry Testing
    End point description
    All treated participants were analyzed. Lab values that met the following criteria were marked as abnormalities: Glucose, fasting serum (mmol/L): <0.8*LLN, >1.3*ULN (if Pre-Rx<LLN: <0.8*Pre-Rx, >ULN. If Pre-Rx>ULN: >2.0*Pre-Rx, <LLN). Protein (grams per deciliter: g/L): <0.9*LLN, >1.1*ULN (if Pre-Rx<LLN: <0.9*Pre-Rx, >ULN. If Pre-Rx>ULN: >1.1*Pre-Rx, <LLN). Albumin (g/L): <0.9*LLN (if Pre-Rx<LLN: <0.9*Pre-Rx). Uric Acid (mmol/L): >1.2*ULN (if Pre-Rx>ULN: >1.25*Pre-Rx). Lactate Dehydrogenase (U/L): >1.25*ULN (if Pre-Rx>ULN: >1.5*Pre-Rx)
    End point type
    Secondary
    End point timeframe
    Day 1 (Pre-dose) to Day 3
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    8
    8
    8
    Units: participants
        Glucose, fasting serum, low (n=7, 7, 7)
    0
    0
    0
        Glucose, fasting serum, high (n=7, 7, 7)
    1
    1
    0
        Albumin (n= 8, 8, 8)
    0
    0
    0
        Protein, total (8, 8, 8)
    0
    0
    0
        Uric acid (n=7, 8, 7)
    0
    0
    0
        Lactate dehydrogenase (n=8, 8, 8)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Marked Urinalysis Abnormalities

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    End point title
    		 Number of Participants With Marked Urinalysis Abnormalities
    End point description
    All treated participants with evaluable urinalysis profiles were analyzed. Lab values that met the following criteria were marked as abnormalities: Blood, urine (Qualitative): >=2 (If Pre-Rx >= 1, >=2*Pre-Rx). Glucose, urine (Qualitative): >=1, (If Pre-Rx >=1, >=2*Pre- Rx). Protein, urine (Qualitative): >=2 (If Pre-Rx >=1, >=2*Pre-Rx). Red Blood Cells (RBC), urine (RBC per High Power Field (hpf)): >=2 (If Pre-Rx>=2, >=4). White Blood Cells (WBC), urine (hpf): >=2 (If Pre-Rx>=2, >=4).
    End point type
    Secondary
    End point timeframe
    Day 1 (Pre-dose) to Day 3
    End point values
    		 Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
    Number of subjects analysed
    8
    8
    8
    Units: participants
        Blood, urine, high (n= 8, 8, 8)
    0
    0
    2
        Glucose, urine, high (n=8, 8, 8)
    2
    3
    4
        Protein, urine, high (n=8, 8, 8)
    0
    0
    3
        RBC, urine, high (n=1, 1, 4)
    0
    0
    3
        WBC, urine, high (n=4, 2, 3)
    1
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 30 days after the last dose of the study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Dapagliflozin 2.5 mg
    Reporting group description
    		 Dapagliflozin: Tablet, Oral, 2.5 mg, Single-dose

    Reporting group title
    Dapagliflozin 10 mg
    Reporting group description
    		 Dapagliflozin: Tablet, Oral, 10 mg, Single-dose

    Reporting group title
    Dapagliflozin 5 mg
    Reporting group description
    		 Dapagliflozin: Tablet, Oral, 5 mg, Single-dose

    Serious adverse events
    		 Dapagliflozin 2.5 mg Dapagliflozin 10 mg Dapagliflozin 5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dapagliflozin 2.5 mg Dapagliflozin 10 mg Dapagliflozin 5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 8 (37.50%)
    1 / 8 (12.50%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Peripheral swelling
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Skin irritation
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2012
    Removed the following urinary PK parameters: %UR and CLR(0-24h)
    11 Jul 2012
    Removed the caffeine consumption restriction from the exclusion criteria and specified that the Day -1 labs will be non-fasting. Also clarified that subjects have the option to report to the clinical facility early in the morning on Day 1 for dosing.
    08 Aug 2012
    Clarified several eligibility criteria in the protocol
    17 Jan 2013
    Clarified that diagnosis of type 2 diabetes will be based on WHO or ADA criteria. Changed the lower bound of the HbA1c range from 6.5% to 6% and removed the requirement for BMI 85th percentile for inclusion. Revised the sampling schedule and pharmacokinetic parameters for dried blood spot (DBS) samples. Clarifications to endpoint objectives and analyses were made. Administrative updates included.
    22 Oct 2013
    Removed insulin treatment as exclusion requirement and provided allowance to decrease insulin and adjust dosage schedule as needed on Day -1. Added EUDRACT number.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27291448
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