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    Clinical Trial Results:
    DAPASALT: An Open Label, Phase IV, Mechanistic, Three-Arm Study to Evaluate the Natriuretic Effect of 2-Week Dapagliflozin treatment in Type 2 Diabetes Mellitus Patients with Either Preserved or Impaired Renal Function and Non-Diabetics with Impaired Renal Function

    Summary
    EudraCT number
    		 2016-002961-79
    Trial protocol
    		 NL   SE  
    Global end of trial date
    20 Mar 2020

    Results information
    Results version number
    		 v1
    This version publication date
    02 Apr 2021
    First version publication date
    02 Apr 2021
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    D1690C00049
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03152084
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    151 85, Södertälje, Sweden,
    Public contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, 1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, 1 8772409479, information.center@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
    27 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Mar 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of the study is to to evaluate the changes in average 24-hour sodium excretion during dapagliflozin treatment in subjects with T2DM with preserved or impaired kidney function and in non-diabetics with impaired kidney function.
    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 (ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca policy on Bioethics.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Jul 2017
    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
    Netherlands: 23
    Country: Number of subjects enrolled
    Sweden: 1
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    11
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted between 12-Jul-2017 and 20-Mar-2020. Subjects who met all the inclusion and none of the exclusion criteria were enrolled in the study.

    Pre-assignment
    Screening details
    		 No subjects in Group 1 (Type 2 diabetes mellitus (T2DM) subjects with impaired kidney function) were enrolled into the Run-in set due to failure to meet inclusion/exclusion criteria, screen failure, or other reasons and it was decided that no more Group 1 subjects would be enrolled in the study.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 2
    Arm description
    		 Type 2 diabetes mellitus (T2DM) subjects with preserved kidney function received oral dose of dapagliflozin 10 mg/day from Day 1 to Day 14, following which they entered Follow-up Period from Day 15 to Day 19.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Dapagliflozin propanediol monohydrate
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg oral administration

    Arm title
    		 Group 3
    Arm description
    		 Non-diabetic subjects with impaired kidney function received oral dose of dapagliflozin 10 mg/day from Day 1 to Day 14, following which they entered Follow-up Period from Day 15 to Day 19.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Dapagliflozin propanediol monohydrate
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg oral administration

    Number of subjects in period 1
    		Group 2 Group 3
    Started
    17
    7
    Completed
    17
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 2
    Reporting group description
    		 Type 2 diabetes mellitus (T2DM) subjects with preserved kidney function received oral dose of dapagliflozin 10 mg/day from Day 1 to Day 14, following which they entered Follow-up Period from Day 15 to Day 19.

    Reporting group title
    Group 3
    Reporting group description
    		 Non-diabetic subjects with impaired kidney function received oral dose of dapagliflozin 10 mg/day from Day 1 to Day 14, following which they entered Follow-up Period from Day 15 to Day 19.

    Reporting group values
    		 Group 2 Group 3 Total
    Number of subjects
    		 17 7 24
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0
        Between 18 and 80 years
    		 17 7 24
        >=80 years
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.24 ( 7.33 ) 66.00 ( 9.29 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 6 2 8
        Male
    		 11 5 16
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 1 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 16 7 23
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Group 2
    Reporting group description
    		 Type 2 diabetes mellitus (T2DM) subjects with preserved kidney function received oral dose of dapagliflozin 10 mg/day from Day 1 to Day 14, following which they entered Follow-up Period from Day 15 to Day 19.

    Reporting group title
    Group 3
    Reporting group description
    		 Non-diabetic subjects with impaired kidney function received oral dose of dapagliflozin 10 mg/day from Day 1 to Day 14, following which they entered Follow-up Period from Day 15 to Day 19.

    Subject analysis set title
    Group 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Type 2 diabetes mellitus (T2DM) subjects with preserved kidney function received oral dose of dapagliflozin 10 mg/day from Day 1 to Day 14, following which they entered Follow-up Period from Day 15 to Day 19.

    Primary: Change in 24-hour sodium excretion from baseline to start of treatment

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    End point title
    		 Change in 24-hour sodium excretion from baseline to start of treatment
    End point description
    Average change in 24-hour sodium excretion during dapagliflozin treatment from average baseline to average values at Days 2 to 4 within each study group in subjects with T2DM with preserved kidney function and in non-diabetics with impaired kidney function was assessed.
    End point type
    Primary
    End point timeframe
    From baseline (Day -3 to Day -1) to start of treatment (Day 2 to Day 4)
    End point values
    		 Group 2 Group 3 Group 2
    Number of subjects analysed
    15
    6
    15
    Units: mmol/24 hour
        median (full range (min-max))
    -5.33 (-53.667 to 44.000)
    -27.67 (-69.334 to 13.334)
    -5.33 (-53.667 to 44.000)
    Statistical analysis title
    		 Statistical analysis of change in urine sodium
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.4462 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean
    Point estimate
    -5.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.542
         upper limit
    		 9.12
    Notes
    [1] - Within-group change (Group 2): 15 subjects were included in this analysis
    [2] - Start of treatment vs baseline

    Secondary: Change in 24-hour sodium excretion from baseline to end of treatment and during follow-up

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    End point title
    		 Change in 24-hour sodium excretion from baseline to end of treatment and during follow-up
    End point description
    Average change in 24-hour sodium excretion from average baseline values to average end of treatment values (Day 12 to 14); and from average end of treatment values (Day 12 to 14) to average values during follow-up (Day 15 to 17).
    End point type
    Secondary
    End point timeframe
    From baseline (Day -3 to Day -1) to end of treatment (Day 12 to 14); and from end of treatment (Day 12 to 14) to follow-up (Day 15 to 17)
    End point values
    		 Group 2 Group 3 Group 2
    Number of subjects analysed
    15
    6
    15
    Units: mmol/24 hour
    median (full range (min-max))
        End of treatment vs baseline
    2.67 (-64.000 to 143.167)
    -23.83 (-107.000 to 0.667)
    2.67 (-64.000 to 143.167)
        Follow-up vs end of treatment
    1.33 (-135.334 to 25.000)
    6.17 (-70.333 to 20.333)
    1.33 (-135.334 to 25.000)
    Statistical analysis title
    		 Statistical analysis of change in urine sodium
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.7842 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean
    Point estimate
    3.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.817
         upper limit
    		 32.195
    Notes
    [3] - Within-group change (Group 2): 15 subjects were included in this analysis
    [4] - End of treatment vs baseline
    Statistical analysis title
    		 Statistical analysis of change in urine sodium
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.0581 [6]
    Method
    		 Regression, Linear
    Parameter type
    		 Least square mean
    Point estimate
    -16.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.109
         upper limit
    		 0.664
    Notes
    [5] - Within-group change (Group 2): 15 subjects were included in this analysis
    [6] - Follow-up vs End of treatment

    Secondary: Change in 24-hour glucose excretion

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    End point title
    		 Change in 24-hour glucose excretion
    End point description
    Average change in 24-hour glucose excretion from average baseline values to average values at Day 2 to 4; from average baseline values to average end of treatment values (Day 12 to 14); and from average end of treatment values (Day 12 to 14) to average values during follow-up (Day 15 to 17). Here, n represents subjects with available data that were analyzed for the end point.
    End point type
    Secondary
    End point timeframe
    From baseline (Day -3 to Day -1) to start of treatment (Day 2 to 4); from baseline (Day -3 to Day -1) to end of treatment (Day 12 to 14); and from end of treatment (Day 12 to 14) to follow-up (Day 15 to 17)
    End point values
    		 Group 2 Group 3 Group 2
    Number of subjects analysed
    15
    6
    15
    Units: mmol/24 hour
    median (full range (min-max))
        Start of treatment vs baseline (n=15;5)
    302.61 (191.472 to 635.726)
    43.93 (12.050 to 132.333)
    302.61 (191.472 to 635.726)
        End of treatment vs baseline (n=15;4)
    283.40 (155.876 to 762.801)
    29.88 (15.450 to 113.300)
    283.40 (155.876 to 762.801)
        Follow-up vs end of treatment (n=15;5)
    -168.43 (-376.561 to -107.596)
    -37.02 (-74.733 to -10.584)
    -168.43 (-376.561 to -107.596)
    Statistical analysis title
    		 Statistical Analysis of Change in Urine Glucose
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean
    Point estimate
    344.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 272.785
         upper limit
    		 416.905
    Notes
    [7] - Within-group change (Group 2): 15 subjects were included in this analysis
    [8] - Start of treatment vs baseline
    Statistical analysis title
    		 Statistical Analysis of Change in Urine Glucose
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 < 0.0001 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean
    Point estimate
    311.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 224.528
         upper limit
    		 398.064
    Notes
    [9] - Within-group change (Group 2): 15 subjects were included in this analysis
    [10] - End of treatment vs baseline
    Statistical analysis title
    		 Statistical Analysis of Change in Urine Glucose
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 < 0.0001 [12]
    Method
    		 Regression, Linear
    Parameter type
    		 Least square mean
    Point estimate
    -203.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -235.983
         upper limit
    		 -170.162
    Notes
    [11] - Within-group change (Group 2): 15 subjects were included in this analysis
    [12] - Follow-up vs end of treatment

    Secondary: Change in mean 24-hour systolic blood pressure

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    End point title
    		 Change in mean 24-hour systolic blood pressure
    End point description
    Change in mean 24-hour systolic blood pressure from baseline to Day 4; from baseline to end of treatment (Day 13); and from end of treatment (Day 13) to end of follow-up (Day 18). Here, n represents subjects with available data that were analyzed for the end point.
    End point type
    Secondary
    End point timeframe
    From baseline (Day -1) to start of treatment (Day 4); from baseline (Day -1) to end of treatment (Day 13); and from end of treatment (Day 13) to end of follow-up (Day 18)
    End point values
    		 Group 2 Group 3 Group 2
    Number of subjects analysed
    15
    6
    15
    Units: mmHg
    median (full range (min-max))
        Start of treatment vs baseline (n=13;6)
    -5.4810 (-13.6610 to 5.6100)
    -8.9730 (-24.6570 to 2.7210)
    -5.4810 (-13.6610 to 5.6100)
        End of treatment vs baseline (n=12;6)
    -5.9385 (-16.0060 to 0.9160)
    -10.3290 (-23.4160 to 16.2160)
    -5.9385 (-16.0060 to 0.9160)
        Follow-up vs end of treatment (n=11;5)
    2.5140 (-10.3420 to 8.4590)
    -2.6590 (-16.3110 to 7.4680)
    2.5140 (-10.3420 to 8.4590)
    Statistical analysis title
    		 Statistical Analysis of 24-hour Blood Pressure
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.0047 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean
    Point estimate
    -5.2658
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.5459
         upper limit
    		 -1.9856
    Notes
    [13] - Within-group change (Group 2): 15 subjects were included in this analysis
    [14] - Start of treatment vs baseline
    Statistical analysis title
    		 Statistical Analysis of 24-hour Blood Pressure
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.0003 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean
    Point estimate
    -7.0987
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.0379
         upper limit
    		 -4.1595
    Notes
    [15] - Within-group change (Group 2): 15 subjects were included in this analysis
    [16] - End of treatment vs baseline
    Statistical analysis title
    		 Statistical Analysis of 24-hour Blood Pressure
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.5592 [18]
    Method
    		 Regression, Linear
    Parameter type
    		 Least square mean
    Point estimate
    0.7287
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9894
         upper limit
    		 3.4468
    Notes
    [17] - Within-group change (Group 2): 15 subjects were included in this analysis
    [18] - Follow-up vs end of treatment

    Secondary: Change in plasma volume

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    End point title
    		 Change in plasma volume
    End point description
    Change in plasma volume from baseline to Day 4; from baseline to end of treatment (Day 14); and from end of treatment (Day 14) to end of follow-up (Day 18). Arbitrary number 99.99999 represents that data not available as no subjects were evaluated. Here, n represents subjects with available data that were analyzed for the end point.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) to start of treatment (Day 4); from baseline (Day 1) to end of treatment (Day 14); and from end of treatment (Day 14) to end of follow-up (Day 18)
    End point values
    		 Group 2 Group 3 Group 2
    Number of subjects analysed
    15
    6
    15
    Units: Litres
    median (full range (min-max))
        Start of treatment vs baseline (n=13;3)
    -0.1440 (-1.7819 to 2.6385)
    -0.1139 (-2.0340 to 0.0232)
    -0.1440 (-1.7819 to 2.6385)
        End of treatment vs baseline (n=11;1)
    -0.2122 (-2.8346 to 1.1073)
    2.0557 (2.0557 to 2.0557)
    -0.2122 (-2.8346 to 1.1073)
        Follow-up vs end of treatment (n=12;0)
    0.6464 (-1.5016 to 1.6410)
    99.9999 (99.9999 to 99.9999)
    0.6464 (-1.5016 to 1.6410)
    Statistical analysis title
    		 Statistical Analysis of Change in Plasma Volume
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.9288 [20]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean
    Point estimate
    0.0315
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7274
         upper limit
    		 0.7904
    Notes
    [19] - Within-group change (Group 2): 15 subjects were included in this analysis
    [20] - Start of treatment vs baseline
    Statistical analysis title
    		 Statistical Analysis of Change in Plasma Volume
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.1659 [22]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean
    Point estimate
    -0.4318
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.0761
         upper limit
    		 0.2125
    Notes
    [21] - Within-group change (Group 2): 15 subjects were included in this analysis
    [22] - End of treatment vs baseline
    Statistical analysis title
    		 Statistical Analysis of Change in Plasma Volume
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.019 [24]
    Method
    		 Regression, Linear
    Parameter type
    		 Least square mean
    Point estimate
    0.4755
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0963
         upper limit
    		 0.8548
    Notes
    [23] - Within-group change (Group 2): 15 subjects were included in this analysis
    [24] - Follow-up vs end of treatment

    Secondary: Change in extracellular volume

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    End point title
    		 Change in extracellular volume
    End point description
    Change in extracellular volume from baseline to Day 4; from baseline to end of treatment (Day 14); and from end of treatment (Day 14) to end of follow-up (Day 18). Here, n represents subjects with available data that were analyzed for the end point.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) to start of treatment (Day 4); from baseline (Day 1) to end of treatment (Day 14); and from end of treatment (Day 14) to end of follow-up (Day 18)
    End point values
    		 Group 2 Group 3 Group 2
    Number of subjects analysed
    15
    6
    15
    Units: Litres
    median (full range (min-max))
        Start of treatment vs baseline (n=14;6)
    -0.5783 (-2.7027 to 0.7959)
    -0.4553 (-1.3758 to 0.2282)
    -0.5783 (-2.7027 to 0.7959)
        End of treatment vs baseline (n=13;6)
    0.1248 (-1.4948 to 0.9852)
    -0.1427 (-0.6101 to 1.0055)
    0.1248 (-1.4948 to 0.9852)
        Follow-up vs end of treatment (n=13;6)
    0.1784 (-0.6507 to 0.9780)
    0.1394 (-0.3045 to 0.9014)
    0.1784 (-0.6507 to 0.9780)
    Statistical analysis title
    		 Statistical Analysis of Extracellular Fluid
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 0.0157 [26]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean
    Point estimate
    -0.6713
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1914
         upper limit
    		 -0.1511
    Notes
    [25] - Within-group change (Group 2): 15 subjects were included in this analysis
    [26] - Start of treatment vs baseline
    Statistical analysis title
    		 Statistical Analysis of Extracellular Fluid
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.87 [28]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean
    Point estimate
    -0.0324
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4631
         upper limit
    		 0.3984
    Notes
    [27] - Within-group change (Group 2): 15 subjects were included in this analysis
    [28] - End of treatment vs baseline
    Statistical analysis title
    		 Statistical Analysis of Extracellular Fluid
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    P-value
    		 = 0.2446 [30]
    Method
    		 Regression, Linear
    Parameter type
    		 Least square mean
    Point estimate
    0.1718
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1358
         upper limit
    		 0.4795
    Notes
    [29] - Within-group change (Group 2): 15 subjects were included in this analysis
    [30] - Follow-up vs end of treatment

    Secondary: Change in 24-hour urine albumin:creatinine ratio (UACR)

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    End point title
    		 Change in 24-hour urine albumin:creatinine ratio (UACR)
    End point description
    Average change in mean 24-hour urine albumin:creatinine ratio (UACR) from average baseline to Day 4; and from average baseline values to average end of treatment values (Day 12 to 14).
    End point type
    Secondary
    End point timeframe
    From baseline (Day -3 to Day -1) to start of treatment (Day 4); and from baseline (Day -3 to Day-1) to end of treatment (Day 12 to 14)
    End point values
    		 Group 2 Group 3 Group 2
    Number of subjects analysed
    15
    6
    15
    Units: mg/mmol
    median (full range (min-max))
        Start of treatment vs baseline
    -0.07 (-30.750 to 6.700)
    -5.83 (-35.300 to 0.300)
    -0.07 (-30.750 to 6.700)
        End of treatment vs baseline
    -0.04 (-17.250 to 0.737)
    -7.28 (-35.733 to 0.467)
    -0.04 (-17.250 to 0.737)
    Statistical analysis title
    		 Statistical Analysis of Change in UACR
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    P-value
    		 = 0.0023 [32]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.299
         upper limit
    		 -0.902
    Notes
    [31] - Within-group change (Group 2): 15 subjects were included in this analysis
    [32] - Start of treatment vs baseline
    Statistical analysis title
    		 Statistical Analysis of Change in in UACR
    Statistical analysis description
    Analysis type is comparison
    Comparison groups
    Group 2 v Group 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    P-value
    		 < 0.0001 [34]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean
    Point estimate
    -1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.929
         upper limit
    		 -1.256
    Notes
    [33] - Within-group change (Group 2): 15 subjects were included in this analysis
    [34] - End of treatment vs baseline

    Secondary: Pharmacokinetics of dapagliflozin on Day 4 and Day 14

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    End point title
    		 Pharmacokinetics of dapagliflozin on Day 4 and Day 14
    End point description
    Dapagliflozin plasma concentration on Day 4 (pre-dose) and Day 14 (pre-dose, 1h, 2h, 4h post-dose). Here, n represents subjects with available data that were analyzed for the end point.
    End point type
    Secondary
    End point timeframe
    At pre-dose (Day 4) and at pre-dose, 1h, 2h, 4h post-dose (Day 14)
    End point values
    		 Group 2 Group 3
    Number of subjects analysed
    17
    7
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Day 4, Pre-dose (n=17;7)
    4.58 ( 134.88 )
    19.78 ( 116.54 )
        Day 14, Pre-dose (n=16;6)
    4.54 ( 46.60 )
    15.26 ( 41.97 )
        Day 14, 1 h (n=16;6)
    57.46 ( 110.66 )
    63.83 ( 150.41 )
        Day 14, 2 h (n=16;6)
    46.47 ( 49.30 )
    60.41 ( 140.69 )
        Day 14, 4 h (n=17;6)
    29.71 ( 47.38 )
    47.83 ( 100.41 )
    No statistical analyses for this end point

    Secondary: Number of subjects with AEs and SAEs

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    End point title
    		 Number of subjects with AEs and SAEs
    End point description
    An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. SAE is an AE that results in any untoward medical occurrence that results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, or is a significant medical event.
    End point type
    Secondary
    End point timeframe
    From Day 1 until Day 18 (FU)
    End point values
    		 Group 2 Group 3
    Number of subjects analysed
    17
    7
    Units: Subjects
        Any AE
    6
    2
        AEs judged as causally related to drug
    4
    0
        AEs leading to death
    0
    0
        SAEs (including outcomes = death)
    0
    0
        SAEs causally related to drug
    0
    0
        AEs leading to permanent discontinuation of drug
    0
    0
        SAEs leading to permanent discontinuation of drug
    0
    0
        Hypoglycaemia AEs
    0
    0
        Hypoglycaemia AEs = permanent discontinuation drug
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 until Day 18 (FU)
    Adverse event reporting additional description
    SAEs and non-SAEs are reported for the Safety Set which comprised of all subjects who received at least one dose of study drug and who had data from at least one post-dose safety assessment available.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Group 2
    Reporting group description
    		 Type 2 diabetes mellitus (T2DM) subjects with preserved kidney function received oral dose of dapagliflozin 10 mg/day from Day 1 to Day 14, following which they entered Follow-up Period from Day 15 to Day 19.

    Reporting group title
    Group 3
    Reporting group description
    		 Non-diabetic subjects with impaired kidney function received oral dose of dapagliflozin 10 mg/day from Day 1 to Day 14, following which they entered Follow-up Period from Day 15 to Day 19.

    Serious adverse events
    		 Group 2 Group 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 7 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group 2 Group 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 17 (35.29%)
    2 / 7 (28.57%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Head discomfort
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Somnolence
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Infections and infestations
    Genital infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Dec 2016
    Method change for extracellular volume, from bromo-dilution to Bioimpedance Spectroscopy (BIS). • More in-depth description of study procedures. • More detailed description of potential risks related to use of indocyanine green and BIS. • Additional exploratory variables were introduced.
    04 Oct 2017
    Increased Screening Period to allow sufficient time and improve recruitment. • Treatment flexibility +/- 1 day introduced for practical reasons (patient and physician availability).
    23 Jan 2018
    Changed study population: From Caucasians only to Caucasians, Asians, Middle Eastern subjects but avoiding sub-Saharan subjects who often have a different Chronic Kidney Disease etiology and may thus respond differently. • Changed age limits: Upper age limits changed from 75 years to 80 years to improve recruitment. • Changed the estimated glomerular filtration rate (eGFR) range for ‘normal renal function’ (considering normal age related decline in renal function). • Change in exclusion criteria regarding diuretic use – changed from 4 weeks to 2 weeks prior to Screening Visit.
    28 Apr 2018
    Allowed insulin use in Group 1 in stable regimen for the last 12 weeks prior to Visit 4 (Day 1). • Rationale to improve recruitment. • Longer Run-in Period with food boxes for subjects on insulin. • Added possibility to proceed with partial (final) analysis of Groups 2 and 3 as recruitment for Group 1 is slower than expected. • Rescreening once per patient is allowed under certain circumstances.
    23 Jan 2020
    Inclusion and exclusion criteria modified (angiotensin converting enzyme inhibitor was removed as a prohibited medication and added as an alternative to already approved angiotensin receptor blocker as a required treatment).

    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.
    Due to unsatisfactory recruitment rate, it was decided that no more Group 1 subjects would be enrolled in the study. In Group 2 and 3, 17 and 7 subjects received the investigational product and completed the study, respectively.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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