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    Clinical Trial Results:
    Effect of dapagliflozin, metformin and physical activity on glucose variability, body composition and cardiovascular risk in pre-diabetes (The PRE-D Trial) - A randomised, parallel, open-label, intervention study

    Summary
    EudraCT number
    		 2015-001552-30
    Trial protocol
    		 DK  
    Global end of trial date
    13 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jan 2020
    First version publication date
    26 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PRED-D-TRIAL2015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02695810
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Steno Diabetes Center Copenhagen
    Sponsor organisation address
    Niels Steensens Vej 2, Gentofte, Denmark, 2820
    Public contact
    Sponsor, Steno Diabetes Center A/S, +45 30791461, krif@steno.dk
    Scientific contact
    Sponsor, Steno Diabetes Center A/S, +45 30791461, krif@steno.dk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall objective is to compare the short-term effectiveness of three glucose-lowering interventions (physical activity, metformin, and dapagliflozin) on glucose variability, body composition, and cardiometabolic risk factors in overweight or obese individuals with pre-diabetes (HbA1c 6.0-6.4%).
    Protection of trial subjects
    None
    Background therapy
    		 All participants received general advice on diet and physical activity based on national Danish recommendations
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 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
    Denmark: 120
    Worldwide total number of subjects
    120
    EEA total number of subjects
    120
    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)
    70
    From 65 to 84 years
    50
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Inclusion Criteria: HbA1c: from ≥5.7% (39 mmol/mol) to ≤6.4% (47 mmol/mol) Age: from ≥30 to ≤70 years of age BMI ≥25 kg/m2 Exclusion Criteria: Uncontrolled medical issues including but not limited to cardiovascular pulmonary, rheumatologic, hematologic, oncologic, infectious, gastrointestinal or psychiatric disease; diabetes or

    Pre-assignment period milestones
    Number of subjects started
    		 120
    Number of subjects completed
    		 120

    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Participants were randomised at the end of the baseline visit (V1), but were blinded for group allocation untill the end of the baseline period. Staff were blinded to group allocation at V1, but not in the following free-living period. The data analysts were blinded towards group allocation and results were evaluated before unblinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Metformin
    Arm description
    		 No active treatment in this period
    Arm type
    		 Experimental

    Investigational medicinal product name
    metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    850 mg daily for 1 week and then 850 mg twice daily for the rest of the intervention

    Arm title
    		 Dapagliflozin
    Arm description
    		 No active treatment in this period
    Arm type
    		 Experimental

    Investigational medicinal product name
    dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg once daily

    Arm title
    		 Exercise
    Arm description
    		 No active treatment in this period
    Arm type
    		 Exercise intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Control Metformin Dapagliflozin Exercise
    Started
    30
    30
    30
    30
    Completed
    30
    30
    30
    29
    Not completed
    0
    0
    0
    1
         Consent withdrawn by subject
    -
    -
    -
    1
    Period 2
    Period 2 title
    Active treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open label trial: Neither staff, nor participants were blinded to group allocation during the follow-up period. Data analysts were blinded to groupallocation and results were evaluated by the research group before unblinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Metformin
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    850 mg daily for 1 week and then 850 mg twice daily for the rest of the intervention

    Arm title
    		 Dapagliflozin
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg once daily

    Arm title
    		 Exercise
    Arm description
    		 The exercise intervention consisted of unsupervised interval training, 5 days/week, 30 min/session, with alternating 3-min intervals aiming for intensities of ≥75% and ≤60% of peak heart rate by the end of each interval.
    Arm type
    		 Exercise intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Control Metformin Dapagliflozin Exercise
    Started
    30
    30
    30
    29
    Completed
    28
    29
    28
    27
    Not completed
    2
    1
    2
    2
         Consent withdrawn by subject
    1
    -
    1
    2
         Adverse event, non-fatal
    1
    -
    1
    -
         Lost to follow-up
    -
    1
    -
    -
    Period 3
    Period 3 title
    Follow-up (No active treatment)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open label trial: Neither staff, nor participants were blinded to group allocation during the follow-up period. Data analysts were blinded to groupallocation and results were evaluated by the research group before unblinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Metformin
    Arm description
    		 No active treatment in this period
    Arm type
    		 Experimental

    Investigational medicinal product name
    metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    850 mg daily for 1 week and then 850 mg twice daily for the rest of the intervention

    Arm title
    		 Dapagliflozin
    Arm description
    		 No active treatment in this period
    Arm type
    		 Experimental

    Investigational medicinal product name
    dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg once daily

    Arm title
    		 Exercise
    Arm description
    		 No active treatment in this period
    Arm type
    		 Exercise intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Control Metformin Dapagliflozin Exercise
    Started
    28
    29
    28
    27
    Completed
    27
    29
    28
    27
    Not completed
    1
    0
    0
    0
         Consent withdrawn by subject
    1
    -
    -
    -

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Control
    Reporting group description
    		 -

    Reporting group title
    Metformin
    Reporting group description
    		 No active treatment in this period

    Reporting group title
    Dapagliflozin
    Reporting group description
    		 No active treatment in this period

    Reporting group title
    Exercise
    Reporting group description
    		 No active treatment in this period
    Reporting group title
    Control
    Reporting group description
    		 -

    Reporting group title
    Metformin
    Reporting group description
    		 -

    Reporting group title
    Dapagliflozin
    Reporting group description
    		 -

    Reporting group title
    Exercise
    Reporting group description
    		 The exercise intervention consisted of unsupervised interval training, 5 days/week, 30 min/session, with alternating 3-min intervals aiming for intensities of ≥75% and ≤60% of peak heart rate by the end of each interval.
    Reporting group title
    Control
    Reporting group description
    		 -

    Reporting group title
    Metformin
    Reporting group description
    		 No active treatment in this period

    Reporting group title
    Dapagliflozin
    Reporting group description
    		 No active treatment in this period

    Reporting group title
    Exercise
    Reporting group description
    		 No active treatment in this period

    Primary: Glycemic variability

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    End point title
    		 Glycemic variability
    End point description
    Mean amplitude of glycemic excursions calculated based on a 7-days continous glucose monitoring period.
    End point type
    Primary
    End point timeframe
    Analysed as comparisons between relative changes from baseline (period 1) to end-of-treatment (period 2) for the intervention groups compared with the control group.
    End point values
    		 Control Control Control Metformin Metformin Metformin Dapagliflozin Dapagliflozin Dapagliflozin Exercise Exercise Exercise
    Number of subjects analysed
    30
    28
    26 [1]
    30
    28
    29
    30
    26
    27 [2]
    30
    27
    27
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    1.5 (1.2 to 1.8)
    1.7 (1.4 to 2.3)
    1.9 (1.5 to 2.7)
    1.6 (1.1 to 1.8)
    1.6 (1.3 to 2.0)
    1.5 (1.4 to 1.9)
    1.7 (1.5 to 2.4)
    1.6 (1.2 to 2.2)
    1.9 (1.3 to 2.5)
    1.8 (1.4 to 2.8)
    1.7 (1.2 to 2.5)
    1.8 (1.3 to 2.0)
    Notes
    [1] - One participant missing at random
    [2] - One participant missing at random
    Statistical analysis title
    		 Primary end-point analysis - Met/Con
    Statistical analysis description
    Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Control v Metformin
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.991
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.1
         upper limit
    		 19.4
    Variability estimate
    Standard error of the mean
    Notes
    [3] - Metformin was hypothesized to be non-superior to controls for improving MAGE
    Statistical analysis title
    		 Primary end-point analysis - Dap/Con
    Statistical analysis description
    Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Control v Dapagliflozin
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.042
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    -17.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.8
         upper limit
    		 -0.7
    Variability estimate
    Standard error of the mean
    Notes
    [4] - Dapagliflozin was hypothesized to be superior to controls for improving MAGE; minimally important difference of 0.5mmol/L (approx. 30%)
    Statistical analysis title
    		 Primary end-point analysis - Exe/Con
    Statistical analysis description
    Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Control v Exercise
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.067
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    -15.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.1
         upper limit
    		 1.2
    Variability estimate
    Standard error of the mean
    Notes
    [5] - Exercise was hypothesized to be superior to controls for improving MAGE; minimally important difference of 0.5mmol/L (approx. 30%)
    Statistical analysis title
    		 Follow-up - Dap/Met
    Statistical analysis description
    Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Metformin v Dapagliflozin
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.256
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    -9.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.6
         upper limit
    		 7.8
    Variability estimate
    Standard error of the mean
    Notes
    [6] - Descriptive
    Statistical analysis title
    		 Primary end-point analysis - Exe/Met
    Statistical analysis description
    Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Metformin v Exercise
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.065
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    -15.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.1
         upper limit
    		 1.1
    Variability estimate
    Standard error of the mean
    Notes
    [7] - Exercise was hypothesized to be superior to metformin for improving MAGE; minimally important difference of 0.5mmol/L (approx. 30%)
    Statistical analysis title
    		 Follow-up - Exe/Dap
    Statistical analysis description
    Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Dapagliflozin v Exercise
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.651
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    -4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.2
         upper limit
    		 15.1
    Variability estimate
    Standard error of the mean
    Notes
    [8] - Descriptive
    Statistical analysis title
    		 Follow-up - Met/Con
    Statistical analysis description
    Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Control v Metformin
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.291
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    -9.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.9
         upper limit
    		 8.5
    Variability estimate
    Standard error of the mean
    Notes
    [9] - Descriptive
    Statistical analysis title
    		 Follow-up - Dap/Con
    Statistical analysis description
    Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Control v Dapagliflozin
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.032
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    -18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.7
         upper limit
    		 -1.7
    Variability estimate
    Standard error of the mean
    Notes
    [10] - Descriptive
    Statistical analysis title
    		 Follow-up - Exe/Con
    Statistical analysis description
    Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Exercise v Control
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.009
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    -21.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.5
         upper limit
    		 -5.7
    Variability estimate
    Standard error of the mean
    Notes
    [11] - Descriptive
    Statistical analysis title
    		 Primary end-point analysis - Dap/Met
    Statistical analysis description
    Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Metformin v Dapagliflozin
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.041
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    -17.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.9
         upper limit
    		 -0.8
    Variability estimate
    Standard error of the mean
    Notes
    [12] - Dapagliflozin was hypothesized to be superior to metformin for improving MAGE; minimally important difference of 0.5mmol/L (approx. 30%).
    Statistical analysis title
    		 Follow-up - Exe/Met
    Statistical analysis description
    Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Metformin v Exercise
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.11
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    -13.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.7
         upper limit
    		 3.4
    Variability estimate
    Standard error of the mean
    Notes
    [13] - Descriptive
    Statistical analysis title
    		 Mid treatment analysis - Dap/Con
    Statistical analysis description
    Analysis performed after 6 weeks of intervention. Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Control v Dapagliflozin
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.047
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    -16.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.3
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Notes
    [14] - Descriptive
    Statistical analysis title
    		 Primary end-point - Exe/Dap
    Statistical analysis description
    Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Exercise v Dapagliflozin
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.815
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.8
         upper limit
    		 22.5
    Variability estimate
    Standard error of the mean
    Notes
    [15] - Exercise was hypothesized to be superior to metformin for improving MAGE; minimally important difference of 0.5mmol/L (approx. 30%)
    Statistical analysis title
    		 Mid treatment analysis - Met/Con
    Statistical analysis description
    Analysis performed after 6 weeks of intervention. Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Control v Metformin
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.379
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    -7.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.4
         upper limit
    		 10.2
    Variability estimate
    Standard error of the mean
    Notes
    [16] - Descriptive
    Statistical analysis title
    		 Mid treatment analysis - Exe/Con
    Statistical analysis description
    Analysis performed after 6 weeks of intervention. Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Control v Exercise
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.059
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    -15.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.3
         upper limit
    		 0.6
    Variability estimate
    Standard error of the mean
    Notes
    [17] - Descriptive
    Statistical analysis title
    		 Mid treatment analysis - Dap/Met
    Statistical analysis description
    Analysis performed after 6 weeks of intervention. Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Metformin v Dapagliflozin
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.257
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    -9.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.5
         upper limit
    		 7.8
    Variability estimate
    Standard error of the mean
    Notes
    [18] - Descriptive
    Statistical analysis title
    		 Mid treatment analysis - Exe/Dap
    Statistical analysis description
    Analysis performed after 6 weeks of intervention. Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Dapagliflozin v Exercise
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.903
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.5
         upper limit
    		 20.9
    Variability estimate
    Standard error of the mean
    Notes
    [19] - Descriptive
    Statistical analysis title
    		 Mid treatment analysis - Exe/Met
    Statistical analysis description
    Analysis performed after 6 weeks of intervention. Intention-to-treat analysis. Data were log-transformed for analysis and results were back-transformed and represented as the difference in relative changes: i.e. if group A changed 20% between visit 1 and 2 (A2/A1 = 1.2) and group B changed 10% (B2/B1 = 1.1), then the relative change between group A and B is 1.2/1.1 = 9.1%
    Comparison groups
    Exercise v Metformin
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.305
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference between relative changes
    Point estimate
    -8.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.4
         upper limit
    		 8.7
    Variability estimate
    Standard error of the mean
    Notes
    [20] - Descriptive

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During participation in the trial, systematically recorded at visits.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Metformin
    Reporting group description
    		 No active treatment in this period

    Reporting group title
    Control
    Reporting group description
    		 -

    Reporting group title
    Exercise
    Reporting group description
    		 No active treatment in this period

    Reporting group title
    Dapagliflozin
    Reporting group description
    		 No active treatment in this period

    Serious adverse events
    		 Metformin Control Exercise Dapagliflozin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    lung cancer
    Additional description: Further details unknown.
    alternative dictionary used: None X
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.8%
    Non-serious adverse events
    		 Metformin Control Exercise Dapagliflozin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 30 (80.00%)
    4 / 30 (13.33%)
    7 / 29 (24.14%)
    17 / 30 (56.67%)
    Investigations
    Vasovagal reaction
    Additional description: In relation to exercise test
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Palpitations
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    2
    0
    0
    1
    General disorders and administration site conditions
    Rash
    Additional description: Rash in relation to the use of CGM plaster.
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
    1 / 29 (3.45%)
    1 / 30 (3.33%)
         occurrences all number
    0
    2
    1
    1
    Dehydration
    Additional description: Mild
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    Hot flush
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    1
    0
    0
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 30 (23.33%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    7
    0
    0
    0
    Abdominal discomfort
         subjects affected / exposed
    4 / 30 (13.33%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Constipation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    0
    2
    Flatulence
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Increased appetite
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    2
    Diarrhoea
         subjects affected / exposed
    9 / 30 (30.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    9
    0
    0
    0
    Nausea
         subjects affected / exposed
    4 / 30 (13.33%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Minor bleeding per rectum
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    Reduced appetite
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
    Additional description: Bilateral rash on hands
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Increased sweating
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Itchiness
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Mood swings
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    Renal and urinary disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Pyuria
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Candida infection
    Additional description: Vaginal
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    Polyuria
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Urine odour abnormal
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
    Additional description: Lower extremity
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    5 / 29 (17.24%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    5
    2
    Pain in lower back
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infected insect bite
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Pneumonia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Apr 2016
    Because of a slow recruitment rate, the inclusion criterion for HbA1c was expanded from 42-47 mmol/mol (criterion suggested by the International Expert Committee) to 39-47 mmol/mol (criterion suggested by the American Diabetes Association).
    11 Jul 2016
    The number of participants to be included was reduced from 160 to 120.

    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/28592573
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