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    Clinical Trial Results:
    A Double-blind, Randomized, Phase IV, Mechanistic, Placebo-controlled, Cross-over, Single-center Study to Evaluate the Effects of 5 Weeks Dapagliflozin Treatment on Insulin Sensitivity in Skeletal Muscle in Type 2 Diabetes Mellitus Patients

    Summary
    EudraCT number
    		 2016-003991-27
    Trial protocol
    		 NL  
    Global end of trial date
    04 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Nov 2020
    First version publication date
    18 Nov 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D1690C00047
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03338855
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Pepparedsleden 1, Mölndal, Sweden, SE-431 83
    Public contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +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
    04 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate if dapagliflozin improves skeletal muscle insulin sensitivity expressed as corrected glucose disposal rate (cGDR) in comparison with placebo after 5-week double-blind treatment. Insulin sensitivity was determined using a 2-step euglycemic hyperinsulinemic clamp (EHC) procedure.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation /Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Mar 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 26
    Worldwide total number of subjects
    26
    EEA total number of subjects
    26
    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)
    16
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a double-blind, randomized, placebo-controlled, cross-over Phase IV mechanistic study which was conducted in 1 study center in the Netherlands between 05 March 2018 and 04 November 2019.

    Pre-assignment
    Screening details
    		 Eligible patients with Type 2 diabetes mellitus were randomized to a specific double-blind treatment sequence (either dapagliflozin then placebo or placebo then dapagliflozin). Each of the 2 treatment periods had a maximum duration of 40 days, separated by a wash-out period of 6 to 8 weeks.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dapagliflozin 10 mg then Placebo
    Arm description
    		 Patients received an oral dose of 10 milligrams (mg) dapagliflozin, once daily for 5 weeks. After a wash-out period of 6 to 8 weeks, matched placebo tablets were taken orally, once daily for 5 weeks.
    Arm type
    		 Experimental and Placebo

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Forxiga®, Farxiga®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet was to be taken orally once daily in the morning and at approximately the same time of day during the treatment period.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet was to be taken orally once daily in the morning and at approximately the same time of day during the treatment period.

    Arm title
    		 Placebo then Dapagliflozin 10 mg
    Arm description
    		 Patients received placebo tablets (matched to dapagliflozin) taken orally, once daily for 5 weeks. After a wash-out period of 6 to 8 weeks, patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks.
    Arm type
    		 Experimental and Placebo

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Forxiga®, Farxiga®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet was to be taken orally once daily in the morning and at approximately the same time of day during the treatment period.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet was to be taken orally once daily in the morning and at approximately the same time of day during the treatment period.

    Number of subjects in period 1
    		Dapagliflozin 10 mg then Placebo Placebo then Dapagliflozin 10 mg
    Started
    12
    14
    Received Treatment in Period 1
    12
    14
    Received Treatment in Period 2
    11
    14
    Completed
    11
    14
    Not completed
    1
    0
         Withdrawn as birth control pill stopped
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dapagliflozin 10 mg then Placebo
    Reporting group description
    		 Patients received an oral dose of 10 milligrams (mg) dapagliflozin, once daily for 5 weeks. After a wash-out period of 6 to 8 weeks, matched placebo tablets were taken orally, once daily for 5 weeks.

    Reporting group title
    Placebo then Dapagliflozin 10 mg
    Reporting group description
    		 Patients received placebo tablets (matched to dapagliflozin) taken orally, once daily for 5 weeks. After a wash-out period of 6 to 8 weeks, patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks.

    Reporting group values
    		 Dapagliflozin 10 mg then Placebo Placebo then Dapagliflozin 10 mg Total
    Number of subjects
    		 12 14 26
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 8 8 16
        From 65-84 years
    		 4 6 10
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.0 ( 4.7 ) 64.4 ( 4.7 ) -
    Sex: Female, Male
    Units:
        Female
    		 5 1 6
        Male
    		 7 13 20
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 12 14 26
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 12 14 26
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Dapagliflozin 10 mg then Placebo
    Reporting group description
    		 Patients received an oral dose of 10 milligrams (mg) dapagliflozin, once daily for 5 weeks. After a wash-out period of 6 to 8 weeks, matched placebo tablets were taken orally, once daily for 5 weeks.

    Reporting group title
    Placebo then Dapagliflozin 10 mg
    Reporting group description
    		 Patients received placebo tablets (matched to dapagliflozin) taken orally, once daily for 5 weeks. After a wash-out period of 6 to 8 weeks, patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks.

    Subject analysis set title
    Dapagliflozin 10 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients received an oral dose of placebo, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.

    Primary: Corrected Glucose Disposal Rate (cGDR) Measured as Change in Rate of Disposal (Delta RD) Basal vs High Insulin After 5 Weeks of Treatment

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    End point title
    		 Corrected Glucose Disposal Rate (cGDR) Measured as Change in Rate of Disposal (Delta RD) Basal vs High Insulin After 5 Weeks of Treatment
    End point description
    Skeletal muscle insulin sensitivity was measured as cGDR (referred to as delta RD [basal vs high insulin]) using a 2-step 5.5 hour EHC procedure in combination with infusion of D-glucose (6,6-D2) glucose. Delta RD (basal vs high insulin) was corrected for urinary glucose excretion and measured at the end of Treatment Periods 1 and 2. The evaluable analysis set (clamp) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the clamp method were excluded.
    End point type
    Primary
    End point timeframe
    At end (Week 5) of Treatment Periods 1 and 2
    End point values
    		 Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    22
    22
    Units: micromole/kilogram body weight/minute
        least squares mean (confidence interval 95%)
    8.523 (5.566 to 11.481)
    9.592 (6.634 to 12.549)
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Comparison of delta RD (basal vs high insulin) between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.3047 [2]
    Method
    		 Linear Mixed Effects Model
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    -1.068
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.183
         upper limit
    		 1.047
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.014
    Notes
    [1] - As this is a cross-over study and subject analysis sets are not mutually exclusive, the given automatically calculated number in the statistical analysis reflects the number of data points rather than number of subjects.
    [2] - A linear mixed model with treatment group, treatment sequence, and period as fixed effects and patient as random effect.

    Other pre-specified: Change in Endogenous Glucose Production (EGP) After 5 Weeks of Treatment

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    End point title
    		 Change in Endogenous Glucose Production (EGP) After 5 Weeks of Treatment
    End point description
    A 2 step 5.5 hour EHC in combination with infusion of 6,6-D2 glucose was used to determine rates of EGP at the end of Treatment Periods 1 and 2. Results of the change in EGP are presented as delta EGP (basal vs low insulin and basal vs high insulin). The evaluable analysis set (clamp) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the clamp method were excluded.
    End point type
    Other pre-specified
    End point timeframe
    At end (Week 5) of Treatment Periods 1 and 2
    End point values
    		 Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    22
    22
    Units: micromole/kilogram body weight/minute
    least squares mean (confidence interval 95%)
        Delta EGP (basal vs low insulin)
    -4.656 (-5.494 to -3.817)
    -2.591 (-3.790 to -2.112)
        Delta EGP (basal vs high insulin)
    -10.803 (-11.726 to -9.880)
    -8.512 (-9.435 to -7.589)
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Comparison of delta EGP (basal vs low insulin) between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0036 [4]
    Method
    		 Linear Mixed Effects Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.705
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.784
         upper limit
    		 -0.625
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.517
    Notes
    [3] - As this is a cross-over study and subject analysis sets are not mutually exclusive, the given automatically calculated number in the statistical analysis reflects the number of data points rather than number of subjects.
    [4] - A linear mixed model with treatment group, treatment sequence, and period as fixed effects and patient as random effect.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Comparison of delta EGP (basal vs high insulin) between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Linear Mixed Effects Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.292
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.146
         upper limit
    		 -1.438
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.409
    Notes
    [5] - As this is a cross-over study and subject analysis sets are not mutually exclusive, the given automatically calculated number in the statistical analysis reflects the number of data points rather than number of subjects.
    [6] - A linear mixed model with treatment group, treatment sequence, and period as fixed effects and patient as random effect.

    Other pre-specified: Change in Respiratory Exchange Ratio (RER) from Fasted State to Insulin Stimulated State After 5 Weeks of Treatment

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    End point title
    		 Change in Respiratory Exchange Ratio (RER) from Fasted State to Insulin Stimulated State After 5 Weeks of Treatment
    End point description
    During the indirect calorimetry of the EHC test, respiratory gas exchange was measured using open air circuit respirometry with an automated ventilated hood system. Metabolic flexibility was determined by the change in RER from fasted state to insulin stimulated state at the end of Treatment Periods 1 and 2 and results are presented as delta RER (basal vs high insulin). The evaluable analysis set (indirect calorimetry) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the indirect calorimetry method were excluded.
    End point type
    Other pre-specified
    End point timeframe
    At end (Week 5) of Treatment Periods 1 and 2
    End point values
    		 Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    21
    21
    Units: micromole/kilogram body weight/minute
        least squares mean (confidence interval 95%)
    0.101 (0.080 to 0.122)
    0.089 (0.068 to 0.110)
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Comparison of delta RER (basal vs high insulin) between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.1842 [8]
    Method
    		 Linear Mixed Effects Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.012
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.006
         upper limit
    		 0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.009
    Notes
    [7] - As this is a cross-over study and subject analysis sets are not mutually exclusive, the given automatically calculated number in the statistical analysis reflects the number of data points rather than number of subjects.
    [8] - A linear mixed model with treatment group, treatment sequence, and period as fixed effects and patient as random effect.

    Other pre-specified: 24-Hour RER After 5 Weeks of Treatment

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    End point title
    		 24-Hour RER After 5 Weeks of Treatment
    End point description
    RER was measured before and after meals over a 24-hour period. The evaluable analysis set (chamber) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the chamber method were excluded.
    End point type
    Other pre-specified
    End point timeframe
    At end (Week 5) of Treatment Periods 1 and 2
    End point values
    		 Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    24
    24
    Units: ratio
        least squares mean (confidence interval 95%)
    0.812 (0.803 to 0.821)
    0.835 (0.826 to 0.844)
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Comparison of 24-hour RER between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.0001 [10]
    Method
    		 Linear Mixed Effects Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.023
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.033
         upper limit
    		 -0.013
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.005
    Notes
    [9] - As this is a cross-over study and subject analysis sets are not mutually exclusive, the given automatically calculated number in the statistical analysis reflects the number of data points rather than number of subjects.
    [10] - A linear mixed model with treatment group, treatment sequence, and period as fixed effects and patient as random effect.

    Other pre-specified: 24-Hour Energy Expenditure After 5 Weeks of Treatment

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    End point title
    		 24-Hour Energy Expenditure After 5 Weeks of Treatment
    End point description
    Whole body energy expenditure was measured over a 24-hour period. The evaluable analysis set (chamber) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the chamber method were excluded.
    End point type
    Other pre-specified
    End point timeframe
    At end (Week 5) of Treatment Periods 1 and 2
    End point values
    		 Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    24
    24
    Units: megajoules/day
        least squares mean (confidence interval 95%)
    9.519 (9.017 to 10.020)
    9.628 (9.126 to 10.130)
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Comparison of energy expenditure between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.1095 [12]
    Method
    		 Linear Mixed Effects Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.109
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.245
         upper limit
    		 0.027
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.065
    Notes
    [11] - As this is a cross-over study and subject analysis sets are not mutually exclusive, the given automatically calculated number in the statistical analysis reflects the number of data points rather than number of subjects.
    [12] - A linear mixed model with treatment group, treatment sequence, and period as fixed effects and patient as random effect.

    Other pre-specified: Body Composition (Fat Mass and Lean Mass) After 5 Weeks of Treatment

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    End point title
    		 Body Composition (Fat Mass and Lean Mass) After 5 Weeks of Treatment
    End point description
    On Day 6, 7 or 8 of the end of treatment visit in both treatment periods, a Dual-energy X-ray absorptiometry (DEXA) scan was used to determine body composition. The evaluable analysis set (DEXA) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with procedure specific protocol deviations regarding the DEXA method were excluded.
    End point type
    Other pre-specified
    End point timeframe
    At end (Week 5) of Treatment Periods 1 and 2
    End point values
    		 Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    24
    24
    Units: grams
    least squares mean (confidence interval 95%)
        Fat Mass
    25318.3 (22978.4 to 27658.1)
    25564.9 (23225.0 to 27904.8)
        Lean Mass
    59929.0 (56762.1 to 63095.8)
    60595.4 (57428.5 to 63762.3)
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Comparison of fat mass between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.6005 [14]
    Method
    		 Linear Mixed Effects Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -246.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1209.5
         upper limit
    		 716.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    464.3
    Notes
    [13] - As this is a cross-over study and subject analysis sets are not mutually exclusive, the given automatically calculated number in the statistical analysis reflects the number of data points rather than number of subjects.
    [14] - A linear mixed model with treatment group, treatment sequence, and period as fixed effects and patient as random effect.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Comparison of lean mass between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.0376 [16]
    Method
    		 Linear Mixed Effects Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -666.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1291
         upper limit
    		 -41.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    301.1
    Notes
    [15] - As this is a cross-over study and subject analysis sets are not mutually exclusive, the given automatically calculated number in the statistical analysis reflects the number of data points rather than number of subjects.
    [16] - A linear mixed model with treatment group, treatment sequence, and period as fixed effects and patient as random effect.

    Other pre-specified: Body Composition (Total Mass) After 5 Weeks of Treatment

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    End point title
    		 Body Composition (Total Mass) After 5 Weeks of Treatment
    End point description
    On Day 6, 7 or 8 of the end of treatment visit in both treatment periods a DEXA scan was used to determine body composition. The evaluable analysis set (DEXA) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the DEXA method were excluded.
    End point type
    Other pre-specified
    End point timeframe
    At end (Week 5) of Treatment Periods 1 and 2
    End point values
    		 Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    24
    24
    Units: kilograms
        least squares mean (confidence interval 95%)
    85.248 (81.608 to 88.888)
    86.504 (82.864 to 90.143)
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Comparison of total mass between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.0003 [18]
    Method
    		 Linear Mixed Effects Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.256
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.854
         upper limit
    		 -0.657
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.289
    Notes
    [17] - As this is a cross-over study and subject analysis sets are not mutually exclusive, the given automatically calculated number in the statistical analysis reflects the number of data points rather than number of subjects.
    [18] - A linear mixed model with treatment group, treatment sequence, and period as fixed effects and patient as random effect.

    Other pre-specified: Fibroblast Growth Factor 21 (FGF21) Area Under the Curve (AUC) in Plasma After 5 Weeks of Treatment

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    End point title
    		 Fibroblast Growth Factor 21 (FGF21) Area Under the Curve (AUC) in Plasma After 5 Weeks of Treatment
    End point description
    From the end of Day 1 until the morning of Day 3 of the end of each treatment visit, the patients stayed in the metabolic chamber (36 hours). During this stay FGF21 was measured in plasma before and after meals and before bed-time to determine the AUC (last 24 hours). The evaluable analysis set (chamber) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the chamber method were excluded.
    End point type
    Other pre-specified
    End point timeframe
    At end (Week 5) of Treatment Periods 1 and 2
    End point values
    		 Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    21
    21
    Units: nanograms/liter/hour
        least squares mean (confidence interval 95%)
    3310.415 (2626.919 to 3993.911)
    3554.716 (2871.270 to 4238.212)
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Comparison of FGF21 AUC between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.1555 [20]
    Method
    		 Linear Mixed Effects Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -244.301
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -590.002
         upper limit
    		 101.401
    Variability estimate
    Standard error of the mean
    Dispersion value
    165.168
    Notes
    [19] - As this is a cross-over study and subject analysis sets are not mutually exclusive, the given automatically calculated number in the statistical analysis reflects the number of data points rather than number of subjects.
    [20] - A linear mixed model with treatment group, treatment sequence, and period as fixed effects and patient as random effect.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events (AEs) were reported for an overall time frame up to a maximum of 19 weeks (including both 5-week treatment periods, 6-8 weeks wash-out and 5-10 days safety follow-up after last dose of study drug).
    Adverse event reporting additional description
    In this study, collection of AE data was limited to the collection of serious AEs, discontinuation of investigational product due to an AE and potential diabetic ketoacidosis events only. The safety analysis set consisted of all patients who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Dapagliflozin 10mg
    Reporting group description
    		 Patients received an oral dose of 10mg dapagliflozin, once daily for 5 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received placebo tablets (matched to dapagliflozin) taken orally, once daily for 5 weeks.

    Serious adverse events
    		 Dapagliflozin 10mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dapagliflozin 10mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There were no non serious adverse events above the 5% threshold in either reporting group.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Dec 2017
    Exclusion criterion added to exclude patients who did not want to be informed about unexpected medical findings or did not wish their physician to be informed about coincidental findings. Laboratory safety assessments updated to include serum/plasma potassium. The section entitled “Storage and destruction of Biological Samples” was updated to clarify length of time biological samples were to be retained. Sample size estimation also updated to provide more details of assumptions made and specify software used.
    20 Jun 2018
    Exploratory objectives updated to include assessment of effect of dapagliflozin on citrate synthase activity in muscle biopsy. New exploratory objective added to investigate the effect of dapagliflozin on body weight, body mass index (BMI), and systolic and diastolic blood pressure. Inclusion criteria updated to specify that eligible patients could be on a stable dose of dipeptidyl peptidase IV inhibitor treatment for at least 3 months and also to specify patients should have a BMI of ≤ 38 kg/m2. Criteria for withdrawal updated to permit rescreening of patients. The section entitled “Study termination” was added. Biomarker assessments updated to include amino acids in addition to acetylcarnitine. Sample size estimation updated to specify screen failure rate, to ensure enough evaluable patients evenly distributed across the treatment sequences.
    13 Aug 2018
    The section entitled “Study termination” was removed.
    12 Sep 2018
    Implemented a pre-screening telephone call prior to Visit 1 to explain the study and ask the patients some questions relating to inclusion and exclusion criteria to verify eligibility. Included provision of a lifestyle card to the patient at Visit 2 to inform them of lifestyle advice to be adhered to during the study.

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

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