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    Clinical Trial Results:
    A Double-Blind, Randomized, Parallel Group, Phase IV Study To Investigate The Effects Of Dapagliflozin On Cardiac Substrate Uptake, Myocardial Efficiency And Myocardial Contractile Work In Type 2 Diabetes Patients

    Summary
    EudraCT number
    		 2017-003820-58
    Trial protocol
    		 FI   SE  
    Global end of trial date
    19 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Mar 2020
    First version publication date
    27 Mar 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D1690C00063
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03387683
    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, +1 302 885 1180, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca Clinical, +1 877-240-9479, 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
    19 Mar 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effects of dapagliflozin on cardiac substrate uptake, myocardial efficiency, and myocardial contractile work versus placebo after 6 weeks of double-blind treatment in patients with type 2 diabetes.
    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
    28 Feb 2018
    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
    Sweden: 15
    Country: Number of subjects enrolled
    Finland: 38
    Worldwide total number of subjects
    53
    EEA total number of subjects
    53
    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)
    23
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Fifty three patients with type 2 diabetes and on a stable dose of metformin for at least 6 weeks were enrolled in 1 study center in Sweden and 1 center in Finland. The first patient was enrolled on 28 February 2018 and the last patient's last visit was on 19 March 2019.

    Pre-assignment
    Screening details
    		 Eligible patients were aged between 40 and 75 years, had type 2 diabetes for at least 6 months and had no significant coronary artery disease symptoms. Patients were randomized in a 1:1 ratio, to receive 10 milligrams (mg) dapagliflozin or placebo.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dapagliflozin 10 mg
    Arm description
    		 Patients were randomized to receive an oral dose of 10 mg dapagliflozin, once daily, for 6 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Forxiga®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet of 10 mg dapagliflozin to be taken orally, once daily, in the morning.

    Arm title
    		 Placebo
    Arm description
    		 Patients were randomized to receive an oral dose of placebo (to match 10 mg dapagliflozin), once daily, for 6 weeks.
    Arm type
    		 Placebo

    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 matched placebo tablet be taken orally, once daily, in the morning.

    Number of subjects in period 1
    		Dapagliflozin 10 mg Placebo
    Started
    27
    26
    Completed
    25
    26
    Not completed
    2
    0
         In receipt of disallowed medication
    1
    -
         Did not receive treatment
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dapagliflozin 10 mg
    Reporting group description
    		 Patients were randomized to receive an oral dose of 10 mg dapagliflozin, once daily, for 6 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were randomized to receive an oral dose of placebo (to match 10 mg dapagliflozin), once daily, for 6 weeks.

    Reporting group values
    		 Dapagliflozin 10 mg Placebo Total
    Number of subjects
    		 27 26 53
    Age, Customized
    Units: Subjects
        <65 years
    		 12 11 23
        ≥65 years
    		 15 15 30
    Sex: Female, Male
    Units: Subjects
        Female
    		 8 15 23
        Male
    		 19 11 30
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 27 26 53

    End points

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    End points reporting groups
    Reporting group title
    Dapagliflozin 10 mg
    Reporting group description
    		 Patients were randomized to receive an oral dose of 10 mg dapagliflozin, once daily, for 6 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were randomized to receive an oral dose of placebo (to match 10 mg dapagliflozin), once daily, for 6 weeks.

    Primary: Adjusted Mean Change from Baseline in Global Longitudinal Strain of the Left Ventricle (GLSLV) at End of Treatment.

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    End point title
    		 Adjusted Mean Change from Baseline in Global Longitudinal Strain of the Left Ventricle (GLSLV) at End of Treatment.
    End point description
    Patients underwent magnetic resonance imaging (MRI) examination to determine the GLSLV, which is expressed as a percentage. The least square mean (LSM) change from baseline estimates were generated from an analysis of covariance (ANCOVA) model with treatment and baseline value of the endpoint as covariates.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and end of treatment (Day 42)
    End point values
    		 Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    24
    24
    Units: Percent
        least squares mean (confidence interval 95%)
    0.30769 (-0.35001 to 0.96538)
    -0.00352 (-0.66121 to 0.65417)
    Statistical analysis title
    		 Difference in LSM (Placebo - Dapagliflozin 10 mg)
    Statistical analysis description
    The LSM estimate and corresponding p-value were obtained from a linear model with treatment and baseline value of the endpoint as covariates.
    Comparison groups
    Dapagliflozin 10 mg v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.504 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    0.31121
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.619
         upper limit
    		 1.24141
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.46184
    Notes
    [1] - Statistical significance was inferred at a (2-sided) 0.05 level.

    Secondary: Adjusted Mean Change from Baseline in Myocardial Efficiency at End of Treatment.

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    End point title
    		 Adjusted Mean Change from Baseline in Myocardial Efficiency at End of Treatment.
    End point description
    A clinical radiologic assessment of acquired computed tomography and positron emission tomography (CT-PET)-[11C]-acetate images was performed to determine myocardial efficiency. The myocardial efficiency calculation was based on an estimate of energy used for producing LV contractile work (mean arterial pressure (MAP) x stroke volume (SV) x heart rate (HR) / myocardial mass) compared to the total cardiac work (calculated based on the total myocardial oxygen consumption per myocardial mass) and is expressed as a percentage. The LSM change from baseline estimates, were generated from an ANCOVA model with treatment and baseline value of the endpoint as covariates. Results are presented for patients in the CT-PET-[11C]-acetate evaluable analysis set who, as per clinical judgment, had fasted and abstained from products containing nicotine, caffeine and alcohol for at least 6 hours prior to both of the times when CT-PET-[11C]-acetate measurements were taken.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and end of treatment (Day 42)
    End point values
    		 Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    24
    24
    Units: Percent
        least squares mean (confidence interval 95%)
    -0.71474 (-3.74654 to 2.31706)
    -2.46443 (-5.49623 to 0.56737)
    Statistical analysis title
    		 Difference in LSM (Placebo - Dapagliflozin 10 mg)
    Statistical analysis description
    The LSM estimate and corresponding p-value were obtained from a linear model with treatment and baseline value of the endpoint as covariates.
    Comparison groups
    Placebo v Dapagliflozin 10 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.427 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    1.74969
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.64837
         upper limit
    		 6.14775
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.18363
    Notes
    [2] - Statistical significance was inferred at a (2-sided) 0.05 level.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected from start of treatment until 1 week after end of treatment (Day 1 to Day 49).
    Adverse event reporting additional description
    Collection of AE data was limited to the collection of Serious AEs and AEs leading to the discontinuation of study medication only. Data is presented for the Safety Analysis Set which consisted of all subjects who received at least one dose of study medication during the treatment period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Dapagliflozin 10 mg
    Reporting group description
    		 Patients were randomized to receive an oral dose of 10 mg dapagliflozin, once daily, for 6 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were randomized to receive an oral dose of placebo (to match 10 mg dapagliflozin), once daily, for 6 weeks.

    Serious adverse events
    		 Dapagliflozin 10 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Dapagliflozin 10 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (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: In this Study the collection of AE data was limited to collection of serious adverse events and adverse events leading to discontinuation of study medication only as per the protocol.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Feb 2018
    • Included additional scanner type (integrated MRI/PET machine) for assessment of PET-related endpoints to provide the possibility to use several machines to optimize PET assessment availability. • Updated regarding PET assessment with [^18F]- fluoro-6-thia-heptadecanoic acid (FTHA) tracer. The [^18F]-FTHA examinations were exploratory and were not to be performed in all the randomized patients. Instead, a minimum of 40 and a maximum of 44 randomized patients were to undergo the examinations.

    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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    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
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