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    Clinical Trial Results:
    Research into the Effect Of SGLT2 inhibition on left ventricular Remodelling in patients with heart failure and diabetes Mellitus

    Summary
    EudraCT number
    		 2014-002742-42
    Trial protocol
    		 GB  
    Global end of trial date
    11 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jul 2019
    First version publication date
    14 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2013DM19
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02397421
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Sponsor reference: 2013DM19
    Sponsors
    Sponsor organisation name
    Tayside Clinical Trials Unit
    Sponsor organisation address
    George Pirie Way, Dundee, United Kingdom, DD1 9SY
    Public contact
    Dr Fiona Hoagrth, University of Dundee, Tayside Clinical Trials Unit, +44 01382383233, f.j.hogarth@dundee.ac.uk
    Scientific contact
    Dr Fiona Hoagrth, University of Dundee, Tayside Clinical Trials Unit, +44 01382383233, f.j.hogarth@dundee.ac.uk
    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
    01 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective will be to see if Dapagliflozin can change the harmful effect of scarring in the left ventricle in the heart of type 2 diabetic patients who have mild heart failure. This will be done by measuring the size of the left side of the heart muscle with an MRI scan before and after one years of treatment with dapagliflozin or placebo.
    Protection of trial subjects
    Approval of trial methods by East of Scotland Ethics Committee No further specific protection methods required
    Background therapy
    		 Various medications for host of co-morbidities as indicated (eg Aspirin, beta-blockers, ACE-inhibitiors, mineralocorticoid receptor antagoinsts, metformin, insulin etc)
    Evidence for comparator
    		 Comparator was standard of care
    Actual start date of recruitment
    15 May 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
    United Kingdom: 56
    Worldwide total number of subjects
    56
    EEA total number of subjects
    56
    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
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment from May 2015 till Aug 2016 Occurred in single center: Ninewells Hospital and Medical School, Dundee, UK

    Pre-assignment
    Screening details
    		 Initial screening of e-health records: 2955 Pre screening via telephone: 265 Invited to participate: 85 Informed consent: 62 Recruited: 56

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    After successful recruitment into the trial, patients were randomised to either dapagliflozin 10 mg or matching placebo in a double-blind fashion. The trial medication (dapagliflozin or placebo) was prepared, packaged and labelled by our onsite clinical trials pharmaceutical manufacturer. Randomisation was carried out by our dedicated clinical trials pharmacy using block randomisation. They used a validated randomisation program and securely backed-up both the randomisation seed and the treatmen

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment arm
    Arm description
    		 Dapagliflozin 10mg OD for 1 year
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    10mg once daily at any time with or without food

    Arm title
    		 Comparator Arm
    Arm description
    		 Comparator with placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet once daily

    Number of subjects in period 1
    		Treatment arm Comparator Arm
    Started
    28
    28
    Completed
    26
    23
    Not completed
    2
    5
         Consent withdrawn by subject
    1
    1
         Non-adverse event death
    -
    3
         New onset of cancer
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 56 56
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 16 16
        From 65-84 years
    		 40 40
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.1 ± 6.8 -
    Gender categorical
    Units: Subjects
        Female
    		 19 19
        Male
    		 37 37
    New York Heart Association Functional Classification for Heart Failure
    Units: Subjects
        NYHA I
    		 25 25
        NYHA II
    		 24 24
        NYHA III
    		 7 7
    Left ventricular end systolic volume
    Units: ml
        arithmetic mean (standard deviation)
    		 102.7 ± 50.5 -
    Left ventricular end diastolic volume
    Units: ml
        arithmetic mean (standard deviation)
    		 180.0 ± 61.0 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 95.1 ± 18.6 -
    Systolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 133.9 ± 17.1 -
    Diastolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 72.7 ± 10.0 -
    Left ventricular ejection fraction
    Units: percent
        arithmetic mean (standard deviation)
    		 45.5 ± 12.0 -
    Left ventricular mass indexed
    Units: mg/m2
        arithmetic mean (standard deviation)
    		 71.5 ± 17.7 -

    End points

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    End points reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    		 Dapagliflozin 10mg OD for 1 year

    Reporting group title
    Comparator Arm
    Reporting group description
    		 Comparator with placebo

    Primary: Left ventricular end-systolic volume

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    End point title
    		 Left ventricular end-systolic volume
    End point description
    Cardiac MRI determined Left ventricular end-systolic volume
    End point type
    Primary
    End point timeframe
    1 year
    End point values
    		 Treatment arm Comparator Arm
    Number of subjects analysed
    26
    23
    Units: ml
        arithmetic mean (standard deviation)
    90.5 ± 40.0
    87.6 ± 41.5
    Statistical analysis title
    		 Multivariable linear regression
    Statistical analysis description
    Linear regression analysis comparing final outcome variables between dapagliflozin and placebo groups, while controlling for baseline values, age, gender and renal function (ANCOVA).
    Comparison groups
    Treatment arm v Comparator Arm
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.1
         upper limit
    		 19
    Variability estimate
    Standard deviation

    Secondary: Weight

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    End point title
    		 Weight
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Treatment arm Comparator Arm
    Number of subjects analysed
    26
    23
    Units: kg
        arithmetic mean (standard deviation)
    91.5 ± 18.9
    90.3 ± 18.7
    No statistical analyses for this end point

    Secondary: Left ventricular end diastolic volume

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    End point title
    		 Left ventricular end diastolic volume
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Treatment arm Comparator Arm
    Number of subjects analysed
    26 [1]
    23
    Units: ml
        arithmetic mean (standard deviation)
    164.4 ± 50.8
    164.3 ± 62.3
    Notes
    [1] -
    No statistical analyses for this end point

    Secondary: Left ventricular mass indexed

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    End point title
    		 Left ventricular mass indexed
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Treatment arm Comparator Arm
    Number of subjects analysed
    26
    23
    Units: kg/m2
        arithmetic mean (standard deviation)
    74.3 ± 21.0
    74.3 ± 18.3
    No statistical analyses for this end point

    Secondary: Hemoglobin

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    End point title
    		 Hemoglobin
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Treatment arm Comparator Arm
    Number of subjects analysed
    26
    23
    Units: g/dl
        arithmetic mean (standard deviation)
    14.4 ± 1.4
    13.7 ± 1.7
    No statistical analyses for this end point

    Secondary: Systolic blood pressure

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    End point title
    		 Systolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Treatment arm Comparator Arm
    Number of subjects analysed
    26
    23
    Units: mmHg
        arithmetic mean (standard deviation)
    137.7 ± 17.0
    136.4 ± 24.5
    No statistical analyses for this end point

    Secondary: Diastolic blood pressure

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    End point title
    		 Diastolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Treatment arm Comparator Arm
    Number of subjects analysed
    26
    23
    Units: mmHg
        arithmetic mean (standard deviation)
    73.7 ± 9.3
    80.2 ± 11.6
    No statistical analyses for this end point

    Secondary: Left ventricular ejection fraction

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    End point title
    		 Left ventricular ejection fraction
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Treatment arm Comparator Arm
    Number of subjects analysed
    26
    23
    Units: percent
        arithmetic mean (standard deviation)
    47.1 ± 11.4
    47.9 ± 10.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1 year
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    		 Dapagliflozin 10mg OD for 1 year

    Reporting group title
    Comparator Arm
    Reporting group description
    		 Comparator with placebo

    Serious adverse events
    		 Treatment arm Comparator Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 28 (10.71%)
    10 / 28 (35.71%)
         number of deaths (all causes)
    0
    3
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure acute
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina unstable
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Ear and labyrinth disorders
    Otitis externa bacterial
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung cancer metastatic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment arm Comparator Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 28 (39.29%)
    14 / 28 (50.00%)
    General disorders and administration site conditions
    Dehydration
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 28 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 28 (10.71%)
    2 / 28 (7.14%)
         occurrences all number
    3
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    Candida infection
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 28 (0.00%)
         occurrences all number
    3
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    3 / 28 (10.71%)
    2 / 28 (7.14%)
         occurrences all number
    4
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jan 2015
    • This was made upon REC request for clarification of safety measures, withdrawal and early discontinuation of IMP. Final favorable opinion from REC was granted on 15th January 2015.
    25 Aug 2015
    • Submitted for approval on 16th June 2015, all relevant approvals were obtained by 25th August 2015. • Inclusion/exclusion criteria was altered to include patients taking sulphonylureas and to increase the maximal furosemide dose. • Secondary endpoints of the trial were amended to include measurement of urinary albumin: creatinine ratio and urinary sodium excretion. • Measurements of atrial dimensions and left ventricular remodelling index has been added to the cardiac MRI. • Assessment of fluid status using the BIA machine at every visit has been added.
    15 Dec 2015
    • Submitted for approval on 22nd October 2015, all relevant approvals were obtained by 15th December 2015. • Primary outcome measures was amended to include left ventricle volume measurement which was previously a secondary outcome measure. • The exclusion criteria has been altered to allow the concomitant use of insulin with IMP and the cut off for renal disease was lowered to 45mL/min.
    01 Jul 2016
    • Updating the PIS, informed consent form and trial protocol to reflect new MHRA advisory regarding non-hyperglycaemic ketoacidosis among patients on SGLT2-inhibitor therapy. • Addition of the University of Dundee’s GO-DARTS database as a new source of recruitment.

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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