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    Clinical Trial Results:
    Effects of SGLT-2 Inhibitor on Myocardial Perfusion, Function and Metabolism in Type 2 DM Patients at high cardiovascular risk: The SIMPle Randomized Clinical Trial

    Summary
    EudraCT number
    		 2016-003743-10
    Trial protocol
    		 DK  
    Global end of trial date
    22 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Nov 2021
    First version publication date
    07 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2016-779
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03151343
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Herlev & Gentofte Hospital
    Sponsor organisation address
    Herlev Ringvej 75, Herlev, Denmark, 2730
    Public contact
    Center for Endokrinologi, Herlev og Gentofte Hospital, mikkel.juergens.01@regionh.dk
    Scientific contact
    Center for Endokrinologi, Herlev & Gentofte Hospital, mikkel.juergens.01@regionh.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
    28 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 May 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    22 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To examine the mechanism behind the cardioprotective effects of the SGLT-2 inhibitor empagliflozine in a population of type 2 diabetics at high cardiovascular risk.
    Protection of trial subjects
    Schedueled safety assessments, in-person as well as by telephone. The trial was monitored by the Good Clinical Practice (GCP) unit in Copenhagen.
    Background therapy
    		 -
    Evidence for comparator
    		 Comparator was placebo
    Actual start date of recruitment
    29 Mar 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 91
    Worldwide total number of subjects
    91
    EEA total number of subjects
    91
    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)
    34
    From 65 to 84 years
    57
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from outpatient clinics at Herlev & Gentofte Hospital and Rigshospitalet in Denmark, in the period 29 Mar 2017 to 12 Feb 2020.

    Pre-assignment
    Screening details
    		 Key inclusion criteria were a diagnosis of type 2 diabetes and established cardiovascular disease. Key exclusion criteria were eGFR ≤30 mL/min, and treatment with any SGLT2i within 1 month before study enrollment.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Subject
    Blinding implementation details
    Trial medication and randomization sequence was provided by a central pharmacy (Glostrup Apotek). Patients and investigators were blinded to group allocation for the duration of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg, once daily

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

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

    Number of subjects in period 1 [1]
    		Active Placebo
    Started
    45
    45
    Completed
    42
    36
    Not completed
    3
    9
         COVID lockdown
    -
    3
         Adverse event, non-fatal
    2
    1
         Claustrophobia
    -
    3
         Technical issues
    1
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One person was enrolled but not randomized. The person dropped out before randomization due to medical reasons.

    Baseline characteristics

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

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Active Placebo Total
    Number of subjects
    		 45 45 90
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66 ( 9 ) 67 ( 9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 11 7 18
        Male
    		 34 38 72
    Myocardial Flow Reserve at baseline
    Units: ratio
        arithmetic mean (standard deviation)
    		 2.17 ( 0.63 ) 2.26 ( 0.67 ) -

    End points

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

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Myocardial Flow Reserve

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    End point title
    		 Myocardial Flow Reserve
    End point description
    End point type
    Primary
    End point timeframe
    Change from baseline to 13 weeks
    End point values
    		 Active Placebo
    Number of subjects analysed
    45
    45
    Units: ratio
        arithmetic mean (confidence interval 95%)
    0.01 (-0.18 to 0.21)
    0.06 (-0.15 to 0.27)
    Statistical analysis title
    		 Constrained linear mixed model
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 0.23
    Notes
    [1] - Difference in change in means

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing the informed consent form until two weeks after the end of the study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    2021-07-31
    Reporting groups
    Reporting group title
    Active
    Reporting group description
    		 Participants receiving active treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Participants receiving placebo

    Serious adverse events
    		 Active Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 45 (4.44%)
    3 / 45 (6.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm of colon and/or rectum
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Transient ischemic attac
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Low blood pressure
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erysipelas
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Abscess
    Additional description: Right foot. Condition led to amputation of toes 1 and 2.
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         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: 3%
    Non-serious adverse events
    		 Active Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 45 (44.44%)
    9 / 45 (20.00%)
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    Angina
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    Reproductive system and breast disorders
    Vaginitis
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 45 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 45 (2.22%)
    3 / 45 (6.67%)
         occurrences all number
    1
    3
    Renal and urinary disorders
    Increased frequency of urination
         subjects affected / exposed
    14 / 45 (31.11%)
    1 / 45 (2.22%)
         occurrences all number
    14
    1
    Musculoskeletal and connective tissue disorders
    Low back pain
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 45 (4.44%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    The study had a small number of participants (90), and some data could not be obtained due to COVID restrictions

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34278803
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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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