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    Clinical Trial Results:
    Randomized, double-blind, placebo controlled, crossover clinical study to analyse the effect of empagliflozin on microvascular circulation

    Summary
    EudraCT number
    		 2014-003053-34
    Trial protocol
    		 DE  
    Global end of trial date
    01 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jul 2021
    First version publication date
    09 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRC2014EMPA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IPPMED Institut für Pharmakologie und präventive Medizin GmbH
    Sponsor organisation address
    B, C, Germany, 49661
    Public contact
    Clinical Research Unit, Medizinische Klinik 4, 0049 91318536245, roland.schmieder@uk-erlangen.de
    Scientific contact
    Clinical Research Unit, Medizinische Klinik 4, 0049 91318536245, roland.schmieder@uk-erlangen.de
    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
    Interim
    Date of interim/final analysis
    01 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to analyse the effect of empagliflozin on the microcirculation as assessed by the pulse wave reflection in the peripheral arterial tree (indicative of microvascular changes) with the parameters central (aortic) systolic pressure and pulse pressure, augmentation pressure, forward and backward wave amplitude.
    Protection of trial subjects
    Physical examinations, vital signs, checking concomitant medication, assessment of adverse events, measurement of safety laboratory markers (including glucose levels, biochemistry, haematology and urinanalsis) were done regularly in the course of the study. Patients were provided with a glucometer and kept an individual diary for blood glucose measurements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Feb 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
    Germany: 74
    Worldwide total number of subjects
    74
    EEA total number of subjects
    74
    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)
    46
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patient will be recruited simultaneously at the two locations (Erlangen, Nürnberg) from investigator outpatient clinics, referring physicians, and advertisement in local newspapers. After a first contact by phone eligible patients will be invited to a screening visit.

    Pre-assignment
    Screening details
    		 Male and Female patients at the age of 18 - 75 years with Type 2 diabetes mellitus, defined by fasting glucose ≥ 126 mg/dl or HbA1c ≥ 6.5% or on blood glucose lowering medication. Patients not pretreated with anti-diabetic medication did not have a 4 week run-in/wash-out Phase.

    Period 1
    Period 1 title
    Treatment Period 1 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Empagliflozin
    Arm description
    		 The study followed randomized cross-over-design, i.e. subjects underwent both treatment arms in randomized order for 6 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg once daily

    Arm title
    		 Placebo
    Arm description
    		 The study followed randomized cross-over-design, i.e. subjects underwent both treatment arms in randomized order 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
    once daily

    Number of subjects in period 1
    		Empagliflozin Placebo
    Started
    74
    74
    Completed
    71
    71
    Not completed
    3
    3
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    1
    1
         Protocol deviation
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period 1
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Period 1 Total
    Number of subjects
    		 74 74
    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)
    		 46 46
        From 65-84 years
    		 28 28
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 30 30
        Male
    		 44 44

    End points

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    End points reporting groups
    Reporting group title
    Empagliflozin
    Reporting group description
    		 The study followed randomized cross-over-design, i.e. subjects underwent both treatment arms in randomized order for 6 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 The study followed randomized cross-over-design, i.e. subjects underwent both treatment arms in randomized order for 6 weeks.

    Primary: effect of IMP on change of central SBP

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    End point title
    		 effect of IMP on change of central SBP
    End point description
    measured by SphygmoCor
    End point type
    Primary
    End point timeframe
    6 weeks
    End point values
    		 Empagliflozin Placebo
    Number of subjects analysed
    71
    71
    Units: mmHg
        arithmetic mean (standard deviation)
    -6.1 ± 9.4
    -0.96 ± 11
    Statistical analysis title
    		 effect of IMP on change of central SBP
    Comparison groups
    Placebo v Empagliflozin
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 ≤ 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 2.5

    Primary: effect of IMP on change of central pulse pressure

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    End point title
    		 effect of IMP on change of central pulse pressure
    End point description
    measured by SphygmoCor
    End point type
    Primary
    End point timeframe
    6 weeks
    End point values
    		 Empagliflozin Placebo
    Number of subjects analysed
    71
    71
    Units: mmHg
        arithmetic mean (standard deviation)
    -4.01 ± 7.8
    -1.24 ± 0.9
    Statistical analysis title
    		 effect of IMP on change of central pulse pressure
    Comparison groups
    Empagliflozin v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 ≤ 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%

    Primary: effect of IMP on change of augmentation pressure

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    End point title
    		 effect of IMP on change of augmentation pressure
    End point description
    measured by SphygmCor
    End point type
    Primary
    End point timeframe
    6 weeks
    End point values
    		 Empagliflozin Placebo
    Number of subjects analysed
    71
    71
    Units: mmHg
        arithmetic mean (standard deviation)
    -1.44 ± 4.3
    -0.53 ± 4.6
    Statistical analysis title
    		 effect of IMP on change of augmentation pressure
    Comparison groups
    Empagliflozin v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 ≤ 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 2.5

    Primary: effect of IMP on change of forward wave amplitude

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    End point title
    		 effect of IMP on change of forward wave amplitude
    End point description
    measured by SphygmoCor
    End point type
    Primary
    End point timeframe
    6 weeks
    End point values
    		 Empagliflozin Placebo
    Number of subjects analysed
    69
    68
    Units: mmHg
        arithmetic mean (standard deviation)
    -2.13 ± 4.6
    -0.36 ± 5.6
    Statistical analysis title
    		 effect of IMP on change of forward wave amplitude
    Comparison groups
    Empagliflozin v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 ≤ 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 2.5

    Primary: effect of IMP on change of backward wave amplitude

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    End point title
    		 effect of IMP on change of backward wave amplitude
    End point description
    measured by SphygmoCor
    End point type
    Primary
    End point timeframe
    6 weeks
    End point values
    		 Empagliflozin Placebo
    Number of subjects analysed
    69
    68
    Units: mmHg
        arithmetic mean (standard deviation)
    -2.14 ± 4.2
    -0.74 ± 5.2
    Statistical analysis title
    		 effect of IMP on change of backward wave amplitude
    Comparison groups
    Empagliflozin v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 ≤ 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 2.5

    Secondary: effect of IMP on change of retinal capillary flow

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    End point title
    		 effect of IMP on change of retinal capillary flow
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Empagliflozin Placebo
    Number of subjects analysed
    63
    63
    Units: AU
        arithmetic mean (standard deviation)
    7.9 ± 101
    8.21 ± 84
    No statistical analyses for this end point

    Secondary: effect of IMP on change of retinal capillary flow after flickering

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    End point title
    		 effect of IMP on change of retinal capillary flow after flickering
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Empagliflozin Placebo
    Number of subjects analysed
    67
    67
    Units: AU
        arithmetic mean (standard deviation)
    -0.14 ± 84
    -1.88 ± 85
    No statistical analyses for this end point

    Secondary: effect of IMP on change of pulse wave velocity

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    End point title
    		 effect of IMP on change of pulse wave velocity
    End point description
    measured by SphygmoCor
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Empagliflozin Placebo
    Number of subjects analysed
    67
    67
    Units: m/s
        arithmetic mean (standard deviation)
    -0.01 ± 1.5
    0.01 ± 1.5
    No statistical analyses for this end point

    Secondary: effect of IMP on change of 24-h-ambulatory systolic blood pressure

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    End point title
    		 effect of IMP on change of 24-h-ambulatory systolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Empagliflozin Placebo
    Number of subjects analysed
    71
    70
    Units: mmHg
        arithmetic mean (standard deviation)
    -2.08 ± 8.1
    -0.07 ± 7.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    In the course of the intire study , each adverse event had to be reported on an Adverse Event Case Report Form as soon as known, in general at the subsequent study visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    all patients treated with IMP
    Reporting group description
    		 -

    Serious adverse events
    		 all patients treated with IMP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 74 (1.35%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Skin and subcutaneous tissue disorders
    Basal cell carcinoma
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 all patients treated with IMP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 74 (50.00%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    5
    Headache
         subjects affected / exposed
    8 / 74 (10.81%)
         occurrences all number
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    5
    Back pain
         subjects affected / exposed
    6 / 74 (8.11%)
         occurrences all number
    6
    Infections and infestations
    Cystitis
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    5
    Nasopharyngitis
         subjects affected / exposed
    8 / 74 (10.81%)
         occurrences all number
    8

    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.
    None reported
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