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    Clinical Trial Results:
    A double-blind randomized study to determine the effect of empagliflozin versus placebo on brain insulin sensitivity in patients with prediabetes

    Summary
    EudraCT number
    		 2016-003477-18
    Trial protocol
    		 DE  
    Global end of trial date
    25 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Mar 2022
    First version publication date
    29 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Empabrain01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03227484
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital Tuebingen
    Sponsor organisation address
    Geissweg 3, Tuebingen, Germany, 72076
    Public contact
    PD Dr.med. Martin Heni, University Hospital Tuebingen, +49 70712982711, martin.heni@med.uni-tuebingen.de
    Scientific contact
    PD Dr.med. Martin Heni, University Hospital Tuebingen, +49 70712982711, martin.heni@med.uni-tuebingen.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
    Final
    Date of interim/final analysis
    18 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Key objective: to assess the effect of treatment with 25 mg empagliflozin daily versus placebo on regional brain insulin sensitivity. Effect of 8 weeks treatment with 25 mg empagliflozin or placebo on regional brain insulin sensitivity assessed by functional magnetic resonance imaging as change in regional cerebral blood flow from before to 30 minutes after nasal insulin spray application.
    Protection of trial subjects
    The study was conducted in a GCP-compliant manner. The ethics committee and the higher federal authority evaluated the study before start. The subjects were informed in detail prior to consent. The study was conducted in conformance to all relevant regulations regarding the protection of human subjects participating in clinical studies.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jul 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
    Germany: 42
    Worldwide total number of subjects
    42
    EEA total number of subjects
    42
    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)
    27
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at one site in Germany. Subjects were recruited from July 2017 to August 2019.

    Pre-assignment
    Screening details
    		 82 subjects were screened on fasting blood glucose betweeen 100 and 125 mg/dl and/or 2-hour post load glucose betwween 140 and 199 mg/dl during a 75 g oral glucose tolerance test and on a body mass index between 25 and 40 kg/m². 42 were enrolled and randomized.

    Pre-assignment period milestones
    Number of subjects started
    		 42
    Number of subjects completed

    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
    		 Investigator, Monitor, Carer, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Empagliflozin
    Arm description
    		 During the treatment phase of this trial participants will receive 25mg Empagliflozin daily. Human nasal insulin was only used to examine brain insulin resistance.
    Arm type
    		 Active comparator

    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
    The subjects were treated with 25mg empagliflozin daily for 8 weeks.

    Investigational medicinal product name
    Human nasal insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Nasal use
    Dosage and administration details
    160 IU, nasal

    Arm title
    		 Placebo
    Arm description
    		 Subjects got Placebo matching empagliflozin 25 mg daily for 8 weeks. Human nasal insulin was only used to examine brain insulin resistance.
    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
    The subjects got placebo matching empagliflozin 25 mg.

    Investigational medicinal product name
    Human nasal insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Nasal use
    Dosage and administration details
    160 IU, nasal

    Number of subjects in period 1 [1]
    		Empagliflozin Placebo
    Started
    19
    21
    Completed
    19
    21
    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: 40 patients were planned, 82 were screened between 2017 - 2019. 42 patients were enrolled and 40 analyzed. 2 patients were drop-outs.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Empagliflozin
    Reporting group description
    		 During the treatment phase of this trial participants will receive 25mg Empagliflozin daily. Human nasal insulin was only used to examine brain insulin resistance.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects got Placebo matching empagliflozin 25 mg daily for 8 weeks. Human nasal insulin was only used to examine brain insulin resistance.

    Reporting group values
    		 Empagliflozin Placebo Total
    Number of subjects
    		 19 21 40
    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)
    		 15 10 25
        From 65-84 years
    		 4 11 15
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 19 ± 0 21 ± 0 -
    Gender categorical
    Units: Subjects
        Female
    		 14 10 24
        Male
    		 5 11 16

    End points

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    End points reporting groups
    Reporting group title
    Empagliflozin
    Reporting group description
    		 During the treatment phase of this trial participants will receive 25mg Empagliflozin daily. Human nasal insulin was only used to examine brain insulin resistance.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects got Placebo matching empagliflozin 25 mg daily for 8 weeks. Human nasal insulin was only used to examine brain insulin resistance.

    Primary: • Effect of 8 weeks treatment with 25 mg empagliflozin or placebo on regional brain insulin sensitivity

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    End point title
    		 • Effect of 8 weeks treatment with 25 mg empagliflozin or placebo on regional brain insulin sensitivity [1]
    End point description
    End point type
    Primary
    End point timeframe
    Effect of 8 weeks treatment with 25 mg empagliflozin or placebo on regional brain insulin sensitivity assessed by functional magnetic resonance imaging as change in regional cerebral blood flow from before to 30 minutes after nasal insulin spray applica
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have ben specified for this primary endpoint. Statistical analysis can be found in the attached documents.
    End point values
    		 Empagliflozin Placebo
    Number of subjects analysed
    19
    21
    Units: hypothalamus insulin sensitivity
        number (not applicable)
    19
    21
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    09.08.2017 - 25.10.2019
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Empagliflozin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Empagliflozin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (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: 5%
    Non-serious adverse events
    		 Empagliflozin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 19 (63.16%)
    9 / 21 (42.86%)
    Investigations
    Urine leukocyte esterase positive
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    Blood creatine phosphokinase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Injury, poisoning and procedural complications
    Fall
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
         occurrences all number
    2
    2
    Vascular disorders
    Presyncope
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Haematoma
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Ear and labyrinth disorders
    Deafness unilateral
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Eye disorders
    Hordeolum
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    Gingival pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    Toothache
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Fibrinous bronchitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    Nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 19 (15.79%)
    1 / 21 (4.76%)
         occurrences all number
    4
    4
    Skin and subcutaneous tissue disorders
    Pruritus
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    Rash
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Dysuria
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 21 (4.76%)
         occurrences all number
    2
    2
    Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 21 (9.52%)
         occurrences all number
    3
    3
    Renal cyst
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthritis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    Spinal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Pain in extremity
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Myalgia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    Back pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1

    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
    For support, Contact us.
    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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