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    Clinical Trial Results:
    Effects on blood pressure and central sympathetic nerve traffic by SGLT2-inhibition with empagliflozin compared to hydrochlorothiazide in patients with type 2 diabetes mellitus

    Summary
    EudraCT number
    		 2017-002175-25
    Trial protocol
    		 DE  
    Global end of trial date
    20 Apr 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Dec 2021
    First version publication date
    05 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Empa2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03254849
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Profil Institut für Stoffwechselforschung GmbH
    Sponsor organisation address
    Hellersbergstr. 9, Neuss, Germany, 41460
    Public contact
    Project Management, Profil Institut für Stoffwechselforschung GmbH, +49 21314018146, empa2@profil.com
    Scientific contact
    Project Management, Profil Institut für Stoffwechselforschung GmbH, +49 21314018146, empa2@profil.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
    12 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To show that BP reduction with empagliflozin treatment is associated with lesser increase in sympathetic nerve traffic when compared to HCT treatment
    Protection of trial subjects
    In this study, many patients were on a combination therapy with RAS inhibitors and HCT at screening. Intermediate pausing and re-initiation of HCT treatment appeared to be a safe procedure in patients having previously taken and tolerated the combination therapy. Patients were advised about the risks of volume loss and hypovolemia in association with diuretic treatment, and should report to the investigator immediately in case of vomiting, diarrhea and comparable situations. Both IMPs are approved for treatment of patients with type 2 diabetes mellitus or hypertension, respectively, in Germany.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Oct 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: 41
    Worldwide total number of subjects
    41
    EEA total number of subjects
    41
    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)
    21
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment from the own database; advertisement on homepage

    Pre-assignment
    Screening details
    		 - women and men ≥ 50 and ≤ 80 years of age - type 2 diabetes mellitus for ≥ 2 years - only metformin monotherapy is allowed; metformin dose must have been stable for ≥ 12 weeks - stable or no antihypertensive treatment - HbA1c ≥ 6.5% and ≤ 10.0% - body mass index > 25 kg/m2 and < 40 kg/m²

    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
    		 Subject, Investigator
    Blinding implementation details
    Placebo tablets closely match empagliflozin or HCT tablets.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Empagliflozin arm
    Arm description
    		 Empagliflozin 25 mg (1 tablet) + HCT placebo (1 tablet)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Jardiance (Empagliflozin)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg/day for 6 weeks

    Investigational medicinal product name
    HCT Placebo (P-Tabletten weiß 8 mm Lichtenstein)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo administration for 6 weeks

    Arm title
    		 HCT arm
    Arm description
    		 Hydrochlorthiazide 25 (1 tablet) + empagliflozin placebo (1 tablet)
    Arm type
    		 Experimental

    Investigational medicinal product name
    HCT-ratiopharm® 25 mg Tabletten
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg/day for 6 weeks

    Investigational medicinal product name
    Empagliflozin placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 placebo tablet/day for 6 weeks

    Number of subjects in period 1
    		Empagliflozin arm HCT arm
    Started
    20
    21
    Completed
    18
    20
    Not completed
    2
    1
         unsuccessful MSNA attempts at Profiling 2
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (overall period)
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial (overall period) Total
    Number of subjects
    		 41 41
    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)
    		 21 21
        From 65-84 years
    		 20 20
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 64.0 ( 6.35 ) -
    Gender categorical
    Units: Subjects
        Female
    		 16 16
        Male
    		 25 25
    BMI
    Body mass index
    Units: kg/m²
        median (standard deviation)
    		 30.80 ( 3.489 ) -
    Weight
    Units: kg
        median (standard deviation)
    		 87.00 ( 14.729 ) -
    Height
    Units: cm
        median (standard deviation)
    		 171.0 ( 9.66 ) -

    End points

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    End points reporting groups
    Reporting group title
    Empagliflozin arm
    Reporting group description
    		 Empagliflozin 25 mg (1 tablet) + HCT placebo (1 tablet)

    Reporting group title
    HCT arm
    Reporting group description
    		 Hydrochlorthiazide 25 (1 tablet) + empagliflozin placebo (1 tablet)

    Primary: Change in MSNA (muscle sympathetic nerve activity) burst frequency

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    End point title
    		 Change in MSNA (muscle sympathetic nerve activity) burst frequency
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to the end of therapy
    End point values
    		 Empagliflozin arm HCT arm
    Number of subjects analysed
    18
    20
    Units: MSNA burst frequency (burst/min)
        arithmetic mean (standard deviation)
    -0.821 ( 9.6601 )
    3.621 ( 12.0446 )
    Statistical analysis title
    		 Primary Endpoint
    Comparison groups
    Empagliflozin arm v HCT arm
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5406
    Method
    		 Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to end of trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Empagliflozin arm
    Reporting group description
    		 -

    Reporting group title
    HCT arm
    Reporting group description
    		 -

    Serious adverse events
    		 Empagliflozin arm HCT arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (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: 0%
    Non-serious adverse events
    		 Empagliflozin arm HCT arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 20 (55.00%)
    11 / 21 (52.38%)
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Allodynia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Neuralgia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Thirst
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 21 (4.76%)
         occurrences all number
    4
    1
    Chest pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Hunger
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    3
    Abdominal pain
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Dry mouth
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    5 / 20 (25.00%)
    5 / 21 (23.81%)
         occurrences all number
    5
    5
    Polyuria
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Pruritus genital
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Arthritis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Pain in extremity
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 21 (14.29%)
         occurrences all number
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Sep 2017
    Changes due to BfArM objections
    17 Jan 2019
    Changes in matching criteria

    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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