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    Clinical Trial Results:
    Effects of empagliflozin on diuresis and renal function in patients with acute decompensated heart failure

    Summary
    EudraCT number
    		 2018-003692-35
    Trial protocol
    		 DE  
    Global end of trial date
    29 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Dec 2023
    First version publication date
    20 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ZKSJ0109
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04049045
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ZKS Protocol Code: ZKSJ0109_EMPAG-HF
    Sponsors
    Sponsor organisation name
    Friedrich-Schiller-Universität Jena
    Sponsor organisation address
    Am Klinikum 1, Jena, Germany, 07747
    Public contact
    Center for Clinical Studies, University Hospital, ZKS@med.uni-jena.de
    Scientific contact
    Department of Internal Medicine I, Division of Cardiology, Pneumology, Angiology and IMC, University Hospital, 0049 3641 9324101, christian.schulze@med.uni-jena.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
    03 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jun 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of empagliflozin plus loop diuretics versus placebo plus loop diuretics in patients with ADHF on the increase of urine output
    Protection of trial subjects
    The application of the Intervention (oral applicateion of investigational drug/matching placebo, one tablet per day) is very similar to the one usually applied in clinical routine. Study specific measures were limited to a few general clinical examinations and additional laboratory parameters.
    Background therapy
    		 -
    Evidence for comparator
    		 matching placebo used
    Actual start date of recruitment
    01 Mar 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    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)
    9
    From 65 to 84 years
    49
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 60 patients were recruited from 29Sep2019 to 30Apr2021.

    Pre-assignment
    Screening details
    		 59 patients treated, one screening failure

    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, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Verum arm
    Arm description
    		 Empagliflozin 25 mg film-coated tablets, for oral use
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin 25 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25mg Empagliflozin once daily for 5 days in addition to routinely administered (weight adjusted) intravenous furosemide

    Arm title
    		 Placebo arm
    Arm description
    		 Placebo tablet, film-coated tablets, for oral use, matching to investigational product.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo once daily for 5 days

    Number of subjects in period 1 [1]
    		Verum arm Placebo arm
    Started
    30
    29
    Completed
    30
    29
    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: 60 patients were screened worldwide, for one patient later turned out that one inclusion criterion wasn`t met (before treatment).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Verum arm
    Reporting group description
    		 Empagliflozin 25 mg film-coated tablets, for oral use

    Reporting group title
    Placebo arm
    Reporting group description
    		 Placebo tablet, film-coated tablets, for oral use, matching to investigational product.

    Reporting group values
    		 Verum arm Placebo arm Total
    Number of subjects
    		 30 29 59
    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
        median (inter-quartile range (Q1-Q3))
    		 76.5 (66 to 81) 80.0 (71 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 11 12 23
        Male
    		 19 17 36
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients with intention to treat

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients without major protocol deviations

    Subject analysis sets values
    		 ITT PP
    Number of subjects
    59
    55
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    80 (68 to 82)
    80 (68 to 82)
    Gender categorical
    Units: Subjects
        Female
    36
    34
        Male
    23
    21

    End points

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    End points reporting groups
    Reporting group title
    Verum arm
    Reporting group description
    		 Empagliflozin 25 mg film-coated tablets, for oral use

    Reporting group title
    Placebo arm
    Reporting group description
    		 Placebo tablet, film-coated tablets, for oral use, matching to investigational product.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients with intention to treat

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients without major protocol deviations

    Primary: Total urine output summed over 5 days

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    End point title
    		 Total urine output summed over 5 days
    End point description
    End point type
    Primary
    End point timeframe
    over 5 days
    End point values
    		 Verum arm Placebo arm ITT PP
    Number of subjects analysed
    28
    29
    57
    53
    Units: ml
        median (inter-quartile range (Q1-Q3))
    10775 (9100 to 12925)
    8650 (6450 to 10350)
    9500 (7750 to 11400)
    9500 (7750 to 11400)
    Statistical analysis title
    		 Mann-Whitney U Test
    Comparison groups
    Verum arm v Placebo arm
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    2125
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 840
         upper limit
    		 3550
    Variability estimate
    Standard error of the mean

    Secondary: net urine output over 5 days

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    End point title
    		 net urine output over 5 days
    End point description
    End point type
    Secondary
    End point timeframe
    over 5 days
    End point values
    		 Verum arm Placebo arm ITT PP
    Number of subjects analysed
    28
    29
    57
    53
    Units: ml
        median (inter-quartile range (Q1-Q3))
    3725 (2621.5 to 5829.5)
    1480 (650 to 3825.7)
    3100 (1200 to 5184)
    3000 (1200 to 5184)
    No statistical analyses for this end point

    Secondary: net fluid output over 5 days

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    End point title
    		 net fluid output over 5 days
    End point description
    End point type
    Secondary
    End point timeframe
    over 5 days
    End point values
    		 Verum arm Placebo arm ITT PP
    Number of subjects analysed
    28
    29
    57
    53
    Units: ml
        median (inter-quartile range (Q1-Q3))
    3925 (2825 to 6505)
    1680 (850 to 4025.7)
    3350 (1400 to 5384)
    3300 (1400 to 5384)
    Statistical analysis title
    		 Mann-Whitney U Test
    Comparison groups
    Verum arm v Placebo arm
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    2005
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 700
         upper limit
    		 3300
    Variability estimate
    Standard error of the mean

    Secondary: change in body weight

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    End point title
    		 change in body weight
    End point description
    End point type
    Secondary
    End point timeframe
    day 5
    End point values
    		 Verum arm Placebo arm ITT
    Number of subjects analysed
    28
    25
    53
    Units: kg
        arithmetic mean (standard deviation)
    -4.19 ( 3.53 )
    -3.02 ( 2.97 )
    -3.64 ( 3.24 )
    Statistical analysis title
    		 Independent samples t-test
    Comparison groups
    Verum arm v Placebo arm
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.198
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.99
         upper limit
    		 0.63
    Variability estimate
    Standard error of the mean

    Secondary: cumulative dose of diuretics

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    End point title
    		 cumulative dose of diuretics
    End point description
    End point type
    Secondary
    End point timeframe
    over 5 days
    End point values
    		 Verum arm Placebo arm ITT
    Number of subjects analysed
    30
    29
    59
    Units: mg Furosemide equivalent
        arithmetic mean (standard deviation)
    313.04 ( 194.57 )
    351.41 ( 220.66 )
    331.9 ( 206.9 )
    Statistical analysis title
    		 indemendent samples t-test
    Comparison groups
    Verum arm v Placebo arm
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.481
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -38.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -176.7
         upper limit
    		 70
    Variability estimate
    Standard error of the mean

    Secondary: diuretic efficiency

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    End point title
    		 diuretic efficiency
    End point description
    End point type
    Secondary
    End point timeframe
    over 5 days
    End point values
    		 Verum arm Placebo arm ITT
    Number of subjects analysed
    28
    29
    57
    Units: mL/mg Furosemide equivalent
        median (inter-quartile range (Q1-Q3))
    8.3 (-32.9 to 58.8)
    -25.9 (-80.3 to 16.8)
    1.0 (-58.6 to 32.5)
    Statistical analysis title
    		 Mann-Whitney U Test
    Comparison groups
    Verum arm v Placebo arm
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.049
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    43.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 93
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to day 30
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Precoded terms
    Dictionary version
    1.0
    Reporting groups
    Reporting group title
    Treatment group
    Reporting group description
    		 -

    Reporting group title
    Placebo group
    Reporting group description
    		 -

    Serious adverse events
    		 Treatment group Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 30 (16.67%)
    7 / 29 (24.14%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    1
    2
    Vascular disorders
    Hypotension
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac tamponade
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina unstable
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 29 (10.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Transient ischaemic attack
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
    Additional description: Heart failure
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory acidosis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment group Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 30 (13.33%)
    9 / 29 (31.03%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Cardiac disorders
    Worsening of heart failure
         subjects affected / exposed
    1 / 30 (3.33%)
    4 / 29 (13.79%)
         occurrences all number
    1
    4
    Infections and infestations
    Covid-19 infection
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 30 (3.33%)
    4 / 29 (13.79%)
         occurrences all number
    1
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 May 2020
    Change of in- and exclusion criteria based on current research results and prolongation of planned study duration.

    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.
    Short observation period not sufficient to observe AEs after discharge. Study not powered for analysis of end points such as cardiovascular mortality. Focus was early decongestion, inclusion within 12 h of hospitalization.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35766022
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