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    Clinical Trial Results:
    Empagliflozin in heart failure patients with reduced ejection fraction: A randomized clinical trial (Empire HF)

    Summary
    EudraCT number
    		 2017-001341-27
    Trial protocol
    		 DK  
    Global end of trial date
    20 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Dec 2020
    First version publication date
    19 Dec 2020
    Other versions
    Summary report(s)
    		 Design paper

    Trial information

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    Trial identification
    Sponsor protocol code
    Empire-2017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03198585
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Morten Schou
    Sponsor organisation address
    Department of Cardiology, Herlev-Gentofte University Hospital, Borgmester Ib Juuls Vej 1, Herlev, Denmark, 2730
    Public contact
    Mr. Jesper Jensen, MD, Department of Cardiology, Herlev-Gentofte University Hospital, +45 38686258, jesper.jensen.06@regionh.dk
    Scientific contact
    Mr. Jesper Jensen, MD, Department of Cardiology, Herlev-Gentofte University Hospital, +45 38686258, jesper.jensen.06@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
    13 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of 3 months’ treatment with Empagliflozin 10 mg a day on changes in plasma concentrations of NT-proBNP in stable, symptomatic HF patients with reduced left ventricular ejection fraction (LVEF).
    Protection of trial subjects
    The safety of randomized patients was monitored continuously based on recordings of adverse and severe adverse events.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Jun 2017
    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
    Denmark: 190
    Worldwide total number of subjects
    190
    EEA total number of subjects
    190
    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)
    100
    From 65 to 84 years
    90
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment period June 29, 2017, to September 10, 2019. Recruited from heart failure clinics in Denmark.

    Pre-assignment
    Screening details
    		 No wash-out or run-in. In total, 697 were assessed for eligibility, 507 were excluded (n=317 not meeting inclusion criteria, n=139 declined to participate, n=51 due to other reasons).

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Empagliflozin
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg once daily

    Arm title
    		 Placebo
    Arm description
    		 -
    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
    Matching

    Number of subjects in period 1
    		Empagliflozin Placebo
    Started
    95
    95
    Completed
    95
    94
    Not completed
    0
    1
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Empagliflozin Placebo Total
    Number of subjects
    		 95 95 190
    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))
    		 64 (57 to 73) 63 (55 to 72) -
    Gender categorical
    Units: Subjects
        Female
    		 16 12 28
        Male
    		 79 83 162

    End points

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

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: NT-proBNP

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    End point title
    		 NT-proBNP
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to 90 days
    End point values
    		 Empagliflozin Placebo
    Number of subjects analysed
    94
    92
    Units: Ratio of change
        median (inter-quartile range (Q1-Q3))
    0.96 (0.69 to 1.24)
    0.93 (0.77 to 1.21)
    Statistical analysis title
    		 NT-proBNP
    Comparison groups
    Empagliflozin v Placebo
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.11

    Secondary: Daily activity level

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    End point title
    		 Daily activity level
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 90 days
    End point values
    		 Empagliflozin Placebo
    Number of subjects analysed
    82
    84
    Units: Difference of change
        arithmetic mean (standard deviation)
    -54.6 ( 253.3 )
    -4.9 ( 198.3 )
    Statistical analysis title
    		 Daily activity level
    Comparison groups
    Empagliflozin v Placebo
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -88
         upper limit
    		 36

    Secondary: Health-related quality of life (KCCQ)

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    End point title
    		 Health-related quality of life (KCCQ)
    End point description
    KCCQ overall summary score
    End point type
    Secondary
    End point timeframe
    Baseline to 90 days
    End point values
    		 Empagliflozin Placebo
    Number of subjects analysed
    94
    92
    Units: Difference of change
        arithmetic mean (standard deviation)
    1.9 ( 12.3 )
    1.2 ( 9.4 )
    Statistical analysis title
    		 KCCQ
    Comparison groups
    Empagliflozin v Placebo
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 3.9

    Secondary: Health-related quality of life (EQ-5D-5L)

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    End point title
    		 Health-related quality of life (EQ-5D-5L)
    End point description
    EQ-5D-5L VAS
    End point type
    Secondary
    End point timeframe
    Baseline to 90 days
    End point values
    		 Empagliflozin Placebo
    Number of subjects analysed
    94
    92
    Units: Difference of change
        arithmetic mean (standard deviation)
    2.4 ( 13.6 )
    3.6 ( 14.6 )
    Statistical analysis title
    		 EQ-5D-5L
    Comparison groups
    Empagliflozin v Placebo
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 2.7

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to 90 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    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
    6 / 95 (6.32%)
    4 / 95 (4.21%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Heart failure hospitalization
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardioversion of atrial fibrillation or flutter
         subjects affected / exposed
    3 / 95 (3.16%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Stroke
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Recurrent bladder cancer
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 95 (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
    Gout
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone fracture
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 95 (1.05%)
         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: 0%
    Non-serious adverse events
    		 Empagliflozin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 95 (7.37%)
    9 / 95 (9.47%)
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    3 / 95 (3.16%)
    3 / 95 (3.16%)
         occurrences all number
    3
    3
    Genital infection
         subjects affected / exposed
    3 / 95 (3.16%)
    5 / 95 (5.26%)
         occurrences all number
    3
    5
    Endocrine disorders
    Hypoglycemia
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 95 (1.05%)
         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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32798787
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