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    Clinical Trial Results:
    A Phase III randomised, double-blind trial to evaluate the effect of 12 weeks treatment of once daily EMPagliflozin 10 mg compared with placebo on ExeRcise ability and heart failure symptoms, In patients with chronic HeArt FaiLure with reduced Ejection Fraction (HFrEF) (EMPERIAL – reduced)

    Summary
    EudraCT number
    		 2017-004073-14
    Trial protocol
    		 ES   GR   PT   PL   SE   NO   IT  
    Global end of trial date
    07 Oct 2019

    Results information
    Results version number
    		 v1
    This version publication date
    15 Oct 2020
    First version publication date
    15 Oct 2020
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    1245-0168
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03448419
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Straße 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim, Call Centre, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim, Call Centre, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.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
    04 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to evaluate the effect of empagliflozin 10 mg vs. placebo on exercise ability using the 6-minute walk test (6MWT) in patients with chronic heart failure (CHF) with reduced left ventricular ejection fraction (LVEF ≤40%). Secondary objectives were to assess patient-reported Outcomes (PRO).
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. An independent DMC was formed to monitor patients’ safety throughout the conduct of the trial at regular meetings. An independent external CEC adjudicated selected hepatic events and ketoacidosis while blinded to the patient’s treatment allocation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Mar 2018
    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
    Australia: 12
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Germany: 63
    Country: Number of subjects enrolled
    Spain: 52
    Country: Number of subjects enrolled
    Greece: 37
    Country: Number of subjects enrolled
    Italy: 27
    Country: Number of subjects enrolled
    Norway: 20
    Country: Number of subjects enrolled
    Poland: 101
    Country: Number of subjects enrolled
    Portugal: 44
    Country: Number of subjects enrolled
    Sweden: 17
    Country: Number of subjects enrolled
    United States: 317
    Worldwide total number of subjects
    707
    EEA total number of subjects
    361
    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)
    258
    From 65 to 84 years
    424
    85 years and over
    25

    Subject disposition

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    Recruitment
    Recruitment details
    		 Randomised, double-blind, placebo-controlled, parallel-group trial in patients with chronic Heart Failure with reduced Ejection Fraction (HFrEF) to evaluate the effect of Empagliflozin versus Placebo on exercise and heart failure symptoms.

    Pre-assignment
    Screening details
    		 Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct.

    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, Data analyst, Subject, Assessor
    Blinding implementation details
    Patients, investigators, and everyone involved in trial conduct or analysis or with any other interest in this double-blind trial remained blinded with regard to the randomised treatment assignments until after database lock. The randomisation code was kept secret by Clinical Trial Support up to database lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 1 film-coated tablet of placebo matching empagliflozin was administered orally once daily for 12 weeks in subjects with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).
    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
    1 film-coated tablet of placebo matching empagliflozin was administered orally once daily for 12 weeks in subjects with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).

    Arm title
    		 10 mg Empagliflozin
    Arm description
    		 1 film-coated tablet of 10 milligram (mg) of empagliflozin was administered orally once daily for 12 weeks in subjects with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Jardiance®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 film-coated tablet of 10 milligram (mg) of Empagliflozin was administered orally once daily for 12 weeks in subjects with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).

    Number of subjects in period 1 [1]
    		Placebo 10 mg Empagliflozin
    Started
    156
    156
    Treated
    156
    155
    Completed
    143
    140
    Not completed
    13
    16
         Adverse event, serious fatal
    3
    1
         Consent withdrawn by subject
    3
    1
         Withdrawn by Sponsor
    -
    1
         Adverse event, non-fatal
    7
    8
         Lost to follow-up
    -
    2
         Patient did not attend all visits
    -
    2
         Not treated
    -
    1
    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: 707 subjects were enrolled worldwide and thereof 312 subjects were included in the trial.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 1 film-coated tablet of placebo matching empagliflozin was administered orally once daily for 12 weeks in subjects with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).

    Reporting group title
    10 mg Empagliflozin
    Reporting group description
    		 1 film-coated tablet of 10 milligram (mg) of empagliflozin was administered orally once daily for 12 weeks in subjects with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).

    Reporting group values
    		 Placebo 10 mg Empagliflozin Total
    Number of subjects
    		 156 156 312
    Age categorical
    Randomised Set: All subjects that were randomised, regardless of whether treated or not.
    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)
    		 48 47 95
        From 65-84 years
    		 97 106 203
        85 years and over
    		 11 3 14
    Age Continuous
    Randomised Set: All subjects that were randomised, regardless of whether treated or not.
    Units: years
        arithmetic mean (standard deviation)
    		 69.3 ( 10.6 ) 68.7 ( 9.9 ) -
    Sex: Female, Male
    Randomised Set: All subjects that were randomised, regardless of whether treated or not.
    Units: Subjects
        Female
    		 45 35 80
        Male
    		 111 121 232
    Race (NIH/OMB)
    Randomised Set: All subjects that were randomised, regardless of whether treated or not.
    Units: Subjects
        American Indian or Alaska Native
    		 1 1 2
        Asian
    		 2 1 3
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 18 24 42
        White
    		 133 130 263
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 1 0 1
    Ethnicity (NIH/OMB)
    Randomised Set: All subjects that were randomised, regardless of whether treated or not.
    Units: Subjects
        Hispanic or Latino
    		 23 20 43
        Not Hispanic or Latino
    		 132 136 268
        Unknown or Not Reported
    		 1 0 1
    Exercise capacity as measured by the 6-Minutes-Walking-Test (6MWT) distance at baseline
    6 Minute Walking test measures the distance walked in 6 minutes in standardised conditions at baseline. Randomised Set: All subjects that were randomised, regardless of whether treated or not.
    Units: Meter
        median (inter-quartile range (Q1-Q3))
    		 309.0 (248.5 to 332.0) 306.0 (260.0 to 333.5) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 1 film-coated tablet of placebo matching empagliflozin was administered orally once daily for 12 weeks in subjects with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).

    Reporting group title
    10 mg Empagliflozin
    Reporting group description
    		 1 film-coated tablet of 10 milligram (mg) of empagliflozin was administered orally once daily for 12 weeks in subjects with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).

    Primary: Change from baseline to week 12 in exercise capacity as measured by the 6-Minutes-Walking-Test (6MWT) distance

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    End point title
    		 Change from baseline to week 12 in exercise capacity as measured by the 6-Minutes-Walking-Test (6MWT) distance
    End point description
    Change from baseline to week 12 in exercise capacity as measured by the distance walked in 6 minutes in standardised conditions. If repeated 6MWT measurements were available for the same day, the longest distance was used for analysis. Change from baseline was defined as the distance walked in 6 minutes at week 12 minus the baseline value. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. If a subject was present at the visit at week 12 but did not perform the 6MWT, the subject was evaluated as having walked a distance of 0 meter. If no value was available for week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above. Randomised Set (RS).
    End point type
    Primary
    End point timeframe
    At baseline and at week 12
    End point values
    		 Placebo 10 mg Empagliflozin
    Number of subjects analysed
    156 [1]
    156 [2]
    Units: Meter (m)
        median (inter-quartile range (Q1-Q3))
    18.0 (-11.5 to 54.0)
    13.5 (-8.0 to 42.0)
    Notes
    [1] - RS
    [2] - RS
    Statistical analysis title
    		 Superiority of Empagliflozin vs. Placebo
    Statistical analysis description
    H0: There is no difference between the effect of placebo and the effect of empagliflozin.
    Comparison groups
    Placebo v 10 mg Empagliflozin
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4236
    Method
    		 Wilcoxon rank test, normal approximation
    Parameter type
    		 Median difference (HL-estimate)
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16
         upper limit
    		 6

    Secondary: Change from baseline to week 12 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS)

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    End point title
    		 Change from baseline to week 12 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS)
    End point description
    Change from baseline in KCCQ-TSS was defined as the endpoint value at week 12 minus the last available measurement before start of treatment with randomised study medication. The KCCQ is 23 item self-administered questionnaire and comprises 7 domains: physical limitation, symptom frequency, symptom burden, symptom stability, social limitation, self-efficacy and quality of life. Additionally 3 summary scores exist: TSS, clinical summary score, and overall summary score. The scores of the KCCQ domains and summary scores range from 0 to 100, with higher score indicating better outcome. If no questionnaire was available at week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above. If no questionnaire was available at baseline, change from baseline was not imputed.
    End point type
    Secondary
    End point timeframe
    At baseline and at week 12
    End point values
    		 Placebo 10 mg Empagliflozin
    Number of subjects analysed
    156 [3]
    156 [4]
    Units: Score on a scale
        median (inter-quartile range (Q1-Q3))
    3.65 (-6.25 to 13.54)
    7.29 (-2.60 to 18.75)
    Notes
    [3] - Ranodmised Set (RS)
    [4] - Randomised Set (RS)
    Statistical analysis title
    		 Superiority of Empagliflozin vs. Placebo
    Statistical analysis description
    H0: There is no difference between the effect of placebo and the effect of empagliflozin.
    Comparison groups
    Placebo v 10 mg Empagliflozin
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0893
    Method
    		 Wilcoxon rank test, normal approximation
    Parameter type
    		 Median difference (HL-estimate)
    Point estimate
    3.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 7.29

    Secondary: Change from baseline to week 12 in Chronic Heart Failure Questionnaire Self- Administered Standardized format (CHQ-SAS) dyspnea score

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    End point title
    		 Change from baseline to week 12 in Chronic Heart Failure Questionnaire Self- Administered Standardized format (CHQ-SAS) dyspnea score
    End point description
    Change from baseline in CHQ-SAS was defined as the endpoint value at week 12 minus the last available endpoint value before start of treatment with randomised study medication. The CHQ-SAS evaluates 3 domains: dyspnoea, fatigue, and emotional function. Scores of the domains range from 1 to 7, with higher score indicating better quality of life. If no questionnaire was available at week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above. If no questionnaire was available at baseline, change from baseline was not imputed. Subjects in the randomised set (RS) who have no missing values at baseline.
    End point type
    Secondary
    End point timeframe
    At baseline and at week 12
    End point values
    		 Placebo 10 mg Empagliflozin
    Number of subjects analysed
    156 [5]
    154 [6]
    Units: Score on scale
        median (confidence interval 95%)
    0.40 (-0.33 to 0.83)
    0.40 (-0.50 to 1.33)
    Notes
    [5] - Subjects in the randomised set (RS) who have no missing values at baseline.
    [6] - Subjects in the randomised set (RS) who have no missing values at baseline.
    Statistical analysis title
    		 Superiority of Empagliflozin vs. Placebo
    Statistical analysis description
    H0: There is no difference between the effect of placebo and the effect of empagliflozin.
    Comparison groups
    Placebo v 10 mg Empagliflozin
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4702
    Method
    		 Wilcoxon rank test, normal approximation
    Parameter type
    		 Median Difference (HL-estimate)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.4

    Secondary: Change from baseline to week 6 in exercise capacity as measured by the 6-Minutes-Walking-Test (6MWT) distance

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    End point title
    		 Change from baseline to week 6 in exercise capacity as measured by the 6-Minutes-Walking-Test (6MWT) distance
    End point description
    Change from baseline to week 6 in exercise capacity as measured by the distance walked in 6 minutes in standardised conditions. Change from baseline was defined as the distance walked in 6 minutes at week 6 minus the baseline value. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. If a subject was present at the visit at week 6 but did not perform the 6MWT, the subject was evaluated as having walked a distance of 0 meter. If no value was available for week 6, an imputed value was used. Randomised Set (RS): All subjects that were randomised, regardless of whether treated or not.
    End point type
    Secondary
    End point timeframe
    At baseline and at week 6
    End point values
    		 Placebo 10 mg Empagliflozin
    Number of subjects analysed
    156 [7]
    156 [8]
    Units: Meter (m)
        median (inter-quartile range (Q1-Q3))
    7.0 (-10.5 to 39.5)
    9.5 (-12.5 to 32.0)
    Notes
    [7] - RS
    [8] - RS
    Statistical analysis title
    		 Superiority of Empagliflozin vs. Placebo
    Statistical analysis description
    H0: There is no difference between the effect of placebo and the effect of empagliflozin.
    Comparison groups
    Placebo v 10 mg Empagliflozin
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.983
    Method
    		 Wilcoxon rank test, normal approximation
    Parameter type
    		 Median difference (HL-estimate)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9
         upper limit
    		 9

    Secondary: Change from baseline to week 12 in Clinical Congestion Score

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    End point title
    		 Change from baseline to week 12 in Clinical Congestion Score
    End point description
    Change from baseline to week 12 in Clinical Congestion score is defined as the score-value at week 12 minus the score-value at baseline. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. The Clinical Congestion score assessed the subjects congestion using a clinician-based outcome assessment of 6 different signs and symptoms: dyspnoea, orthopnoea, fatigue, jugular venous distention (as assessed by the investigator), rales, and oedema. Each category was assessed through a 4-measure questionnaire, which was further converted to a standardised 4-point scale ranging from 0 to 3, which 0 indicating no or fewer symptoms and 3 indicating continous or more symptoms. Mean is adjusted mean. Only subjects in the randomised set (RS) who have baseline and at least one post-baseline value, are included in the analysis.
    End point type
    Secondary
    End point timeframe
    At baseline and at week 12
    End point values
    		 Placebo 10 mg Empagliflozin
    Number of subjects analysed
    153 [9]
    155 [10]
    Units: Score on a scale
        arithmetic mean (standard error)
    -0.30 ( 0.08 )
    -0.61 ( 0.08 )
    Notes
    [9] - Only subjects in the randomised set (RS) who have baseline and at least one post-baseline value.
    [10] - Only subjects in the randomised set (RS) who have baseline and at least one post-baseline value.
    Statistical analysis title
    		 Effect of Empagliflozin vs Placebo
    Statistical analysis description
    Mixed model repeated measure included treatment-by-visit interaction and baseline value-by-visit interaction as fixed effects. Unstructured covariance structure was used to model within-patient errors.
    Comparison groups
    Placebo v 10 mg Empagliflozin
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0053
    Method
    		 Mixed Model repeated Measures (MMRM)
    Parameter type
    		 Adjusted mean
    Point estimate
    -0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 -0.09

    Secondary: Change from baseline to week 12 in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms

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    End point title
    		 Change from baseline to week 12 in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms
    End point description
    Change from baseline to week 12 in PGI-S of Heart Failure Symptoms. The Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms is a 1-item questionnaire to assess the patient’s impression of symptoms severity, specifically: shortness of breath, fatigue and swelling. The PGI-S asks the Patient to choose one response that best describes how his/her heart failure symptoms, specifically: shortness of breath, fatigue and swelling are now on a 5-point scale, ranging from ‘Not at all’ (1) to ‘Very severe’ (5). Number of participants by change in score are reported. Change in score was defined as the number of categories improved/deteriorated from baseline to week 12. Only subjects in the randomised set (RS) who have values at baseline and at week 12 are included in the analysis.
    End point type
    Secondary
    End point timeframe
    At baseline and at week 12
    End point values
    		 Placebo 10 mg Empagliflozin
    Number of subjects analysed
    149 [11]
    147 [12]
    Units: Subjects
        4 categories improvement
    0
    0
        3 categories improvement
    1
    1
        2 categories improvement
    13
    14
        1 category improvement
    41
    41
        No change
    73
    74
        1 category deterioration
    16
    16
        2 categories deterioration
    4
    1
        3 categories deterioration
    1
    0
        4 categories deterioration
    0
    0
    Notes
    [11] - Only subjects in the randomised set (RS) who have values at baseline and at week 12.
    [12] - Only subjects in the randomised set (RS) who have values at baseline and at week 12.
    Statistical analysis title
    		 Effect of Empagliflozin vs Placebo
    Statistical analysis description
    Test on difference in mean treatment scores, based on modified ridit scores.
    Comparison groups
    Placebo v 10 mg Empagliflozin
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6189
    Method
    		 Cochran-Mantel-Haenszel test
    Confidence interval

    Secondary: Change from baseline to week 12 in Patient Global Impression of Severity (PGI-S) of dyspnoea

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    End point title
    		 Change from baseline to week 12 in Patient Global Impression of Severity (PGI-S) of dyspnoea
    End point description
    Change from baseline to week 12 in Patient Global Impression of Severity (PGI-S) of dyspnoea. The PGI-S of Dyspnoea is a 1-item questionnaire designed to assess the participant´s impression of symptom severity, specifically dyspnoea. The PGI-S item asks the participant to choose one response that best describes how his/her dyspnoea is now on a 5-point scale, ranging from 'Not at all’ (1) to ‘Very severe’ (5). Number of subjects by change in score are reported. Change in score was defined as the number of categories improved/deteriorated from baseline to week 12. Only subjects in the randomised set (RS) who have values at baseline and at week 12 are included in the analysis.
    End point type
    Secondary
    End point timeframe
    At baseline and at week 12
    End point values
    		 Placebo 10 mg Empagliflozin
    Number of subjects analysed
    147 [13]
    150 [14]
    Units: Subjects
        4 categories improvment
    0
    0
        3 categories improvment
    3
    2
        2 categories improvement
    8
    11
        1 category improvement
    38
    46
        No change
    83
    70
        1 category deterioration
    13
    17
        2 categories deterioration
    2
    4
        3 categories deterioration
    0
    0
        4 categories deterioration
    0
    0
    Notes
    [13] - Only subjects in the randomised set (RS) who have values at baseline and at week 12.
    [14] - Only subjects in the randomised set (RS) who have values at baseline and at week 12.
    Statistical analysis title
    		 Effect of Empagliflozin vs Placebo
    Statistical analysis description
    Test on difference in mean treatment scores, based on modified ridit scores.
    Comparison groups
    10 mg Empagliflozin v Placebo
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6672
    Method
    		 Cochran-Mantel-Haenszel test
    Confidence interval

    Secondary: Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at week 12

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    End point title
    		 Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at week 12
    End point description
    The Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms is a 1-item questionnaire to assess the patient’s impression of change in heart failure symptoms, specifically: shortness of breath, fatigue, and swelling. The PGI-C asks the patient to choose one Response that best describes the overall change (if any) in his/her heart failure symptoms, specifically: shortness of breath, fatigue, and swelling since he/she started taking the study medication on a 7- category scale ranging from ‘Very much better’ (+3) to ‘Very much worse’ (-3). Only subjects in the randomised set (RS) who have week 12 value are included in the analysis.
    End point type
    Secondary
    End point timeframe
    At week 12
    End point values
    		 Placebo 10 mg Empagliflozin
    Number of subjects analysed
    150 [15]
    147 [16]
    Units: Subjects
        Very much worse
    0
    0
        Much worse
    3
    0
        A little worse
    7
    5
        No change
    57
    51
        A little better
    40
    52
        Much better
    34
    33
        Very much better
    9
    6
    Notes
    [15] - Only subjects in the randomised set (RS) who have week 12 value.
    [16] - Only subjects in the randomised set (RS) who have week 12 value.
    Statistical analysis title
    		 Effect of Empagliflozin vs Placebo
    Statistical analysis description
    Test on difference in mean treatment scores, based on modified ridit scores.
    Comparison groups
    Placebo v 10 mg Empagliflozin
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5147
    Method
    		 Cochran-Mantel-Haenszel test
    Confidence interval

    Secondary: Patient Global Impression of Change (PGI-C) in dyspnea at week 12

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    End point title
    		 Patient Global Impression of Change (PGI-C) in dyspnea at week 12
    End point description
    The PGI-C in Dyspnoea is a 1-item questionnaire designed to assess the patient’s Impression of change in dyspnoea. The PGI-C asks the patient to choose one response that best describes the change (if any) in his/her shortness of breath when performing usual activities since he/she started taking the study medication on a 7-category scale ranging from ‘Very much better’ (+3) to ‘Very much worse’ (-3). Only subjects in the randomised set (RS) who have week 12 value are included in the analysis.
    End point type
    Secondary
    End point timeframe
    At week 12
    End point values
    		 Placebo 10 mg Empagliflozin
    Number of subjects analysed
    149 [17]
    147 [18]
    Units: Subjects
        Very much worse
    0
    0
        Much worse
    2
    0
        A little worse
    6
    3
        No change
    52
    49
        A little better
    45
    59
        Much better
    34
    30
        Very much better
    10
    6
    Notes
    [17] - Only subjects in the randomised set (RS) who have week 12 value.
    [18] - Only subjects in the randomised set (RS) who have week 12 value.
    Statistical analysis title
    		 Effect of Empagliflozin vs Placebo
    Statistical analysis description
    Test on difference in mean treatment scores, based on modified ridit scores.
    Comparison groups
    Placebo v 10 mg Empagliflozin
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.863
    Method
    		 Cochran-Mantel-Haenszel test
    Confidence interval

    Secondary: Relative change from baseline to week 12 in N-terminal pro-brain natriuretic peptide (NTproBNP)

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    End point title
    		 Relative change from baseline to week 12 in N-terminal pro-brain natriuretic peptide (NTproBNP)
    End point description
    Relative change from baseline to week 12 in N-terminal pro-brain natriuretic peptide (NTproBNP). Baseline value was defined as the mean of all available measurements from the screening visit until start of treatment with randomised study medication. Only subjects in the randomised set (RS), who had values at baseline and at least one post baseline value are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Within 3 weeks prior to treatment start and at Week 12
    End point values
    		 Placebo 10 mg Empagliflozin
    Number of subjects analysed
    153 [19]
    155 [20]
    Units: Ratio of adjusted geometric means
        number (confidence interval 95%)
    0.98 (0.90 to 1.06)
    0.89 (0.82 to 0.97)
    Notes
    [19] - Subjects in the randomised set, who have values at baseline and at least on post baseline value.
    [20] - Subjects in the randomised set, who have values at baseline and at least one post-baseline value.
    Statistical analysis title
    		 Effect of Empagliflozin vs Placebo
    Statistical analysis description
    The endpoint ‘relative change from baseline in NT-proBNP at Week 12’ (after log-transformation) was evaluated using an MMRM analysis over time with baseline log-transformed NT-proBNP-by-visit interaction and visit-by-treatment interaction as covariates.Unstructured covariance structure was used to model within-patient errors.
    Comparison groups
    Placebo v 10 mg Empagliflozin
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.141
    Method
    		 Mixed Model repeated Measures (MMRM)
    Parameter type
    		 Adjusted geometric mean ratio
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.03

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From first intake of study medication, until 7 days after last intake of study medication, up to 91 days.
    Adverse event reporting additional description
    Treated Set: All participants wo were treated with at least 1 dose of the study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 1 film-coated tablet of placebo matching empagliflozin was administered orally once daily for 12 weeks in subjects with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).

    Reporting group title
    10 mg Empagliflozin
    Reporting group description
    		 1 film-coated tablet of 10 milligram (mg) of empagliflozin was administered orally once daily for 12 weeks in subjects with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No non-serious adverse events were reported for both arms.
    Serious adverse events
    		 Placebo 10 mg Empagliflozin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 156 (17.31%)
    21 / 155 (13.55%)
         number of deaths (all causes)
    3
    3
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung cancer metastatic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive urgency
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (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
    Acute respiratory failure
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    12 / 156 (7.69%)
    6 / 155 (3.87%)
         occurrences causally related to treatment / all
    1 / 12
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Subcutaneous emphysema
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cyst
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Renal injury
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal pain
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 156 (0.64%)
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo 10 mg Empagliflozin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 155 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 May 2018
    The following changes were introduced by the first global protocol amendment: • Clarification of the inclusion criteria regarding medical therapy for heart failure (HF) (it was allowed to include patients who were not treated according to local guidelines, in such cases the investigator had to document the reasons) • Clarification of the exclusion criteria regarding exclusion of patients randomised in another empagliflozin HF trial (a patient could be a screen failure in another trial and then be considered for inclusion into this trial) • Flowchart: Recommendation that NT-proBNP and safety laboratory measures should be done first at the Screening Visit and then other procedures could be done on a later day • Updates to reflect the final version of the CHQ-SAS questionnaire • Clarification that re-testing for eligibility criteria could be done only once • Clarification that screening data of patients who failed screening can be used in the parallel trial 1245-0167 • Clarification of the exclusion criteria regarding major surgery (patients were not eligible for the trial if they had major surgery scheduled during the duration of the trial) • Update of requirements for emergency situations • Change of instructions for physical examinations • Editorial changes and clarifications regarding the conduct of the 6MWT (described in detail in the Appendix of the CTP)
    20 Jul 2018
    The following changes were introduced by the second global protocol amendment: • Change of the inclusion criteria regarding the NT-proBNP level at baseline (influence of atrial fibrillation was taken into account, new levels were >450 pg/ml for patients without atrial fibrillation and >600 pg/ml for patients with atrial fibrillation) • Flow chart: Clarification that at the time of the NT-proBNP measurement, the baseline rhythm of the patient (e.g. sinus rhythm, atrial fibrillation) had to be determined (i.e. by ECG) in order to assess eligibility (see NT-proBNP cut-offs above)

    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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