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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 preserved Ejection Fraction (HFpEF) (EMPERIAL – preserved)

    Summary
    EudraCT number
    		 2017-004072-59
    Trial protocol
    		 ES   GR   PT   PL   SE   NO   IT  
    Global end of trial date
    09 Oct 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Dec 2021
    First version publication date
    15 Oct 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1245-0167
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03448406
    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, 55216 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim, Call Centre, Boehringer Ingelheim, 55216 18002430127, 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
    11 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    09 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 preserved left ventricular ejection fraction (LVEF >40%).
    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: 10
    Country: Number of subjects enrolled
    Canada: 30
    Country: Number of subjects enrolled
    Germany: 74
    Country: Number of subjects enrolled
    Spain: 33
    Country: Number of subjects enrolled
    Greece: 28
    Country: Number of subjects enrolled
    Italy: 33
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Poland: 120
    Country: Number of subjects enrolled
    Portugal: 42
    Country: Number of subjects enrolled
    Sweden: 25
    Country: Number of subjects enrolled
    United States: 318
    Worldwide total number of subjects
    719
    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)
    176
    From 65 to 84 years
    508
    85 years and over
    35

    Subject disposition

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    Recruitment
    Recruitment details
    		 Randomised, double-blind, placebo-controlled, parallel-group trial in patients with chronic Heart Failure with preserved Ejection Fraction (HFpEF) 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, Subject, Data analyst, 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 participants with chronic Heart Failure (CHF) with preserved 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 admininstered orally once daily for 12 weeks in subjects with chronic heart failure (CHF) with preserved 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 participants with chronic Heart Failure (CHF) with with preserved 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 (m) of Empagliflozin was administered orally once daily for 12 weeks in subjects with chronic heart failure (CHF) with perserved ejection fraction (LVEF > 40%).

    Number of subjects in period 1 [1]
    		Placebo 10 mg Empagliflozin
    Started
    158
    157
    Completed
    147
    144
    Not completed
    11
    13
         Noncompliance of scheduled visits
    1
    2
         Consent withdrawn by subject
    1
    2
         Adverse event, non-fatal
    8
    9
         Protocol deviation
    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: 719 subjects were enrolled worldwide and thereof 315 were entered 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 participants with chronic Heart Failure (CHF) with preserved 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 participants with chronic Heart Failure (CHF) with with preserved ejection fraction (LVEF > 40%).

    Reporting group values
    		 Placebo 10 mg Empagliflozin Total
    Number of subjects
    		 158 157 315
    Age categorical
    Randomised Set: All randomised subjects, 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)
    		 20 25 45
        From 65-84 years
    		 123 124 247
        85 years and over
    		 15 8 23
    Age Continuous
    Randomised Set: All randomised subjects, regardless whether treated or not.
    Units: years
        arithmetic mean (standard deviation)
    		 73.9 ( 8.6 ) 73.0 ( 9.0 ) -
    Sex: Female, Male
    Randomised Set: All randomised subjects, regardless of whether treated or not.
    Units: Participants
        Female
    		 66 70 136
        Male
    		 92 87 179
    Race (NIH/OMB)
    Randomised Set: All randomised subjects, regardless of whether treated or not.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 2 3 5
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 19 13 32
        White
    		 135 140 275
        More than one race
    		 2 0 2
        Unknown or Not Reported
    		 0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 19 18 37
        Not Hispanic or Latino
    		 139 138 277
        Unknown or Not Reported
    		 0 1 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 randomised subjects, regardless of whether treated or not.
    Units: Meter
        median (inter-quartile range (Q1-Q3))
    		 299.5 (245.0 to 331.0) 297.0 (246.0 to 326.0) -

    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 participants with chronic Heart Failure (CHF) with preserved 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 participants with chronic Heart Failure (CHF) with with preserved ejection fraction (LVEF > 40%).

    Primary: Change from baseline to week 12 in exercise capacity as measured by the distance walked in 6 minutes in standardised conditions (6MWTD)

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    End point title
    		 Change from baseline to week 12 in exercise capacity as measured by the distance walked in 6 minutes in standardised conditions (6MWTD)
    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
    158 [1]
    157 [2]
    Units: Meter (m)
        median (inter-quartile range (Q1-Q3))
    5.0 (-20.0 to 33.0)
    10.0 (-10.0 to 32.0)
    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
    10 mg Empagliflozin v Placebo
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.366
    Method
    		 Wilcoxon rank test, normal approximation
    Parameter type
    		 Median difference (HL-estimate)
    Point estimate
    4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 13

    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
    158 [3]
    157 [4]
    Units: Score on a scale
        median (inter-quartile range (Q1-Q3))
    2.08 (-6.25 to 20.83)
    4.17 (-3.13 to 16.67)
    Notes
    [3] - Randomised 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
    315
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2783
    Method
    		 Wilcoxon rank test, normal approximation
    Parameter type
    		 Median difference (HL-estimate)
    Point estimate
    2.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.08
         upper limit
    		 6.25

    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
    158 [5]
    156 [6]
    Units: Score on a scale
        median (inter-quartile range (Q1-Q3))
    0.20 (-0.40 to 1.00)
    0.10 (-0.40 to 1.00)
    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
    314
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5512
    Method
    		 Wilcoxon rank test, normal approximation
    Parameter type
    		 Median difference (HL-estimate)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 0.2

    Secondary: Change from baseline to week 6 in exercise capacity as measured by the distance walked in 6 minutes

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    End point title
    		 Change from baseline to week 6 in exercise capacity as measured by the distance walked in 6 minutes
    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 participant was present at the visit at Week 6 but did not perform the 6-Minuted Walking Test, the participant 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 who 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
    158 [7]
    157 [8]
    Units: Meter (m)
        median (inter-quartile range (Q1-Q3))
    1.0 (-17.0 to 21.0)
    7.0 (-14.0 to 23.0)
    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
    315
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3657
    Method
    		 Wilcoxon rank test, normal approximation
    Parameter type
    		 Median Difference (HL-estimate)
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 11

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

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    End point title
    		 Change from baseline in Clinical Congestion Score at week 12
    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 participants 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, with 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 values at baseline and at week 12 were 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
    155 [9]
    156 [10]
    Units: Score on scale
        arithmetic mean (standard deviation)
    -0.28 ( 0.08 )
    -0.36 ( 0.08 )
    Notes
    [9] - Only subjects in the randomised set (RS) who have values at baseline and at week 12.
    [10] - 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
    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
    311
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.444
    Method
    		 Mixed Model Repeated Measure (MMRM)
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.14
    Variability estimate
    Standard deviation
    Dispersion value
    0.11

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

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    End point title
    		 Change from baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at week 12
    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-category 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 were 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
    154 [11]
    153 [12]
    Units: Participants
        4 categories improvement
    1
    0
        3 categories improvement
    2
    1
        2 categories improvement
    11
    8
        1 category improvement
    46
    42
        No change
    70
    79
        1 category deterioration
    17
    16
        2 categories deterioration
    6
    6
        3 categories deterioration
    0
    1
        4 categories deterioration
    1
    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
    307
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3924
    Method
    		 Cochran-Mantel-Haenszel test
    Confidence interval

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

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    End point title
    		 Change from baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at week 12
    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-category 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 were 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
    154 [13]
    153 [14]
    Units: Participants
        4 categories improvement
    1
    0
        3 categories improvement
    4
    1
        2 categories improvement
    8
    13
        1 category improvement
    45
    48
        No change
    70
    70
        1 category deterioration
    18
    20
        2 categories deterioration
    7
    1
        3 categories deterioration
    1
    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
    Placebo v 10 mg Empagliflozin
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4435
    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 values at week 12 were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo 10 mg Empagliflozin
    Number of subjects analysed
    154 [15]
    153 [16]
    Units: Participants
        Very much worse
    1
    0
        Much worse
    0
    3
        A little worse
    11
    7
        No change
    62
    55
        A little better
    41
    48
        Much better
    31
    35
        Very much better
    8
    5
    Notes
    [15] - Only subjects in the randomised set (RS) who have values at week 12 are included in the analysis.
    [16] - Only subjects in the randomised set (RS) who have values at week 12 are included in the analysis.
    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
    307
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5124
    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 values at week 12 were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo 10 mg Empagliflozin
    Number of subjects analysed
    154 [17]
    153 [18]
    Units: Participants
        Very much worse
    0
    0
        Much worse
    2
    3
        A little worse
    6
    7
        No change
    72
    57
        A little better
    32
    45
        Much better
    31
    36
        Very much better
    11
    5
    Notes
    [17] - Only subjects in the randomised set (RS) who have values at week 12.
    [18] - Only subjects in the randomised set (RS) who have values 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
    307
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5713
    Method
    		 Cochran−Mantel−Haenszel test
    Confidence interval

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

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    End point title
    		 Relative change from baseline in N-terminal pro-brain natriuretic peptide (NTproBNP) at week 12
    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 have values at baseline and at week 12 were 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
    155 [19]
    156 [20]
    Units: Ratio of adjusted geometric means
        number (confidence interval 95%)
    1.04 (0.96 to 1.13)
    0.99 (0.92 to 1.08)
    Notes
    [19] - Only subjects in the randomised set (RS) who have values at baseline and at week 12.
    [20] - 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
    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
    311
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4032
    Method
    		 Mixed model repeated Measure (MMRM)
    Parameter type
    		 Adjusted geometric mean ratio
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.07

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From fist intake of study medication, until 7 days after the last intake of study medication, up to 92 days.
    Adverse event reporting additional description
    Treated Set: All participants who were treated with at least one dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    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 participants with chronic Heart Failure (CHF) with with preserved ejection fraction (LVEF > 40%).

    Reporting group title
    Placebo
    Reporting group description
    		 1 film-coated tablet of Placebo matching empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with preserved 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 for both arms are reported.
    Serious adverse events
    		 10 mg Empagliflozin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 157 (12.74%)
    29 / 158 (18.35%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (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
    Chest pain
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (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
    Aspiration
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 157 (1.27%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (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
    6 / 157 (3.82%)
    13 / 158 (8.23%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain injury
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (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 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic mass
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anuria
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         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 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage urinary tract
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (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
    Back pain
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis bacterial
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asymptomatic bacteriuria
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Helicobacter duodenitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Helicobacter gastritis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         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
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic alkalosis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (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
    		 10 mg Empagliflozin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 158 (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 this protocol amendment: • Update of the affiliation of one of the CIs • Clarification of the inclusion criteria regarding prior use of diuretics (not mandatory for inclusion in the trial; if prescribed, dose had to appropriate and stable for 2 weeks prior to Visit 1) • 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) • Flow chart: 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 1245-0168 • 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 • Clarification that concomitant diseases were to be treated according to best standard of care and in accordance with prevailing guidelines • Correction of jugular venous distension categories • Change of instructions for physical examinations • Clarification when procedures at Visits 2 to 4 were to be done in relation to dosing • Editorial changes and clarifications regarding the conduct of the 6MWT (described in detail in the Appendix of the CTP)

    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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