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    Clinical Trial Results:
    A randomized, double-blind, double-dummy, multi-center study to assess safety and efficacy of BAY- 948862 in subjects with emergency presentation at the hospital because of worsening chronic heart failure with left ventricular systolic dysfunction and either type 2 diabetes mellitus with or without chronic kidney disease or moderate chronic kidney disease alone versus eplerenone

    Summary
    EudraCT number
    		 2012-002627-15
    Trial protocol
    		 FI   AT   SE   LT   DE   HU   CZ   NO   NL   PT   DK   IT   ES   BG   GR   PL  
    Global end of trial date
    22 Jan 2015

    Results information
    Results version number
    		 v3(current)
    This version publication date
    18 Jul 2021
    First version publication date
    09 Jul 2016
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    minor update

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BAY94-8862/14564
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01807221
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    22 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective was to investigate efficacy (percentage of subjects with a relative decrease in N-terminal pro-hormone B-type natriuretic peptide [NT-proBNP] of more than 30 percent [%] from baseline to Day 90 [Day 90+/-2]) and safety of different oral doses of finerenone given once daily OD).
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jun 2013
    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
    Netherlands: 28
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Poland: 117
    Country: Number of subjects enrolled
    Portugal: 26
    Country: Number of subjects enrolled
    Spain: 57
    Country: Number of subjects enrolled
    Sweden: 29
    Country: Number of subjects enrolled
    Austria: 22
    Country: Number of subjects enrolled
    Bulgaria: 128
    Country: Number of subjects enrolled
    Czech Republic: 21
    Country: Number of subjects enrolled
    Denmark: 31
    Country: Number of subjects enrolled
    Finland: 9
    Country: Number of subjects enrolled
    France: 33
    Country: Number of subjects enrolled
    Germany: 73
    Country: Number of subjects enrolled
    Greece: 73
    Country: Number of subjects enrolled
    Hungary: 144
    Country: Number of subjects enrolled
    Italy: 67
    Country: Number of subjects enrolled
    Lithuania: 80
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    United States: 39
    Country: Number of subjects enrolled
    Taiwan: 32
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Canada: 58
    Country: Number of subjects enrolled
    Israel: 153
    Country: Number of subjects enrolled
    South Africa: 22
    Country: Number of subjects enrolled
    Korea, Republic of: 21
    Worldwide total number of subjects
    1286
    EEA total number of subjects
    943
    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)
    349
    From 65 to 84 years
    856
    85 years and over
    81

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted in 168 study centers in 25 countries worldwide, from 17 June 2013 (first subject first visit) to 09 December 2014 (last subject last visit).

    Pre-assignment
    Screening details
    		 Out of 1286 enrolled subjects, 1066 subjects were randomized, 1055 subjects received study treatment and were valid for safety analysis set.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Eplerenone (INSPRA®)
    Arm description
    		 Eplerenone 25 milligram (mg) capsule every other day (EOD), on Day 1, Day 3, Day 5, etc, along with placebo capsule (matched to Eplerenone capsule) on Day 2, Day 4, Day 6, etc., and placebo tablet (matched to Finerenone tablet) once daily (OD).The dose could be increased to 25 mg OD at Day 30 and to 50 mg OD at Day 60 (or 25 mg OD if no up-titration occurred on Day 30) if both up-titration steps were performed. Treatment duration was for 90 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eplerenone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 25mg of Eplerenone EOD up to Day 30. Potential up-titration to 25 mg OD after 30 days and 50 mg OD after 60 days.

    Investigational medicinal product name
    Placebo tablet (matched to Finerenone tablet)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of placebo tablet (matched to Finerenone tablet) during any intervention period of the study.

    Investigational medicinal product name
    Placebo capsule (matched to Eplerenone capsule)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of placebo capsule (matched to Eplerenone capsule) during any intervention period of the study.

    Arm title
    		 Finerenone (BAY94-8862) 2.5-5 mg OD
    Arm description
    		 Finerenone 2.5 mg immediate-release (IR) tablets OD and placebo capsule (matched to Eplerenone capsule) OD, with possible up-titration to 5 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Finerenone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 2.5 mg finerenone tablet OD in the morning, with possible up-titration to 5 mg OD.

    Investigational medicinal product name
    Placebo capsule (matched to Eplerenone capsule)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of placebo capsule (matched to Eplerenone capsule) during any intervention period of the study.

    Arm title
    		 Finerenone (BAY94-8862) 5-10 mg OD
    Arm description
    		 Finerenone 5 mg IR tablets OD and placebo capsule (matched to Eplerenone capsule) OD, with possible up-titration to 10 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Finerenone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 5 mg finerenone tablet OD in the morning, with possible up-titration to 10 mg OD.

    Investigational medicinal product name
    Placebo capsule (matched to Eplerenone capsule)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of placebo capsule (matched to Eplerenone capsule) during any intervention period of the study.

    Arm title
    		 Finerenone (BAY94-8862) 7.5-15 mg OD
    Arm description
    		 Finerenone 7.5 mg IR tablet OD and placebo capsule (matched to Eplerenone capsule) OD, with possible up-titration to 15 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Finerenone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 7.5 mg finerenone tablet OD in the morning, with possible up-titration to 15 mg OD.

    Investigational medicinal product name
    Placebo capsule (matched to Eplerenone capsule)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of placebo capsule (matched to Eplerenone capsule) during any intervention period of the study.

    Arm title
    		 Finerenone (BAY94-8862) 10-20 mg OD
    Arm description
    		 Finerenone 10 mg IR tablet OD and placebo capsule (matched to Eplerenone capsule) OD, with possible up-titration to 20 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Finerenone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 10 mg finerenone tablet OD in the morning, with possible up-titration to 20 mg OD.

    Investigational medicinal product name
    Placebo capsule (matched to Eplerenone capsule)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of placebo capsule (matched to Eplerenone capsule) during any intervention period of the study.

    Arm title
    		 Finerenone (BAY94-8862) 15-20 mg OD
    Arm description
    		 Finerenone 15 mg IR tablet OD and placebo capsule (matched to Eplerenone capsule) OD, with possible up-titration to 20 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Finerenone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 15 mg finerenone tablet OD in the morning, with possible up-titration to 20 mg OD.

    Investigational medicinal product name
    Placebo capsule (matched to Eplerenone capsule)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of placebo capsule (matched to Eplerenone capsule) during any intervention period of the study.

    Number of subjects in period 1 [1]
    		Eplerenone (INSPRA®) Finerenone (BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD
    Started
    224
    173
    165
    169
    170
    165
    Received Treatment
    221
    172
    163
    167
    169
    163
    Completed
    144
    121
    122
    123
    134
    124
    Not completed
    80
    52
    43
    46
    36
    41
         Consent withdrawn by subject
    33
    15
    8
    14
    16
    13
         Physician decision
    2
    1
    -
    -
    -
    -
         Logistical difficulties
    -
    1
    -
    -
    1
    -
         Protocol violation
    -
    2
    1
    2
    -
    1
         Death
    7
    9
    4
    2
    1
    6
         Adverse event
    33
    22
    26
    25
    18
    21
         Non-compliance
    1
    2
    -
    1
    -
    -
         Sponsor decision
    2
    -
    1
    1
    -
    -
         Lost to follow-up
    1
    -
    2
    1
    -
    -
         Progressive disease
    1
    -
    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: Not all the enrolled subjects were treated with study drugs. As baseline only included treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Eplerenone (INSPRA®)
    Reporting group description
    		 Eplerenone 25 milligram (mg) capsule every other day (EOD), on Day 1, Day 3, Day 5, etc, along with placebo capsule (matched to Eplerenone capsule) on Day 2, Day 4, Day 6, etc., and placebo tablet (matched to Finerenone tablet) once daily (OD).The dose could be increased to 25 mg OD at Day 30 and to 50 mg OD at Day 60 (or 25 mg OD if no up-titration occurred on Day 30) if both up-titration steps were performed. Treatment duration was for 90 days.

    Reporting group title
    Finerenone (BAY94-8862) 2.5-5 mg OD
    Reporting group description
    		 Finerenone 2.5 mg immediate-release (IR) tablets OD and placebo capsule (matched to Eplerenone capsule) OD, with possible up-titration to 5 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.

    Reporting group title
    Finerenone (BAY94-8862) 5-10 mg OD
    Reporting group description
    		 Finerenone 5 mg IR tablets OD and placebo capsule (matched to Eplerenone capsule) OD, with possible up-titration to 10 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.

    Reporting group title
    Finerenone (BAY94-8862) 7.5-15 mg OD
    Reporting group description
    		 Finerenone 7.5 mg IR tablet OD and placebo capsule (matched to Eplerenone capsule) OD, with possible up-titration to 15 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.

    Reporting group title
    Finerenone (BAY94-8862) 10-20 mg OD
    Reporting group description
    		 Finerenone 10 mg IR tablet OD and placebo capsule (matched to Eplerenone capsule) OD, with possible up-titration to 20 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.

    Reporting group title
    Finerenone (BAY94-8862) 15-20 mg OD
    Reporting group description
    		 Finerenone 15 mg IR tablet OD and placebo capsule (matched to Eplerenone capsule) OD, with possible up-titration to 20 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.

    Reporting group values
    		 Eplerenone (INSPRA®) Finerenone (BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD Total
    Number of subjects
    		 224 173 165 169 170 165 1066
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 72.38 ± 9.92 72.53 ± 9.74 71.81 ± 10.55 69.27 ± 9.83 71.27 ± 10.27 69.2 ± 10.15 -
    Gender Categorical
    Units: Subjects
        Female
    		 51 37 38 44 41 31 242
        Male
    		 173 136 127 125 129 134 824
    Baseline BNP
    B-type natriuretic peptide (BNP) levels in the blood are used for screening, diagnosis of acute chronic heart failure (CHF) and may be useful to establish prognosis in heart failure. Data for subjects with valid data for this baseline characteristic were reported.
    Units: Pg/ml
        geometric mean (standard deviation)
    		 594.290 ± 2.601 677.906 ± 2.637 574.245 ± 2.543 570.776 ± 2.741 606.080 ± 2.598 552.032 ± 2.698 -
    Baseline NT-proBNP
    N-terminal pro-B type natriuretic peptide (NT-proBNP) levels in the blood are used for screening, diagnosis of acute chronic heart failure (CHF) and may be useful to establish prognosis in heart failure. Data for subjects with valid data for this baseline characteristic were reported.
    Units: Pg/ml
        geometric mean (standard deviation)
    		 4730.170 ± 2.938 4793.430 ± 3.084 4184.631 ± 3.093 3776.859 ± 3.395 4163.898 ± 2.734 3791.677 ± 3.013 -

    End points

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    End points reporting groups
    Reporting group title
    Eplerenone (INSPRA®)
    Reporting group description
    		 Eplerenone 25 milligram (mg) capsule every other day (EOD), on Day 1, Day 3, Day 5, etc, along with placebo capsule (matched to Eplerenone capsule) on Day 2, Day 4, Day 6, etc., and placebo tablet (matched to Finerenone tablet) once daily (OD).The dose could be increased to 25 mg OD at Day 30 and to 50 mg OD at Day 60 (or 25 mg OD if no up-titration occurred on Day 30) if both up-titration steps were performed. Treatment duration was for 90 days.

    Reporting group title
    Finerenone (BAY94-8862) 2.5-5 mg OD
    Reporting group description
    		 Finerenone 2.5 mg immediate-release (IR) tablets OD and placebo capsule (matched to Eplerenone capsule) OD, with possible up-titration to 5 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.

    Reporting group title
    Finerenone (BAY94-8862) 5-10 mg OD
    Reporting group description
    		 Finerenone 5 mg IR tablets OD and placebo capsule (matched to Eplerenone capsule) OD, with possible up-titration to 10 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.

    Reporting group title
    Finerenone (BAY94-8862) 7.5-15 mg OD
    Reporting group description
    		 Finerenone 7.5 mg IR tablet OD and placebo capsule (matched to Eplerenone capsule) OD, with possible up-titration to 15 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.

    Reporting group title
    Finerenone (BAY94-8862) 10-20 mg OD
    Reporting group description
    		 Finerenone 10 mg IR tablet OD and placebo capsule (matched to Eplerenone capsule) OD, with possible up-titration to 20 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.

    Reporting group title
    Finerenone (BAY94-8862) 15-20 mg OD
    Reporting group description
    		 Finerenone 15 mg IR tablet OD and placebo capsule (matched to Eplerenone capsule) OD, with possible up-titration to 20 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    (N=1055) All randomized subjects who took at least one dose of study drug and with data after beginning of treatment.

    Subject analysis set title
    Full Analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    (N=1002) All subjects of the SAF who had baseline and at least one post-baseline NT-proBNP value or who died or experienced permanent (≥5 consecutive days) withdrawal of study drug after cardiovascular (CV) hospitalization or after emergency presentation for WCHF.

    Subject analysis set title
    Per-protocol analysis set (N=PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    (654) All subjects of the FAS who had valid NT-proBNP data at Day 60 (Day 60±2) or later and had no major protocol deviations.

    Subject analysis set title
    Pharmacokinetic analysis set (N=PKS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    (786) All finerenone-treated subjects with at least one valid finerenone plasma concentration and without any protocol deviation that would interfere with the evaluation of the PK data.

    Primary: Percentage of Subjects With a Relative Decrease in NT-proBNP of More Than 30% From Baseline to Day 90

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    End point title
    		 Percentage of Subjects With a Relative Decrease in NT-proBNP of More Than 30% From Baseline to Day 90
    End point description
    N-terminal pro-B type natriuretic peptide (NT-proBNP) levels in the blood are used for screening, diagnosis of acute and chronic heart failure (CHF) and may be useful to establish prognosis in heart failure.
    End point type
    Primary
    End point timeframe
    Baseline and Day 90
    End point values
    		 Eplerenone (INSPRA®) Finerenone (BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD
    Number of subjects analysed
    207 [1]
    162 [2]
    157 [3]
    158 [4]
    160 [5]
    158 [6]
    Units: Percentage of Subjects
        number (confidence interval 90%)
    37.2 (31.6 to 43.1)
    30.9 (24.9 to 37.4)
    32.5 (26.3 to 39.2)
    37.3 (30.9 to 44.1)
    38.8 (32.3 to 45.5)
    34.2 (27.9 to 40.9)
    Notes
    [1] - FAS
    [2] - FAS
    [3] - FAS
    [4] - FAS
    [5] - FAS
    [6] - FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Estimates and two-sided 90% confidence intervals are provided for each treatment group and for the treatment differences πBi - πC. Clopper-Pearson confidence intervals were calculated for each treatment group, while for treatment differences the exact unconditional confidence limits were calculated.
    Comparison groups
    Eplerenone (INSPRA®) v Finerenone (BAY94-8862) 2.5-5 mg OD
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8771
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -14.9
         upper limit
    		 2.3
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Estimates and two-sided 90% confidence intervals are provided for each treatment group and for the treatment differences πBi - πC. Clopper-Pearson confidence intervals were calculated for each treatment group, while for treatment differences the exact unconditional confidence limits were calculated.
    Comparison groups
    Eplerenone (INSPRA®) v Finerenone (BAY94-8862) 5-10 mg OD
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7945
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -13.4
         upper limit
    		 4
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Estimates and two-sided 90% confidence intervals are provided for each treatment group and for the treatment differences πBi - πC. Clopper-Pearsonconfidence intervals were calculated for each treatment group, while for treatment differences the exact unconditional confidence limits were calculated.
    Comparison groups
    Eplerenone (INSPRA®) v Finerenone (BAY94-8862) 7.5-15 mg OD
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -8.5
         upper limit
    		 8.8
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Estimates and two-sided 90% confidence intervals are provided for each treatment group and for the treatment differences πBi - πC. Clopper-Pearsonconfidence intervals were calculated for each treatment group, while for treatment differences the exact unconditional confidence limits were calculated.
    Comparison groups
    Eplerenone (INSPRA®) v Finerenone (BAY94-8862) 10-20 mg OD
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4225
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -7.1
         upper limit
    		 10.2
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Estimates and two-sided 90% confidence intervals are provided for each treatment group and for the treatment differences πBi - πC. Clopper-Pearson confidence intervals were calculated for each treatment group, while for treatment differences the exact unconditional confidence limits were calculated.
    Comparison groups
    Eplerenone (INSPRA®) v Finerenone (BAY94-8862) 15-20 mg OD
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6865
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -11.7
         upper limit
    		 5.7

    Secondary: Number of Subjects With Death due to any Cause

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    End point title
    		 Number of Subjects With Death due to any Cause
    End point description
    Death due to any cause include cardiovascular (CV) death and Non-CV death. Non-CV death was classified by 2 subcategories: non-malignant causes and malignant causes.
    End point type
    Secondary
    End point timeframe
    Day 30, Day 60, Day 90 and Follow-up (30 days post-last dose, assessed up to Day 120)
    End point values
    		 Eplerenone (INSPRA®) Finerenone (BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD
    Number of subjects analysed
    207 [7]
    162 [8]
    157 [9]
    158 [10]
    160 [11]
    158 [12]
    Units: Subjects
        Day 30
    6
    5
    1
    1
    0
    2
        Day 60
    7
    7
    3
    2
    0
    4
        Day 90
    9
    10
    4
    4
    1
    5
        Follow-up
    15
    16
    7
    11
    2
    8
    Notes
    [7] - FAS
    [8] - FAS
    [9] - FAS
    [10] - FAS
    [11] - FAS
    [12] - FAS
    No statistical analyses for this end point

    Secondary: Number of Subjects With Cardiovascular Hospitalization

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    End point title
    		 Number of Subjects With Cardiovascular Hospitalization
    End point description
    Hospitalizations were defined as any unplanned admission to hospital, i.e. completion of hospital admission procedures and one overnight [i.e. date change] stay or until the death of subject occurred. Hospitalizations and deaths were classified by 2 primary categories: CV and non-CV. The pre-specified subcategories for CV hospitalizations were as follows: 1. Worsening heart failure, 2. Acute myocardial infarction, 3. Arrhythmia, 4. Transient ischemic attack and stroke, 5. Other CV hospitalizations.
    End point type
    Secondary
    End point timeframe
    Day 30, Day 60, Day 90 and Follow-up (30 days post-last dose, assessed up to Day 120)
    End point values
    		 Eplerenone (INSPRA®) Finerenone (BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD
    Number of subjects analysed
    207 [13]
    162 [14]
    157 [15]
    158 [16]
    160 [17]
    158 [18]
    Units: Subjects
        Day 30
    28
    23
    14
    8
    7
    15
        Day 60
    43
    33
    23
    21
    15
    23
        Day 90
    45
    35
    26
    29
    22
    28
        Follow-up
    56
    43
    38
    36
    27
    34
    Notes
    [13] - FAS
    [14] - FAS
    [15] - FAS
    [16] - FAS
    [17] - FAS
    [18] - FAS
    No statistical analyses for this end point

    Secondary: Number of Subjects With Emergency Presentations for Worsening Chronic Heart Failure (WCHF)

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    End point title
    		 Number of Subjects With Emergency Presentations for Worsening Chronic Heart Failure (WCHF)
    End point description
    Emergency presentations for WCHF were defined as newly developing signs and symptoms of WCHF after start of treatment with study drug, requiring an additional emergency presentation to hospital and IV treatment with diuretics and/or positive inotropic agents.
    End point type
    Secondary
    End point timeframe
    Day 30, Day 60, Day 90 and Follow-up (30 days post-last dose, assessed up to Day 120)
    End point values
    		 Eplerenone (INSPRA®) Finerenone (BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD
    Number of subjects analysed
    207 [19]
    162 [20]
    157 [21]
    158 [22]
    160 [23]
    158 [24]
    Units: Subjects
        Day 30
    21
    19
    12
    9
    7
    15
        Day 60
    35
    30
    20
    17
    14
    22
        Day 90
    37
    32
    22
    24
    18
    28
        Follow-up
    47
    40
    30
    30
    26
    34
    Notes
    [19] - FAS
    [20] - FAS
    [21] - FAS
    [22] - FAS
    [23] - FAS
    [24] - FAS
    No statistical analyses for this end point

    Secondary: Ratio of BNP at Specified Visits to BNP at Baseline

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    End point title
    		 Ratio of BNP at Specified Visits to BNP at Baseline
    End point description
    B-type natriuretic peptide (BNP) levels in the blood are used for screening, diagnosis of acute chronic heart failure (CHF) and may be useful to establish prognosis in heart failure.
    End point type
    Secondary
    End point timeframe
    Day 30, Day 60, Day 90, Premature discontinuation (only for participants who have discontinued the study prematurely, to be performed as soon as possible after withdrawal of study drug) and Follow-up (30 days post-last dose, assessed up to Day 120)
    End point values
    		 Eplerenone (INSPRA®) Finerenone (BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD
    Number of subjects analysed
    203 [25]
    156 [26]
    151 [27]
    156 [28]
    158 [29]
    155 [30]
    Units: Ratio
    geometric mean (standard deviation)
        Day 30 (n=176, 136, 136, 141, 139, 133)
    0.925 ± 2.02
    0.944 ± 1.952
    0.878 ± 1.713
    0.832 ± 1.959
    0.852 ± 1.901
    0.879 ± 1.968
        Day 60 (n=148, 130, 128, 125, 133, 128)
    0.783 ± 2.194
    0.864 ± 2.139
    0.854 ± 1.854
    0.79 ± 2.179
    0.711 ± 2.116
    0.824 ± 2.142
        Day 90 (n=141, 119, 122, 119, 127, 120)
    0.723 ± 2.202
    0.813 ± 2.412
    0.839 ± 1.93
    0.719 ± 2.204
    0.706 ± 2.34
    0.771 ± 2.197
        Premature discontinuation (n=33,23,22,19,21,22)
    0.896 ± 0.896
    1.104 ± 2.15
    1.006 ± 2.422
    0.884 ± 1.973
    0.848 ± 2.218
    1.044 ± 2.174
        Follow-up (n=165,128,136,126,143,136)
    0.795 ± 2.232
    0.815 ± 2.388
    0.886 ± 2.199
    0.726 ± 2.397
    0.729 ± 2.487
    0.852 ± 2.169
    Notes
    [25] - FAS
    [26] - FAS
    [27] - FAS
    [28] - FAS
    [29] - FAS
    [30] - FAS
    No statistical analyses for this end point

    Secondary: Ratio of NT-proBNP at Specified Visits to NT-proBNP at Baseline

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    End point title
    		 Ratio of NT-proBNP at Specified Visits to NT-proBNP at Baseline
    End point description
    N-terminal pro-B type natriuretic peptide (NT-proBNP) levels in the blood are used for screening, diagnosis of acute chronic heart failure (CHF) and may be useful to establish prognosis in heart failure.
    End point type
    Secondary
    End point timeframe
    Day 30, Day 60, Day 90, Premature discontinuation (only for participants who have discontinued the study prematurely, to be performed as soon as possible after withdrawal of study drug) and Follow-up (30 days post-last dose, assessed up to Day 120)
    End point values
    		 Eplerenone (INSPRA®) Finerenone (BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD
    Number of subjects analysed
    207 [31]
    162 [32]
    157 [33]
    158 [34]
    160 [35]
    158 [36]
    Units: Ratio
    geometric mean (standard deviation)
        Day 30 (n=177, 137, 139, 145, 141, 136)
    0.883 ± 2.458
    0.98 ± 2.158
    0.874 ± 2.14
    0.888 ± 2.123
    0.822 ± 2.217
    0.921 ± 2.136
        Day 60 (n=153, 131, 127, 125, 137, 130)
    0.749 ± 2.73
    0.822 ± 2.423
    0.814 ± 2.178
    0.81 ± 2.268
    0.748 ± 2.496
    0.829 ± 2.288
        Day 90 (n=142, 119, 120, 118, 129, 121)
    0.688 ± 2.59
    0.789 ± 2.661
    0.765 ± 2.214
    0.783 ± 2.454
    0.728 ± 2.795
    0.771 ± 2.471
        Premature discontinuation (n= 36,23,24,21,22,25)
    0.948 ± 2.684
    1.369 ± 2.087
    1.267 ± 2.261
    0.927 ± 1.864
    1.133 ± 2.981
    0.965 ± 2.352
        Follow-up (n=165,130,139,131,144,137)
    0.747 ± 2.616
    0.747 ± 2.741
    0.887 ± 2.604
    0.809 ± 2.647
    0.746 ± 2.472
    0.849 ± 2.348
    Notes
    [31] - FAS
    [32] - FAS
    [33] - FAS
    [34] - FAS
    [35] - FAS
    [36] - FAS
    No statistical analyses for this end point

    Secondary: Change From Baseline in KCCQ Questionnaire Scores at Specified Visits

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    End point title
    		 Change From Baseline in KCCQ Questionnaire Scores at Specified Visits
    End point description
    The Kansas City Cardiomyopathy Questionnaire (KCCQ) was the leading health related quality of life measure for subjects with CHF. KCCQ was a 23 item questionnaire that independently measures the impact of subjects HF, or its treatment, on 7 distinct domains: self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. KCCQ clinical summary score is a composite assessment of physical limitations and total symptom scores. Results from the total symptom summary score are presented. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. In the below table, categorical data represents change from baseline data at respective time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 30 and Day 90
    End point values
    		 Eplerenone (INSPRA®) Finerenone (BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD
    Number of subjects analysed
    203
    161
    156
    158
    160
    157
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Baseline (n= 203, 161, 156, 158, 160, 157)
    43.7 ± 23
    42.8 ± 22.6
    45.4 ± 24
    42.1 ± 23.2
    42.3 ± 23.7
    43.2 ± 22.5
        Day 30 (n=177, 141, 137, 145, 141, 141)
    20.5 ± 26.2
    18.2 ± 22.7
    19.3 ± 26.5
    23 ± 24.4
    24.9 ± 22.9
    20.6 ± 27
        Day 90 (n=141, 118, 121, 118, 129, 119)
    24.3 ± 27.6
    21.3 ± 27.2
    24.5 ± 27
    29.3 ± 28.6
    28.3 ± 23.8
    22.2 ± 30.6
    No statistical analyses for this end point

    Secondary: Change From Baseline in EQ-5D-3L Questionnaire Scores at Specified Visits

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    End point title
    		 Change From Baseline in EQ-5D-3L Questionnaire Scores at Specified Visits
    End point description
    EuroQol Group 5-Dimension, 3-Level (EQ-5D-3L): participant rated questionnaire to assess health-related quality of life. It consists of EQ-5D descriptive system and EQ-5D Visual Analog Scale (VAS). EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems (1), some problems (2), and extreme problems (3). For this population, the possible EQ-5D-3L index scores ranges from -0.11 (that is, 3 for all 5 dimensions) to 1.0 (that is, 1 for all 5 dimensions), where higher scores indicate a better health state.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 30, Day 90, Premature discontinuation (only for participants who have discontinued the study prematurely, to be performed as soon as possible after withdrawal of study drug) and Follow-up (30 days post-last dose, assessed up to Day 120)
    End point values
    		 Eplerenone (INSPRA®) Finerenone (BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD
    Number of subjects analysed
    207 [37]
    162 [38]
    157 [39]
    158 [40]
    160 [41]
    158 [42]
    Units: Scores on scale
    arithmetic mean (standard deviation)
        Baseline (n=201, 160, 156, 157, 158,158)
    0.58 ± 0.25
    0.59 ± 0.25
    0.62 ± 0.23
    0.58 ± 0.23
    0.56 ± 0.25
    0.59 ± 0.24
        Day 30 (n=173, 141,137,143,139,135)
    0.06 ± 0.23
    0.02 ± 0.24
    0.02 ± 0.23
    0.07 ± 0.22
    0.06 ± 0.23
    0.02 ± 0.25
        Day 90 (n=139, 117,122,117,126,120)
    0.08 ± 0.24
    0.03 ± 0.27
    0.04 ± 0.25
    0.08 ± 0.2
    0.1 ± 0.24
    0.06 ± 0.28
        Premature discontinuation (n=33,20,19,21,17,23)
    -0.12 ± 0.25
    -0.06 ± 0.29
    -0.09 ± 0.24
    -0.1 ± 0.24
    -0.05 ± 0.25
    0 ± 0.29
        Follow-up (n=161,129,136,133,144,139)
    0.06 ± 0.26
    0.01 ± 0.25
    0.01 ± 0.27
    0.08 ± 0.23
    0.07 ± 0.23
    0.04 ± 0.28
    Notes
    [37] - FAS
    [38] - FAS
    [39] - FAS
    [40] - FAS
    [41] - FAS
    [42] - FAS
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Serum Potassium at Specified Time Points

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    End point title
    		 Change From Baseline in Serum Potassium at Specified Time Points
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Day 30, Day 60, Day 90 and Follow-up (30 days post-last dose, assessed up to Day 120)
    End point values
    		 Eplerenone (INSPRA®) Finerenone (BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD
    Number of subjects analysed
    221
    172
    162
    167
    168
    163
    Units: millimoles per liter (mmol/L)
    arithmetic mean (standard deviation)
        Baseline (n=221,172,162,167,168,163)
    4.159 ± 0.495
    4.081 ± 0.501
    4.211 ± 0.541
    4.174 ± 0.443
    4.131 ± 0.506
    4.117 ± 0.506
        Day 30 (n=178,136,137,142,143,137)
    0.057 ± 0.608
    0.135 ± 0.573
    0.075 ± 0.523
    0.085 ± 0.475
    0.21 ± 0.592
    0.193 ± 0.556
        Day 60 (n=151,130,125,129,134,129)
    0.179 ± 0.589
    0.091 ± 0.568
    0.131 ± 0.566
    0.171 ± 0.54
    0.274 ± 0.522
    0.216 ± 0.547
        Day 90 (n=143,117,118,121,128,119)
    0.307 ± 0.609
    0.184 ± 0.574
    0.153 ± 0.516
    0.164 ± 0.579
    0.275 ± 0.58
    0.245 ± 0.574
        Follow-up (n=164,131,139,134,145,137)
    0.117 ± 0.621
    0.226 ± 0.694
    0.054 ± 0.623
    0.05 ± 0.572
    0.175 ± 0.559
    0.036 ± 0.556
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Systolic Blood Pressure at Specified Visits

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    End point title
    		 Change From Baseline in Systolic Blood Pressure at Specified Visits
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline,Day 7,14,30,60,90,Premature discontinuation (only for participants who have discontinued the study prematurely, to be performed as soon as possible after withdrawal of study drug) and Follow-up (30 days post-last dose, assessed up to Day 120)
    End point values
    		 Eplerenone (INSPRA®) Finerenone (BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD
    Number of subjects analysed
    218 [43]
    171 [44]
    160 [45]
    165 [46]
    169 [47]
    163 [48]
    Units: millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        Baseline (n=218,171,160,165,169,163)
    120.554 ± 18.706
    119.492 ± 16.348
    118.498 ± 14.355
    119.087 ± 16.677
    116.024 ± 16.895
    116.941 ± 16.548
        Day 7 (n=204,158,154,158,163,157)
    -0.541 ± 13.894
    -3.178 ± 13.72
    -2.565 ± 12.278
    0.568 ± 12.733
    0.162 ± 15.416
    -0.546 ± 13.498
        Day 14 (n=49,27,40,36,37,32)
    -3.442 ± 14.258
    -4.488 ± 10.31
    4.142 ± 15.001
    1.241 ± 13.561
    -3.099 ± 12.591
    -2.906 ± 15.406
        Day 30 (n=177,143,138,147,145,139)
    0.067 ± 15.312
    -0.824 ± 15.747
    -0.367 ± 14.984
    0.374 ± 14.433
    1.786 ± 15.039
    0.899 ± 14.608
        Day 60 (n=155,128,130,129,139,131)
    0.684 ± 16.315
    0.337 ± 14.176
    -1.249 ± 13.659
    -1.811 ± 14.462
    0.981 ± 15.525
    0.667 ± 14.83
        Day 90 (n=141,119,121,121,131,122)
    -0.967 ± 16.408
    0.922 ± 15.847
    0.047 ± 15.643
    -0.664 ± 15.018
    1.216 ± 17.831
    0.956 ± 15.743
        Premature discontinuation (n=37,24,24,23,25,24)
    -2.991 ± 16.456
    -0.41 ± 13.936
    -2.167 ± 19.963
    9.391 ± 22.378
    -2.32 ± 11.963
    -0.028 ± 15.42
        Follow-up (n=165,131,141,135,153,143)
    0.188 ± 16.751
    2.869 ± 15.502
    1.95 ± 16.148
    -0.928 ± 17.953
    2.041 ± 16.189
    3.037 ± 16.782
    Notes
    [43] - SAF
    [44] - SAF
    [45] - SAF
    [46] - SAF
    [47] - SAF
    [48] - SAF
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Diastolic Blood Pressure at Specified Visits

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    End point title
    		 Change From Baseline in Diastolic Blood Pressure at Specified Visits
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline,Day 7,14,30,60,90,Premature discontinuation (only for participants who have discontinued the study prematurely, to be performed as soon as possible after withdrawal of study drug) and Follow-up (30 days post-last dose, assessed up to Day 120)
    End point values
    		 Eplerenone (INSPRA®) Finerenone (BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD
    Number of subjects analysed
    218 [49]
    171 [50]
    160 [51]
    165 [52]
    169 [53]
    163 [54]
    Units: millimeter for mercury (mmHg)
    arithmetic mean (standard deviation)
        Baseline (n=218,171,160,165,169,163)
    71.633 ± 11.647
    71.044 ± 10.762
    71.442 ± 8.508
    70.61 ± 9.692
    70.343 ± 10.394
    71.145 ± 9.809
        Day 7 (n=204,158,154,158,163,157)
    -1.351 ± 10.237
    -1.693 ± 9.911
    -2.143 ± 9.848
    0.013 ± 9.733
    -0.738 ± 10.534
    -1.166 ± 8.964
        Day 14 (n=49,27,40,36,37,32)
    -3.442 ± 10.089
    -0.537 ± 9.59
    1.608 ± 9.423
    -0.083 ± 7.421
    -2.387 ± 10.51
    -0.625 ± 9.41
        Day 30 (n=177,143,138,147,145,139)
    -0.503 ± 10.826
    0.146 ± 10.667
    -0.845 ± 8.91
    -0.068 ± 9.633
    -0.094 ± 10.086
    -1.163 ± 9.622
        Day 60 (n=155,128,130,129,139,131)
    -0.613 ± 11.096
    -0.199 ± 11.297
    -2.144 ± 9.552
    -0.85 ± 10.472
    0.17 ± 10.312
    -0.575 ± 10.427
        Day 90 (n=141,119,121,121,131,122)
    -0.716 ± 11.035
    -0.106 ± 11.148
    -1.738 ± 9.015
    -1.121 ± 9.96
    -0.545 ± 11.212
    -0.877 ± 11.327
        Premature discontinuation (n= 36,24,24,23,25,24)
    -3.185 ± 11.853
    0.868 ± 9.239
    -2.194 ± 15.522
    4.101 ± 12.151
    -2.96 ± 9.199
    -0.083 ± 10.113
        Follow-up (n=165,131,141,135,153,143)
    -1.218 ± 11.477
    0.696 ± 13.172
    -0.444 ± 10.197
    -1.16 ± 11.114
    -0.298 ± 11.521
    -0.172 ± 10.211
    Notes
    [49] - SAF
    [50] - SAF
    [51] - SAF
    [52] - SAF
    [53] - SAF
    [54] - SAF
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Heart rate at Specified Time Points

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    End point title
    		 Change From Baseline in Heart rate at Specified Time Points
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline,Day 7,14,30,60,90,Premature discontinuation (only for participants who have discontinued the study prematurely, to be performed as soon as possible after withdrawal of study drug) and Follow-up (30 days post-last dose, assessed up to Day 120)
    End point values
    		 Eplerenone (INSPRA®) Finerenone (BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD
    Number of subjects analysed
    217 [55]
    171 [56]
    160 [57]
    165 [58]
    169 [59]
    162 [60]
    Units: Beats per minute (Beats/min)
    arithmetic mean (standard deviation)
        Baseline (n=217,171,160,165,169,162)
    74.957 ± 13.813
    73.369 ± 13.396
    72.681 ± 12.623
    74.184 ± 12.369
    73.852 ± 11.999
    74.329 ± 13.187
        Day 7 (n=203,158,153,158,163,157)
    -0.8 ± 10.751
    1.073 ± 13.5
    -0.63 ± 11.696
    -0.719 ± 10.77
    -0.548 ± 11.144
    -1.176 ± 13.398
        Day 14 (n=49,27,40,36,37,32)
    -3.109 ± 15.101
    0.599 ± 16.387
    1.842 ± 14.988
    -1.324 ± 13.666
    0.423 ± 11.247
    -3.969 ± 13.715
        Day 30(n=176,143,138,147,145,139)
    0.294 ± 13.61
    1.064 ± 14.128
    0.435 ± 13.63
    -0.349 ± 12.636
    -0.802 ± 11.311
    -1.633 ± 12.719
        Day 60 (n=155,128,130,129,139,131)
    0.297 ± 13.033
    -0.975 ± 14.953
    -1.741 ± 10.86
    -2.318 ± 14.225
    0.192 ± 13.377
    -1.608 ± 13.828
        Day 90 (n=141,119,121,121,131,122)
    -0.189 ± 12.289
    -1.647 ± 13.001
    -2.89 ± 12.034
    -2.212 ± 12.041
    -0.71 ± 13.777
    -1.145 ± 14.284
        Premature discontinuation (n= 36,24,24,23,25,23)
    -2.278 ± 15.909
    -1.424 ± 15.587
    -0.222 ± 7.591
    1.101 ± 10.22
    4.733 ± 13.646
    -2.072 ± 19.731
        Follow-up (n=165,131,141,135,153,143)
    -1.281 ± 13.789
    -2.057 ± 13.982
    -0.626 ± 14.196
    -1.326 ± 15.488
    0.834 ± 14.159
    -1.317 ± 14.636
    Notes
    [55] - SAF
    [56] - SAF
    [57] - SAF
    [58] - SAF
    [59] - SAF
    [60] - SAF
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events: from the start of study treatment until 3 days post-last dose, up to approximately 93 days. All Cause Mortality: assessed until 30 days post-last dose, up to approximately 120 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Eplerenone (INSPRA®)
    Reporting group description
    		 Eplerenone 25mg capsule every other day (EOD), on Day 1, Day 3, Day 5, etc, along with placebo capsule (matched to Eplerenone capsule) on Day 2, Day 4, Day 6, etc., and placebo tablet (matched to Finerenone tablet) once daily (OD). The dose could be increased to 25 mg OD at Day 30 and to 50 mg OD at Day 60 (or 25 mg OD if no up-titration occurred on Day 30) if both up-titration steps were performed. Treatment duration was for 90 days.

    Reporting group title
    Finerenone(BAY94-8862) 2.5-5 mg OD
    Reporting group description
    		 Finerenone 2.5 mg immediate-release (IR) tablets OD and placebo-matched to Eplerenone capsule OD, with possible up-titration to 5 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.

    Reporting group title
    Finerenone (BAY94-8862) 5-10 mg OD
    Reporting group description
    		 Finerenone 5 mg IR tablets OD and placebo-matched to Eplerenone capsule OD, with possible up-titration to 10 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.

    Reporting group title
    Finerenone (BAY94-8862) 7.5-15 mg OD
    Reporting group description
    		 Finerenone 7.5 mg IR tablet OD and placebo-matched to Eplerenone capsule OD, with possible up-titration to 15 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.

    Reporting group title
    Finerenone (BAY94-8862) 10-20 mg OD
    Reporting group description
    		 Finerenone 10 mg IR tablet OD and placebo-matched to Eplerenone capsule OD, with possible up-titration to 20 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.

    Reporting group title
    Finerenone (BAY94-8862) 15-20 mg OD
    Reporting group description
    		 Finerenone 15 mg IR tablet OD and placebo-matched to Eplerenone capsule OD, with possible up-titration to 20 mg OD at Day 30 (Day 30±2) and sham up-titration at Day 60 (Day 60±2). Treatment duration was for 90 days.

    Serious adverse events
    		 Eplerenone (INSPRA®) Finerenone(BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    77 / 221 (34.84%)
    72 / 172 (41.86%)
    47 / 163 (28.83%)
    52 / 167 (31.14%)
    46 / 169 (27.22%)
    57 / 163 (34.97%)
         number of deaths (all causes)
    19
    17
    9
    12
    2
    9
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to liver
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 221 (0.45%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral artery occlusion
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cardiac pacemaker insertion
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    2 / 169 (1.18%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac pacemaker removal
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardioversion
         subjects affected / exposed
    2 / 221 (0.90%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot amputation
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toe amputation
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implantable defibrillator insertion
         subjects affected / exposed
    1 / 221 (0.45%)
    2 / 172 (1.16%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular assist device insertion
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac rehabilitation therapy
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac resynchronisation therapy
         subjects affected / exposed
    0 / 221 (0.00%)
    2 / 172 (1.16%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac ablation
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth extraction
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Percutaneous coronary intervention
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 221 (0.45%)
    2 / 172 (1.16%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    2 / 163 (1.23%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Oedema due to cardiac disease
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant site haematoma
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant site ulcer
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stent-graft endoleak
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Choking
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 221 (0.90%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Delirium
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sleep disorder
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood potassium increased
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    2 / 163 (1.23%)
    1 / 167 (0.60%)
    1 / 169 (0.59%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    1 / 1
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Computerised tomogram abdomen abnormal
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin T increased
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Allergic transfusion reaction
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 221 (0.45%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 221 (0.45%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    2 / 169 (1.18%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 221 (1.36%)
    1 / 172 (0.58%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    Cardiac failure
         subjects affected / exposed
    21 / 221 (9.50%)
    16 / 172 (9.30%)
    15 / 163 (9.20%)
    21 / 167 (12.57%)
    11 / 169 (6.51%)
    13 / 163 (7.98%)
         occurrences causally related to treatment / all
    0 / 27
    0 / 26
    0 / 17
    1 / 33
    0 / 12
    0 / 14
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    0 / 2
    0 / 4
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    6 / 221 (2.71%)
    6 / 172 (3.49%)
    3 / 163 (1.84%)
    1 / 167 (0.60%)
    3 / 169 (1.78%)
    5 / 163 (3.07%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 6
    0 / 3
    0 / 1
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    13 / 221 (5.88%)
    9 / 172 (5.23%)
    7 / 163 (4.29%)
    8 / 167 (4.79%)
    6 / 169 (3.55%)
    12 / 163 (7.36%)
         occurrences causally related to treatment / all
    1 / 16
    0 / 11
    0 / 7
    0 / 9
    0 / 6
    0 / 16
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Cardiac failure congestive
         subjects affected / exposed
    4 / 221 (1.81%)
    5 / 172 (2.91%)
    2 / 163 (1.23%)
    2 / 167 (1.20%)
    0 / 169 (0.00%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
    0 / 2
    0 / 2
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 221 (0.45%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 221 (0.90%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial haemorrhage
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    3 / 221 (1.36%)
    3 / 172 (1.74%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    2 / 221 (0.90%)
    4 / 172 (2.33%)
    0 / 163 (0.00%)
    3 / 167 (1.80%)
    1 / 169 (0.59%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
    0 / 0
    0 / 5
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachyarrhythmia
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebellar syndrome
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 221 (0.90%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular insufficiency
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 221 (0.90%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 221 (0.45%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract nuclear
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 221 (0.45%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stasis dermatitis
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    1 / 221 (0.45%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 221 (0.45%)
    2 / 172 (1.16%)
    1 / 163 (0.61%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 221 (0.00%)
    5 / 172 (2.91%)
    1 / 163 (0.61%)
    4 / 167 (2.40%)
    2 / 169 (1.18%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
    1 / 1
    1 / 4
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure chronic
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    2 / 167 (1.20%)
    0 / 169 (0.00%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 2
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle haemorrhage
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 221 (0.45%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    2 / 163 (1.23%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 221 (0.90%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 221 (0.45%)
    3 / 172 (1.74%)
    3 / 163 (1.84%)
    1 / 167 (0.60%)
    2 / 169 (1.18%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 3
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    2 / 167 (1.20%)
    2 / 169 (1.18%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 221 (0.90%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asymptomatic bacteriuria
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    1 / 169 (0.59%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis bacterial
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    1 / 163 (0.61%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    5 / 221 (2.26%)
    6 / 172 (3.49%)
    4 / 163 (2.45%)
    7 / 167 (4.19%)
    5 / 169 (2.96%)
    6 / 163 (3.68%)
         occurrences causally related to treatment / all
    5 / 5
    4 / 6
    3 / 4
    6 / 7
    5 / 5
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    1 / 169 (0.59%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    2 / 169 (1.18%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 221 (0.45%)
    1 / 172 (0.58%)
    0 / 163 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 172 (0.00%)
    0 / 163 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Eplerenone (INSPRA®) Finerenone(BAY94-8862) 2.5-5 mg OD Finerenone (BAY94-8862) 5-10 mg OD Finerenone (BAY94-8862) 7.5-15 mg OD Finerenone (BAY94-8862) 10-20 mg OD Finerenone (BAY94-8862) 15-20 mg OD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    85 / 221 (38.46%)
    63 / 172 (36.63%)
    59 / 163 (36.20%)
    50 / 167 (29.94%)
    50 / 169 (29.59%)
    65 / 163 (39.88%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    12 / 221 (5.43%)
    5 / 172 (2.91%)
    7 / 163 (4.29%)
    3 / 167 (1.80%)
    4 / 169 (2.37%)
    8 / 163 (4.91%)
         occurrences all number
    14
    5
    7
    3
    4
    9
    Vascular disorders
    Hypotension
         subjects affected / exposed
    11 / 221 (4.98%)
    7 / 172 (4.07%)
    11 / 163 (6.75%)
    11 / 167 (6.59%)
    7 / 169 (4.14%)
    8 / 163 (4.91%)
         occurrences all number
    13
    7
    12
    14
    7
    8
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    13 / 221 (5.88%)
    14 / 172 (8.14%)
    10 / 163 (6.13%)
    5 / 167 (2.99%)
    7 / 169 (4.14%)
    10 / 163 (6.13%)
         occurrences all number
    14
    20
    11
    6
    7
    10
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 221 (5.43%)
    8 / 172 (4.65%)
    6 / 163 (3.68%)
    6 / 167 (3.59%)
    7 / 169 (4.14%)
    6 / 163 (3.68%)
         occurrences all number
    13
    8
    7
    6
    7
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 221 (3.62%)
    6 / 172 (3.49%)
    6 / 163 (3.68%)
    10 / 167 (5.99%)
    6 / 169 (3.55%)
    7 / 163 (4.29%)
         occurrences all number
    8
    6
    6
    11
    6
    9
    Nausea
         subjects affected / exposed
    7 / 221 (3.17%)
    9 / 172 (5.23%)
    2 / 163 (1.23%)
    5 / 167 (2.99%)
    2 / 169 (1.18%)
    6 / 163 (3.68%)
         occurrences all number
    7
    12
    2
    7
    2
    6
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    11 / 221 (4.98%)
    12 / 172 (6.98%)
    7 / 163 (4.29%)
    6 / 167 (3.59%)
    3 / 169 (1.78%)
    10 / 163 (6.13%)
         occurrences all number
    12
    13
    7
    7
    4
    11
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    8 / 221 (3.62%)
    6 / 172 (3.49%)
    7 / 163 (4.29%)
    6 / 167 (3.59%)
    8 / 169 (4.73%)
    9 / 163 (5.52%)
         occurrences all number
    10
    8
    9
    10
    11
    9
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    8 / 221 (3.62%)
    5 / 172 (2.91%)
    7 / 163 (4.29%)
    7 / 167 (4.19%)
    6 / 169 (3.55%)
    9 / 163 (5.52%)
         occurrences all number
    9
    5
    10
    7
    6
    9
    Hypokalaemia
         subjects affected / exposed
    34 / 221 (15.38%)
    20 / 172 (11.63%)
    21 / 163 (12.88%)
    15 / 167 (8.98%)
    14 / 169 (8.28%)
    17 / 163 (10.43%)
         occurrences all number
    44
    26
    28
    30
    18
    20

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jan 2014
    1. The specification that potassium was to be monitored in serum was removed; potassium during the treatment period could be monitored in serum or plasma. A paragraph detailing the prohibited use of potassium lowering agents was added. 2. The inclusion criteria were modified with respect to the inclusion of women of childbearing potential. 3. A cap of 45% for subjects with atrial fibrillation was introduced. 4. Definitions of “mineralocorticoid receptor antagonist (MRA) naïve” and “previous MRA use” for stratification were added. 5. It was clarified that concomitant treatment with an angiotensin-converting enzyme inhibitor (ACEI) and an angiotensin receptor blocker (ARB) was prohibited. Diltiazem was removed from the list of moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitory. 6. A pregnancy test was added at the screening visit for women of childbearing potential. 7. It was clarified that the latest assessed left ventricular ejection fraction (LVEF) value recorded for medical history had to be prior to the screening visit. 8. The symptom burden domain and the total symptom scale were added to the KCCQ. 9. The requirement to report adverse event (AEs) of special interest as serious adverse event (SAEs) was added. 10. An un-blinding waiver and exemption from expedited reporting requirements were introduced for specific disease related AEs. 11. The assessment schedule if the screening visit and Visit 1 (Day 1) took place on the same day was clarified. 12. The definition of the SAF was modified to all randomized subjects who took at least one dose of study drug and with data after beginning of treatment. 13. Further details were added on general statistical considerations, the analysis of the primary efficacy variable, health related quality of life, AEs, safety laboratory parameters, and safety biomarkers, and subgroup analyses.

    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.
    Occurrence of "±” in relation with geometric CV is autogenerated and cannot be deleted. Decimal places were automatically truncated if last decimal equals zero.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25678098
    http://www.ncbi.nlm.nih.gov/pubmed/27130705
    http://www.ncbi.nlm.nih.gov/pubmed/33107592
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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