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    Clinical Trial Results:
    A randomized parallel-group, placebo-controlled, double-blind, multi-center dose finding phase II trial exploring the pharmacodynamic effects, safety and tolerability, and pharmacokinetics of four dose regimens of the oral sGC stimulator BAY 1021189 over 12 weeks in patients with worsening heart failure and preserved ejection fraction (HFpEF)

    Summary
    EudraCT number
    		 2013-002288-25
    Trial protocol
    		 CZ   IT   AT   BE   SE   DK   NL   ES   HU   BG   PT   GR  
    Global end of trial date
    16 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Sep 2016
    First version publication date
    23 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY1021189/15829
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01951638
    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
    16 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To find the optimal dose of oral soluble guanylate cyclase (sGC) stimulator BAY1021189 for Phase III that can be given in addition to standard diuretic and comorbidity treatment by characterizing the safety, tolerability, pharmacodynamic effects, and pharmacokinetics, and detecting a significant dose-response relationship in at least one of the two primary end points change in N-terminal pro-brain natriuretic peptide (NT-ProBNP) and change of left atrial volume at 12 weeks in subjects with worsening chronic heart failure and preserved ejection fraction (HFpEF).
    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
    06 Nov 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: 3
    Country: Number of subjects enrolled
    Poland: 37
    Country: Number of subjects enrolled
    Portugal: 9
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    Sweden: 9
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Austria: 40
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Bulgaria: 69
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    Greece: 17
    Country: Number of subjects enrolled
    Hungary: 16
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    Singapore: 6
    Country: Number of subjects enrolled
    Taiwan: 19
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Japan: 39
    Country: Number of subjects enrolled
    Israel: 39
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 2
    Country: Number of subjects enrolled
    United States: 32
    Country: Number of subjects enrolled
    Australia: 9
    Worldwide total number of subjects
    477
    EEA total number of subjects
    324
    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)
    80
    From 65 to 84 years
    350
    85 years and over
    47

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 158 centers in 25 countries between 06 November 2013 (first subject first visit) and 16 September 2015 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall, 632 subjects were enrolled, of them 477 were randomized and 475 were treated. Among the 477 subjects who were randomized, 404 subjects completed both treatment and follow-up [FU] periods. All arms in FU period were mutually exclusive, this question below is ticked No because of database validation rule constraints.

    Period 1
    Period 1 title
    Treatment 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
    		 Placebo
    Arm description
    		 Subjects received placebo matched to vericiguat (BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to vericiguat (BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Arm title
    		 BAY1021189 1.25 mg
    Arm description
    		 Subjects received vericiguat (BAY1021189) 1.25 milligram (mg) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vericiguat
    Investigational medicinal product code
    BAY1021189
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received vericiguat (BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Arm title
    		 BAY1021189 2.5 mg
    Arm description
    		 Subjects received vericiguat (BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vericiguat
    Investigational medicinal product code
    BAY1021189
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received vericiguat (BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Arm title
    		 BAY1021189 2.5 mg to 5 mg
    Arm description
    		 Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg after 14 or 28 days. Sham titration included on Day 28.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vericiguat
    Investigational medicinal product code
    BAY1021189
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg after 14 or 28 days. Sham titration included on Day 28.

    Arm title
    		 BAY1021189 2.5 mg to 10 mg
    Arm description
    		 Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg once daily after 14 days, and up-titration to 10 mg once daily after 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vericiguat
    Investigational medicinal product code
    BAY1021189
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg once daily after 14 days, and up-titration to 10 mg once daily after 28 days.

    Number of subjects in period 1
    		Placebo BAY1021189 1.25 mg BAY1021189 2.5 mg BAY1021189 2.5 mg to 5 mg BAY1021189 2.5 mg to 10 mg
    Started
    93
    96
    96
    96
    96
    Completed
    80
    82
    83
    80
    86
    Not completed
    13
    14
    13
    16
    10
         Consent withdrawn by subject
    9
    6
    4
    5
    4
         Logistical difficulties
    -
    1
    1
    -
    -
         Adverse Event
    3
    4
    8
    6
    5
         Death
    -
    -
    -
    3
    1
         Protocol-driven decision point
    1
    3
    -
    -
    -
         Protocol deviation
    -
    -
    -
    2
    -
    Period 2
    Period 2 title
    Follow-up Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo matched to vericiguat (BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to vericiguat (BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Arm title
    		 BAY1021189 1.25 mg
    Arm description
    		 Subjects received vericiguat (BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vericiguat
    Investigational medicinal product code
    BAY1021189
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received vericiguat (BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Arm title
    		 BAY1021189 2.5 mg
    Arm description
    		 Subjects received vericiguat (BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vericiguat
    Investigational medicinal product code
    BAY1021189
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received vericiguat (BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Arm title
    		 BAY1021189 2.5 mg to 5 mg
    Arm description
    		 Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg after 14 or 28 days. Sham titration included on Day 28.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vericiguat
    Investigational medicinal product code
    BAY1021189
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg after 14 or 28 days. Sham titration included on Day 28.

    Arm title
    		 BAY1021189 2.5 mg to 10 mg
    Arm description
    		 Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg once daily after 14 days, and up-titration to 10 mg once daily after 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vericiguat
    Investigational medicinal product code
    BAY1021189
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg once daily after 14 days, and up-titration to 10 mg once daily after 28 days.

    Number of subjects in period 2
    		Placebo BAY1021189 1.25 mg BAY1021189 2.5 mg BAY1021189 2.5 mg to 5 mg BAY1021189 2.5 mg to 10 mg
    Started
    89
    95
    95
    88
    94
    Completed
    87
    86
    90
    80
    89
    Not completed
    2
    9
    5
    8
    5
         Consent withdrawn by subject
    1
    5
    2
    1
    2
         Logistical difficulties
    -
    2
    -
    -
    1
         Adverse Event
    -
    1
    2
    1
    1
         Death
    1
    -
    1
    4
    1
         Lost to follow-up
    -
    1
    -
    1
    -
         Protocol deviation
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to vericiguat (BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Reporting group title
    BAY1021189 1.25 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) 1.25 milligram (mg) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Reporting group title
    BAY1021189 2.5 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Reporting group title
    BAY1021189 2.5 mg to 5 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg after 14 or 28 days. Sham titration included on Day 28.

    Reporting group title
    BAY1021189 2.5 mg to 10 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg once daily after 14 days, and up-titration to 10 mg once daily after 28 days.

    Reporting group values
    		 Placebo BAY1021189 1.25 mg BAY1021189 2.5 mg BAY1021189 2.5 mg to 5 mg BAY1021189 2.5 mg to 10 mg Total
    Number of subjects
    		 93 96 96 96 96 477
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 73.7 ( 9.1 ) 73.8 ( 10 ) 72 ( 10.7 ) 73.9 ( 7.9 ) 72.5 ( 10.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 46 51 43 43 44 227
        Male
    		 47 45 53 53 52 250

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to vericiguat (BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Reporting group title
    BAY1021189 1.25 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) 1.25 milligram (mg) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Reporting group title
    BAY1021189 2.5 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Reporting group title
    BAY1021189 2.5 mg to 5 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg after 14 or 28 days. Sham titration included on Day 28.

    Reporting group title
    BAY1021189 2.5 mg to 10 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg once daily after 14 days, and up-titration to 10 mg once daily after 28 days.
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to vericiguat (BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Reporting group title
    BAY1021189 1.25 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Reporting group title
    BAY1021189 2.5 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Reporting group title
    BAY1021189 2.5 mg to 5 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg after 14 or 28 days. Sham titration included on Day 28.

    Reporting group title
    BAY1021189 2.5 mg to 10 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg once daily after 14 days, and up-titration to 10 mg once daily after 28 days.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS (N = 477) included all subjects who were randomized to treatment.

    Subject analysis set title
    Safety Analysis Set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF (N = 475) included all subjects from FAS who had at least one dose of study drug administered.

    Subject analysis set title
    Per Protocol Set (PPS) NT-pro BNP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PPS NT-pro BNP (N=345) included all subjects randomized to treatment who had a valid measurement of NT-pro BNP at baseline and at Week 12 (Visit 5) and showed no major protocol deviations.

    Subject analysis set title
    PPS Left Atrial Volume (LAV)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PPS LAV (N=338) included all subjects randomized to treatment who had a valid measurement of LAV at baseline and at Week 12 (Visit 5) and showed no major protocol deviations.

    Subject analysis set title
    Pooled BAY1021189 2.5 mg up to 10 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pooled 2.5 mg up to 10 mg (N = 195). The three highest dose arms (BAY1021189 2.5mg, 2.5-5mg, and 2.5-10mg) were pooled and used for the primary analysis of the primary end point. This Pooled 2.5 mg up to 10 mg group is serving as "Reporting Group" for primary analysis instead of "Sub-group analysis", however "Sub-group analysis" is chosen as analysis set type because there is no proper option provided in the database.

    Subject analysis set title
    SAF excluding subjects with incorrectly assigned dose
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF excluding subjects with incorrectly assigned dose (N = 427) included all subjects from the SAF except 48 subjects who received lower than planned doses owing to an erroneous software update of the drug dispensation system.

    Primary: Change From Baseline to Week 12 in Log-transformed N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)

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    End point title
    		 Change From Baseline to Week 12 in Log-transformed N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)
    End point description
    NTproBNP is a circulating plasma biomarker of cardiovascular function and prognosis in heart failure (HF).
    End point type
    Primary
    End point timeframe
    Baseline, Week 12 (end of treatment [EOT])
    End point values
    		 Placebo BAY1021189 1.25 mg BAY1021189 2.5 mg BAY1021189 2.5 mg to 5 mg BAY1021189 2.5 mg to 10 mg Pooled BAY1021189 2.5 mg up to 10 mg
    Number of subjects analysed
    73 [1]
    77 [2]
    78 [3]
    57 [4]
    60 [5]
    195 [6]
    Units: log-transformed picograms per milliliter
        arithmetic mean (standard deviation)
    -0.098 ( 0.778 )
    -0.047 ( 0.788 )
    0.071 ( 0.818 )
    0.057 ( 0.819 )
    -0.023 ( 0.705 )
    0.038 ( 0.782 )
    Notes
    [1] - PPS NT-proBNP
    [2] - PPS NT-proBNP
    [3] - PPS NT-proBNP
    [4] - PPS NT-proBNP
    [5] - PPS NT-proBNP
    [6] - PPS NT-proBNP
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    For the primary analysis, the three highest active treatment groups BAY1021189 (2.5mg, 2.5 to 5mg, 2.5 to 10mg) were pooled and compared to the assigned placebo treatment group with a one-sided two-sample t-test. The Hochberg procedure was used to test the two primary end points at study-wise significance level of 5%. Results are reported including 90% confidence intervals (CI) for the difference of means. The difference between the comparison groups is difference of means on the log scale.
    Comparison groups
    Placebo v Pooled BAY1021189 2.5 mg up to 10 mg
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8991
    Method
    		 t-test, 1-sided
    Parameter type
    		 Log-Scale mean difference
    Point estimate
    0.137
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.31
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.
    Comparison groups
    BAY1021189 2.5 mg to 10 mg v Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7194
    Method
    		 t-test, 1-sided
    Parameter type
    		 Log-Scale mean difference
    Point estimate
    0.076
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0.33
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.
    Comparison groups
    BAY1021189 2.5 mg to 5 mg v Placebo
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8653
    Method
    		 t-test, 1-sided
    Parameter type
    		 Log-Scale mean difference
    Point estimate
    0.156
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.43
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.
    Comparison groups
    BAY1021189 2.5 mg v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9041
    Method
    		 t-test, 1-sided
    Parameter type
    		 Log-Scale mean difference
    Point estimate
    0.171
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.43
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.
    Comparison groups
    BAY1021189 1.25 mg v Placebo
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6572
    Method
    		 t-test, 1-sided
    Parameter type
    		 Log-Scale mean difference
    Point estimate
    0.052
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.3

    Primary: Change From Baseline to Week 12 in Left Atrial Volume (LAV)

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    End point title
    		 Change From Baseline to Week 12 in Left Atrial Volume (LAV)
    End point description
    Left atrial volume was measured by echocardiography.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12 (EOT)
    End point values
    		 Placebo BAY1021189 1.25 mg BAY1021189 2.5 mg BAY1021189 2.5 mg to 5 mg BAY1021189 2.5 mg to 10 mg Pooled BAY1021189 2.5 mg up to 10 mg
    Number of subjects analysed
    67 [7]
    77 [8]
    78 [9]
    57 [10]
    59 [11]
    194 [12]
    Units: milliliter
        arithmetic mean (standard deviation)
    -3.361 ( 12.654 )
    -2.163 ( 7.895 )
    -2.142 ( 11.931 )
    -1.252 ( 16.139 )
    -1.654 ( 10.245 )
    -1.732 ( 12.808 )
    Notes
    [7] - PPS LAV
    [8] - PPS LAV
    [9] - PPS LAV
    [10] - PPS LAV
    [11] - PPS LAV
    [12] - PPS LAV
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    For the primary analysis, the three highest active treatment groups (BAY1021189 2.5mg, BAY1021189 2.5 to 5mg, BAY1021189 2.5 to 10mg) were pooled and compared to the assigned placebo treatment group with a one-sided two-sample t-test. The Hochberg procedure was used to test the two primary end points at study-wise significance level of 5%. Results are reported including 90% confidence intervals (CI) for the difference of means.
    Comparison groups
    Placebo v Pooled BAY1021189 2.5 mg up to 10 mg
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8156
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.629
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.36
         upper limit
    		 4.62
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.
    Comparison groups
    Placebo v BAY1021189 2.5 mg to 10 mg
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7945
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.707
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.39
         upper limit
    		 5.8
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.
    Comparison groups
    Placebo v BAY1021189 2.5 mg to 5 mg
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7917
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.109
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.01
         upper limit
    		 7.23
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.
    Comparison groups
    Placebo v BAY1021189 2.5 mg
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7241
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.219
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.82
         upper limit
    		 5.26
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.
    Comparison groups
    Placebo v BAY1021189 1.25 mg
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7546
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.198
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.23
         upper limit
    		 4.63

    Other pre-specified: Change From Baseline to Week 12 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

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    End point title
    		 Change From Baseline to Week 12 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
    End point description
    Blood pressure was measured after at least 10 minutes resting in a sitting position (3 measurements taken approximately 2 minutes apart).The changes in blood pressure were recorded and the mean of the three measurements was analyzed. Here, n = subjects evaluable for specified category for each arm, respectively.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12 (EOT)
    End point values
    		 Placebo BAY1021189 1.25 mg BAY1021189 2.5 mg BAY1021189 2.5 mg to 5 mg BAY1021189 2.5 mg to 10 mg
    Number of subjects analysed
    93 [13]
    96 [14]
    95 [15]
    75 [16]
    68 [17]
    Units: millimeter of mercury
    arithmetic mean (standard deviation)
        Change in SBP: (n=80,82,83,61,61)
    1.458 ( 18.865 )
    0.703 ( 16.993 )
    -1.819 ( 19.438 )
    -1.486 ( 17.179 )
    -0.913 ( 15.498 )
        Change in DBP: (n=80,82,83,61,61)
    1.887 ( 11.435 )
    0.911 ( 10.037 )
    -2.173 ( 11.249 )
    -1.142 ( 11.4 )
    -0.629 ( 10.271 )
    Notes
    [13] - SAF
    [14] - SAF
    [15] - SAF
    [16] - SAF excluding subjects with incorrectly assigned dose
    [17] - SAF excluding subjects with incorrectly assigned dose
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline to Week 12 in Heart Rate

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    End point title
    		 Change From Baseline to Week 12 in Heart Rate
    End point description
    Heart rate was measured after 10 minutes resting in a sitting position (3 measurements taken approximatly 2 minutes apart). The changes in heart rate were recorded and the mean of the three measurements was analyzed.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12 (EOT)
    End point values
    		 Placebo BAY1021189 1.25 mg BAY1021189 2.5 mg BAY1021189 2.5 mg to 5 mg BAY1021189 2.5 mg to 10 mg
    Number of subjects analysed
    80 [18]
    82 [19]
    83 [20]
    61 [21]
    61 [22]
    Units: beats per minute
        arithmetic mean (standard deviation)
    3.287 ( 13.582 )
    1.776 ( 11.42 )
    -0.373 ( 9.845 )
    1.055 ( 13.331 )
    -2.623 ( 9.639 )
    Notes
    [18] - SAF with subjects evaluable for this end point.
    [19] - SAF with subjects evaluable for this end point.
    [20] - SAF with subjects evaluable for this end point.
    [21] - SAF excluding subjects with incorrectly assigned dose, with subjects evaluable for this end point.
    [22] - SAF excluding subjects with incorrectly assigned dose, with subjects evaluable for this end point.
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Clinical Events (Heart Failure Hospitalization and Cardio-vascular [CV] Mortality)

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    End point title
    		 Number of Subjects With Clinical Events (Heart Failure Hospitalization and Cardio-vascular [CV] Mortality)
    End point description
    Clinical events (heart failure and mortality) were analyzed as CV death, and HF hospitalization at specified time points.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 16 including 12 week treatment period and 4 week follow-up period
    End point values
    		 Placebo BAY1021189 1.25 mg BAY1021189 2.5 mg BAY1021189 2.5 mg to 5 mg BAY1021189 2.5 mg to 10 mg
    Number of subjects analysed
    93 [23]
    96 [24]
    96 [25]
    96 [26]
    96 [27]
    Units: subjects
        HF hospitalizations
    8
    6
    11
    8
    5
        CV Mortality
    1
    0
    0
    5
    1
    Notes
    [23] - FAS
    [24] - FAS
    [25] - FAS
    [26] - FAS
    [27] - FAS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent AEs were collected after first application of study medication up to 5 calendar days after end of treatment with study medication
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to vericiguat (BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Reporting group title
    BAY1021189 1.25 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Reporting group title
    BAY1021189 2.5 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28.

    Reporting group title
    BAY1021189 from 2.5 to 5 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg once daily after 14 or 28 days. Sham titration included on Day 28.

    Reporting group title
    BAY1021189 from 2.5 to 10 mg
    Reporting group description
    		 Subjects received vericiguat (BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg once daily after 14 days, and up-titration to 10 mg once daily after 28 days.

    Serious adverse events
    		 Placebo BAY1021189 1.25 mg BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 93 (21.51%)
    20 / 96 (20.83%)
    24 / 95 (25.26%)
    18 / 95 (18.95%)
    21 / 96 (21.88%)
         number of deaths (all causes)
    1
    0
    1
    7
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    1 / 95 (1.05%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal stromal tumour
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    1 / 95 (1.05%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    1 / 95 (1.05%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    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
    Orthostatic hypotension
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Surgical and medical procedures
    Eyelid operation
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    1 / 95 (1.05%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Pain
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    1 / 95 (1.05%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Pyrexia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Sudden death
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    1 / 95 (1.05%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 96 (1.04%)
    1 / 95 (1.05%)
    1 / 95 (1.05%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    1 / 95 (1.05%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Pleural effusion
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    1 / 95 (1.05%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory failure
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    1 / 95 (1.05%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Investigations
    Coagulation time prolonged
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Intraocular pressure increased
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    1 / 95 (1.05%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Radius fracture
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    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
    Ulna fracture
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    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
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Contusion
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    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
    Post procedural haematoma
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Atrial fibrillation
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    2 / 95 (2.11%)
    1 / 95 (1.05%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    1 / 95 (1.05%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiac failure
         subjects affected / exposed
    6 / 93 (6.45%)
    4 / 96 (4.17%)
    7 / 95 (7.37%)
    5 / 95 (5.26%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 4
    0 / 12
    0 / 8
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 96 (1.04%)
    3 / 95 (3.16%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    2 / 93 (2.15%)
    4 / 96 (4.17%)
    3 / 95 (3.16%)
    2 / 95 (2.11%)
    4 / 96 (4.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 3
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 96 (0.00%)
    1 / 95 (1.05%)
    3 / 95 (3.16%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    1 / 95 (1.05%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    1 / 95 (1.05%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Right ventricular failure
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    1 / 95 (1.05%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Tachyarrhythmia
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    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
    Acute coronary syndrome
         subjects affected / exposed
    0 / 93 (0.00%)
    2 / 96 (2.08%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    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
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    1 / 95 (1.05%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Presyncope
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    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
    Syncope
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    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
    Cervicogenic headache
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    1 / 95 (1.05%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 93 (2.15%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia of chronic disease
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    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
    Eye disorders
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    1 / 95 (1.05%)
    1 / 95 (1.05%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Large intestine polyp
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    1 / 95 (1.05%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Jaundice cholestatic
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    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
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Acute kidney injury
         subjects affected / exposed
    2 / 93 (2.15%)
    1 / 96 (1.04%)
    1 / 95 (1.05%)
    4 / 95 (4.21%)
    3 / 96 (3.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    1 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteochondrosis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Carbuncle
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Diabetic gangrene
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Erysipelas
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    1 / 95 (1.05%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Gangrene
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastroenteritis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Hepatitis C
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Osteomyelitis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumonia
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    3 / 96 (3.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    1 / 95 (1.05%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Urinary tract infection
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    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
    Urosepsis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Enterococcal sepsis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Chlamydial infection
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    1 / 95 (1.05%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory tract infection
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 96 (0.00%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    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
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    1 / 95 (1.05%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Failure to thrive
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 96 (0.00%)
    1 / 95 (1.05%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypoglycaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    0 / 95 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo BAY1021189 1.25 mg BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 93 (22.58%)
    33 / 96 (34.38%)
    40 / 95 (42.11%)
    38 / 95 (40.00%)
    33 / 96 (34.38%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 93 (1.08%)
    4 / 96 (4.17%)
    4 / 95 (4.21%)
    5 / 95 (5.26%)
    2 / 96 (2.08%)
         occurrences all number
    1
    4
    6
    5
    2
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    5 / 93 (5.38%)
    1 / 96 (1.04%)
    3 / 95 (3.16%)
    3 / 95 (3.16%)
    2 / 96 (2.08%)
         occurrences all number
    5
    1
    4
    3
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 93 (3.23%)
    2 / 96 (2.08%)
    10 / 95 (10.53%)
    6 / 95 (6.32%)
    7 / 96 (7.29%)
         occurrences all number
    3
    4
    11
    6
    7
    Headache
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 96 (1.04%)
    6 / 95 (6.32%)
    4 / 95 (4.21%)
    4 / 96 (4.17%)
         occurrences all number
    1
    1
    6
    4
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 93 (2.15%)
    2 / 96 (2.08%)
    3 / 95 (3.16%)
    6 / 95 (6.32%)
    4 / 96 (4.17%)
         occurrences all number
    3
    2
    3
    6
    4
    Oedema peripheral
         subjects affected / exposed
    2 / 93 (2.15%)
    3 / 96 (3.13%)
    2 / 95 (2.11%)
    6 / 95 (6.32%)
    1 / 96 (1.04%)
         occurrences all number
    3
    4
    3
    7
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 96 (1.04%)
    5 / 95 (5.26%)
    2 / 95 (2.11%)
    0 / 96 (0.00%)
         occurrences all number
    1
    1
    5
    2
    0
    Nausea
         subjects affected / exposed
    2 / 93 (2.15%)
    2 / 96 (2.08%)
    4 / 95 (4.21%)
    5 / 95 (5.26%)
    4 / 96 (4.17%)
         occurrences all number
    2
    2
    5
    5
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 93 (1.08%)
    5 / 96 (5.21%)
    6 / 95 (6.32%)
    2 / 95 (2.11%)
    2 / 96 (2.08%)
         occurrences all number
    1
    5
    6
    2
    2
    Dyspnoea
         subjects affected / exposed
    3 / 93 (3.23%)
    6 / 96 (6.25%)
    9 / 95 (9.47%)
    5 / 95 (5.26%)
    3 / 96 (3.13%)
         occurrences all number
    3
    7
    10
    6
    3
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 93 (2.15%)
    5 / 96 (5.21%)
    0 / 95 (0.00%)
    1 / 95 (1.05%)
    0 / 96 (0.00%)
         occurrences all number
    3
    5
    0
    1
    0
    Acute kidney injury
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 96 (1.04%)
    0 / 95 (0.00%)
    5 / 95 (5.26%)
    1 / 96 (1.04%)
         occurrences all number
    1
    1
    0
    5
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 96 (1.04%)
    2 / 95 (2.11%)
    4 / 95 (4.21%)
    6 / 96 (6.25%)
         occurrences all number
    1
    1
    2
    4
    6
    Nasopharyngitis
         subjects affected / exposed
    3 / 93 (3.23%)
    4 / 96 (4.17%)
    6 / 95 (6.32%)
    1 / 95 (1.05%)
    5 / 96 (5.21%)
         occurrences all number
    3
    4
    8
    1
    5
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    6 / 96 (6.25%)
    2 / 95 (2.11%)
    3 / 95 (3.16%)
    3 / 96 (3.13%)
         occurrences all number
    0
    6
    2
    3
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jul 2014
    The purpose of amendment was to implement clarifications primarily in exclusion criteria, additions in the study procedures and to correct minor errors or omissions.

    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.
    End points, "Health-related quality of life, Composite Congestion Score, NYHA function class, echo parameters other than LAV, biomarker and background HF therapies" were exploratory. “Incidence of atrial fibrillation” is reported in AE section.
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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