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    Clinical Trial Results:
    A randomized parallel-group, placebo-controlled, double-blind, multicenter, dose-finding Phase II trial exploring the pharmacodynamic effects, safety and tolerability, and pharmacokinetics of four dose regimens of the oral sGC stimulator vericiguat over 12 weeks in patients with worsening heart failure and reduced ejection fraction (HFrEF) - Soluble guanylate Cyclase stimulator in heart failure patients with REDUCED EF (SOCRATES-REDUCED)

    Summary
    EudraCT number
    		 2013-002287-11
    Trial protocol
    		 CZ   IT   AT   BE   SE   DK   DE   ES   NL   HU   BG   GR  
    Global end of trial date
    09 Jun 2015

    Results information
    Results version number
    		 v3(current)
    This version publication date
    03 Apr 2022
    First version publication date
    25 Jun 2016
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    updates on data presentation

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY1021189/15371
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01951625
    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
    29 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the study was to find the optimal dose of the oral soluble guanylate cyclase (sGC) stimulator vericiguat for Phase III that can be given in addition to standard therapy for heart failure with reduced ejection fraction (EF) (HFrEF) by characterizing the safety, tolerability, pharmacodynamic effects, and pharmacokinetics (PK), and detecting a significant dose-response relationship in the primary endpoint change in N-terminal pro-brain natriuretic peptide (NT-ProBNP) at 12 weeks in subjects with worsening chronic heart failure with reduced ejection fraction (HFrEF).
    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 and/or their legally authorized representative. 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
    29 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
    Spain: 32
    Country: Number of subjects enrolled
    Sweden: 15
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Taiwan: 24
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 25
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Austria: 17
    Country: Number of subjects enrolled
    Belgium: 23
    Country: Number of subjects enrolled
    Bulgaria: 41
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    Greece: 17
    Country: Number of subjects enrolled
    Hungary: 24
    Country: Number of subjects enrolled
    Israel: 42
    Country: Number of subjects enrolled
    Italy: 40
    Country: Number of subjects enrolled
    Japan: 30
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Poland: 32
    Country: Number of subjects enrolled
    Singapore: 21
    Worldwide total number of subjects
    456
    EEA total number of subjects
    300
    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)
    172
    From 65 to 84 years
    256
    85 years and over
    28

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 144 centers in 24 countries between 29 November 2013 (first subject first visit) and 09 June 2015 (last subject last visit).

    Pre-assignment
    Screening details
    		 Of the total 632 subjects enrolled, 176 were screen failure and 456 were randomized. After randomization 1 did not receive study drug, and of the 455 treated subjects 348 completed both Treatment and Follow Up 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
    		 Carer, Assessor, Subject, Investigator

    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
    Placebo
    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 milligram (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 single oral dose of Vericiguat tablet (BAY1021189) 1.25 mg once daily for 12 weeks with sham titrations on 14 and 28 days.

    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 from 2.5 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 once daily 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 2.5mg once daily with potential up-titration to 5 mg once daily after 14 or 28 days. Sham titration included on Day 28.

    Arm title
    		 BAY1021189 from 2.5 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 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Started
    92
    91
    91
    91
    91
    Completed
    73
    70
    76
    69
    74
    Not completed
    19
    21
    15
    22
    17
         Adverse event, serious fatal
    3
    2
    2
    1
    2
         Consent withdrawn by subject
    5
    2
    1
    7
    3
         Physician decision
    -
    -
    -
    -
    1
         Adverse event, non-fatal
    7
    10
    9
    8
    8
         Protocol driven decision point
    -
    5
    -
    2
    1
         Lost to follow-up
    1
    -
    -
    1
    -
         Non compliance with study drug
    1
    2
    2
    -
    -
         Protocol deviation
    2
    -
    1
    3
    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
    		 Carer, Assessor, Subject, Investigator

    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
    Placebo
    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 milligram (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 single oral dose of Vericiguat tablet (BAY1021189) 1.25 mg once daily for 12 weeks with sham titrations on 14 and 28 days.

    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 from 2.5 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 once daily 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 2.5mg once daily with potential up-titration to 5 mg once daily after 14 or 28 days. Sham titration included on Day 28.

    Arm title
    		 BAY1021189 from 2.5 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 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Started
    87
    88
    88
    87
    88
    Completed
    79
    79
    84
    76
    78
    Not completed
    8
    9
    4
    11
    10
         Adverse event, serious fatal
    1
    3
    2
    2
    1
         Consent withdrawn by subject
    4
    1
    -
    5
    3
         Logistical difficulties
    1
    2
    -
    -
    -
         Adverse event, non-fatal
    -
    3
    2
    3
    5
         Non-compliance with study drug
    1
    -
    -
    -
    -
         Lost to follow-up
    1
    -
    -
    1
    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 milligram (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.

    Reporting group values
    		 Placebo BAY1021189 1.25 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg Total
    Number of subjects
    		 92 91 91 91 91 456
    Age categorical
    Units: Subjects
        <65
    		 38 38 30 38 28 172
        65-75
    		 26 19 37 32 34 148
        >=75
    		 28 34 24 21 29 136
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67 ( 13.1 ) 67.6 ( 12.9 ) 67.6 ( 11.5 ) 66.7 ( 11.6 ) 68.9 ( 12.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 19 21 19 17 14 90
        Male
    		 73 70 72 74 77 366

    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 milligram (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.
    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 milligram (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.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS (N=456) included all subjects randomized to treatment and was used to display baseline characteristics and efficacy analyses.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF (N=455) included all subjects from FAS who received at least 1 dose of study drug and was used to display baseline characteristics and safety analyses.

    Subject analysis set title
    Per protocol set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PPS (N=351) included subjects who were randomized to treatment and had a valid measurement of NT-proBNP at baseline and at Week 12 and showed no major protocol deviations. The PPS was the primary analysis set for the primary efficacy analysis and was used for further efficacy analyses and baseline characteristics.

    Subject analysis set title
    Pooled 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= 213) The three highest dose arms (BAY1021189 2.5 mg, 2.5-5 mg, and 2.5-10 mg) were pooled and used for the primary analysis of the primary endpoint. 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 database.

    Primary: Change From Baseline in Log-Transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) to Week 12

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    End point title
    		 Change From Baseline in Log-Transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) to Week 12
    End point description
    Log-Transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) is a circulating plasma biomarker of cardiovascular function and prognosis in heart failure.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo BAY1021189 1.25 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg Pooled 2.5 mg up to 10 mg
    Number of subjects analysed
    69 [1]
    69 [2]
    73 [3]
    67 [4]
    73 [5]
    213
    Units: log-transformed picograms per milliliter
        arithmetic mean (standard deviation)
    -0.28 ( 0.8197 )
    -0.265 ( 0.7658 )
    -0.32 ( 0.7799 )
    -0.353 ( 0.8404 )
    -0.529 ( 0.9475 )
    -0.402 ( 0.8603 )
    Notes
    [1] - PPS
    [2] - PPS
    [3] - PPS
    [4] - PPS
    [5] - PPS
    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 at the significance level of 5 percent (%). Results are reported including 90% confidence intervals (CI) for the difference of means. The difference between the pooled treatment group and the placebo group is difference of means on the log scale.
    Comparison groups
    Placebo v Pooled 2.5 mg up to 10 mg
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1506
    Method
    		 t-test, 1-sided
    Parameter type
    		 Log-Scale mean difference
    Point estimate
    -0.122
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.07
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    In case of a significant result in the primary analysis of the primary endpoint, 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 from 2.5 to 10 mg
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0483
    Method
    		 t-test, 1-sided
    Parameter type
    		 Log-Scale mean difference
    Point estimate
    -0.2494
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    In case of a significant result in the primary analysis of the primary endpoint, 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 from 2.5 to 5 mg
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3042
    Method
    		 t-test, 1-sided
    Parameter type
    		 Log-Scale mean difference
    Point estimate
    -0.0731
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.16
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    In case of a significant result in the primary analysis of the primary endpoint, 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
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3841
    Method
    		 t-test, 1-sided
    Parameter type
    		 Log-Scale mean difference
    Point estimate
    -0.0396
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.18
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    In case of a significant result in the primary analysis of the primary endpoint, 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 milligram (mg)
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5444
    Method
    		 t-test, 1-sided
    Parameter type
    		 Log-Scale mean difference
    Point estimate
    0.0151
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.24

    Other pre-specified: Changes in Heart Function as Measured by Echocardiography, Left Ventricular Ejection Fraction (LVEF), Left Ventricular End-Diastolic Volume (LVEDV), and Left Ventricular End-Systolic Volume (LVESV) From Baseline to Week 12

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    End point title
    		 Changes in Heart Function as Measured by Echocardiography, Left Ventricular Ejection Fraction (LVEF), Left Ventricular End-Diastolic Volume (LVEDV), and Left Ventricular End-Systolic Volume (LVESV) From Baseline to Week 12
    End point description
    Left Ventricular End-Diastolic Volume (LVEDV) and Left ventricular end-systolic volume (LVESV) are measured echocardiography parameter. These are acquired during a non-invasive echocardiography examination. The left ventricular ejection fraction work index (LVEF) is a calculated echocardiography parameter. LVEF is derived from the directly measured parameters left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). Formula: LVEF = 100*(LVEDV - LVESV)/LVEDV. Here, n = subjects evaluable for specified category for each arm, respectively.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo BAY1021189 1.25 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Number of subjects analysed
    92 [6]
    91 [7]
    91 [8]
    91 [9]
    91 [10]
    Units: % for LVEF; ml for LVEDV/LVESV
    arithmetic mean (standard deviation)
        Change in LVEF (%): (n=70,65,69,63,71)
    1.515 ( 4.736 )
    2.84 ( 3.635 )
    2.741 ( 4.371 )
    2.07 ( 4.808 )
    3.682 ( 6.19 )
        Change in LVEDV (milliliter): (n=70,65,69,63,70)
    -7.259 ( 40.676 )
    -5.525 ( 34.75 )
    -9.632 ( 35.081 )
    -17.093 ( 53.307 )
    -7.324 ( 31.896 )
        Change in LVESV (milliliter): (n=70,65,69,63,71)
    -6.83 ( 32.407 )
    -8.585 ( 27.385 )
    -10.935 ( 27.146 )
    -15.485 ( 43.191 )
    -11.017 ( 26.525 )
    Notes
    [6] - Evaluable subjects in FAS
    [7] - Evaluable subjects in FAS
    [8] - Evaluable subjects in FAS
    [9] - Evaluable subjects in FAS
    [10] - Evaluable subjects in FAS
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Systolic and Diastolic Blood Pressure to Week 12

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    End point title
    		 Change From Baseline in Systolic and Diastolic Blood Pressure to Week 12
    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
    End point values
    		 Placebo BAY1021189 1.25 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Number of subjects analysed
    92 [11]
    91 [12]
    90 [13]
    91 [14]
    91 [15]
    Units: millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        Change in SBP: (n= 73, 70, 75, 69, 74)
    -5.142 ( 12.829 )
    -4.033 ( 13.3 )
    -3.733 ( 16.509 )
    -3.043 ( 15.934 )
    -5.64 ( 15.509 )
        Change in DBP: (n= 73, 70, 75, 69, 74)
    -4.173 ( 8.6 )
    -0.486 ( 9.298 )
    -2.938 ( 11.101 )
    -1.338 ( 9.528 )
    -4.045 ( 10.604 )
    Notes
    [11] - SAF
    [12] - SAF
    [13] - SAF
    [14] - SAF
    [15] - SAF
    No statistical analyses for this end point

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

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    End point title
    		 Change From Baseline in Heart rate to Week 12
    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. Here, n = subjects evaluable for specified category for each arm, respectively.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo BAY1021189 1.25 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Number of subjects analysed
    92 [16]
    91 [17]
    90 [18]
    91 [19]
    91 [20]
    Units: Beats per minute
    arithmetic mean (standard deviation)
        Change at Week 12 (n= 73, 70, 75, 69, 74)
    -0.562 ( 12.897 )
    -0.352 ( 10.153 )
    -1.556 ( 10.2 )
    -0.99 ( 11.295 )
    0.545 ( 10.636 )
    Notes
    [16] - SAF
    [17] - SAF
    [18] - SAF
    [19] - SAF
    [20] - SAF
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects With Clinical Events (Heart Failure [HF] 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 until 16 weeks including 12 week treatment period and 4 week follow-up period
    End point values
    		 Placebo BAY1021189 1.25 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Number of subjects analysed
    92 [21]
    91 [22]
    91 [23]
    91 [24]
    91 [25]
    Units: subjects
        HF hospitalizations
    21
    18
    20
    10
    9
        CV death
    6
    5
    4
    2
    4
    Notes
    [21] - FAS
    [22] - FAS
    [23] - FAS
    [24] - FAS
    [25] - FAS
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Implantable Cardioverter Defibrillators Cardiac Resynchronization Therapy With Defibrillation (ICD/CRT-D) Therapy

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    End point title
    		 Number of Subjects With Implantable Cardioverter Defibrillators Cardiac Resynchronization Therapy With Defibrillation (ICD/CRT-D) Therapy
    End point description
    ICD / CRT with defibrillation therapy (CRT-D) included previous appropriate interventions such as shocks or anti-tachycardic pacing (ATP) when diagnostic of sustained ventricular tachycardias in pre defined rapid zone.
    End point type
    Other pre-specified
    End point timeframe
    Baseline upto 16 weeks
    End point values
    		 Placebo BAY1021189 1.25 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Number of subjects analysed
    0 [26]
    0 [27]
    0 [28]
    0 [29]
    0 [30]
    Units: subjects
    Notes
    [26] - No analysis was performed for this end point.
    [27] - No analysis was performed for this end point.
    [28] - No analysis was performed for this end point.
    [29] - No analysis was performed for this end point.
    [30] - No analysis was performed for this end point.
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Treatment-Emergent Adverse Events

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; and another medically important serious event as judged by the investigator. AEs are considered to be treatment-emergent if they have started or worsened after first application of study drug up to 5 days after end of treatment with study drug.
    End point type
    Other pre-specified
    End point timeframe
    From the start of study treatment upto 5 days after the last dose of study drug
    End point values
    		 Placebo BAY1021189 1.25 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Number of subjects analysed
    92 [31]
    91 [32]
    90 [33]
    91 [34]
    91 [35]
    Units: Number of subjects
    66
    60
    62
    62
    56
    Notes
    [31] - SAF
    [32] - SAF
    [33] - SAF
    [34] - SAF
    [35] - SAF
    No statistical analyses for this end point

    Other pre-specified: Change in biomarkers from baseline to week 12: Osteopontin (ng/mL)

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    End point title
    		 Change in biomarkers from baseline to week 12: Osteopontin (ng/mL)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo BAY1021189 1.25 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Number of subjects analysed
    73 [36]
    69 [37]
    73 [38]
    65 [39]
    71 [40]
    Units: nanogram(s)/milliliter (ng/mL)
        arithmetic mean (standard deviation)
    2.79 ( 42.049 )
    3.812 ( 39.248 )
    3.266 ( 52.957 )
    8.485 ( 41.97 )
    3.709 ( 36.048 )
    Notes
    [36] - Evaluable subjects in FAS
    [37] - Evaluable subjects in FAS
    [38] - Evaluable subjects in FAS
    [39] - Evaluable subjects in FAS
    [40] - Evaluable subjects in FAS
    No statistical analyses for this end point

    Other pre-specified: Change in biomarkers from baseline to week 12: TIMP-4 (pg/mL)

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    End point title
    		 Change in biomarkers from baseline to week 12: TIMP-4 (pg/mL)
    End point description
    TIMP-4: tissue inhibitor of matrix metalloproteinases 4
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo BAY1021189 1.25 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Number of subjects analysed
    73 [41]
    69 [42]
    72 [43]
    67 [44]
    72 [45]
    Units: picogram(s)/millilitre (pg/mL)
        arithmetic mean (standard deviation)
    451.889 ( 1392.03 )
    1128.635 ( 1949.351 )
    643.626 ( 1441.954 )
    876.584 ( 1559.768 )
    397.603 ( 1420.223 )
    Notes
    [41] - Evaluable subjects in FAS
    [42] - Evaluable subjects in FAS
    [43] - Evaluable subjects in FAS
    [44] - Evaluable subjects in FAS
    [45] - Evaluable subjects in FAS
    No statistical analyses for this end point

    Other pre-specified: Change in biomarkers from baseline to week 12: cGMP (pmol/mL)

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    End point title
    		 Change in biomarkers from baseline to week 12: cGMP (pmol/mL)
    End point description
    cGMP: cyclic guanosine monophosphate
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo BAY1021189 1.25 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Number of subjects analysed
    73 [46]
    69 [47]
    73 [48]
    66 [49]
    71 [50]
    Units: picomole(s)/milliliter (pmol/mL)
        arithmetic mean (standard deviation)
    78.874 ( 143.321 )
    79.767 ( 123.031 )
    92.352 ( 121.477 )
    80.888 ( 114.09 )
    63.563 ( 127.448 )
    Notes
    [46] - Evaluable subjects in FAS
    [47] - Evaluable subjects in FAS
    [48] - Evaluable subjects in FAS
    [49] - Evaluable subjects in FAS
    [50] - Evaluable subjects in FAS
    No statistical analyses for this end point

    Other pre-specified: Change in biomarkers from baseline to week 12: PIIINP (mcg/L)

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    End point title
    		 Change in biomarkers from baseline to week 12: PIIINP (mcg/L)
    End point description
    PIIINP: pro-collagen III N-terminal peptide
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo BAY1021189 1.25 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Number of subjects analysed
    70 [51]
    69 [52]
    72 [53]
    67 [54]
    73 [55]
    Units: microgram(s)/liter (mcg/L)
        arithmetic mean (standard deviation)
    -0.701 ( 7.246 )
    0.092 ( 3.958 )
    0.106 ( 5.145 )
    -0.71 ( 3.774 )
    -0.321 ( 4.452 )
    Notes
    [51] - Evaluable subjects in FAS
    [52] - Evaluable subjects in FAS
    [53] - Evaluable subjects in FAS
    [54] - Evaluable subjects in FAS
    [55] - Evaluable subjects in FAS
    No statistical analyses for this end point

    Other pre-specified: Change in biomarkers from baseline to week 12: GDF-15 (pg/mL)

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    End point title
    		 Change in biomarkers from baseline to week 12: GDF-15 (pg/mL)
    End point description
    GDF-15: growth differentiation factor 15
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo BAY1021189 1.25 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Number of subjects analysed
    73 [56]
    69 [57]
    73 [58]
    66 [59]
    71 [60]
    Units: pg/mL
        arithmetic mean (standard deviation)
    429.432 ( 3212.229 )
    496.456 ( 3132.738 )
    285.472 ( 2837.237 )
    468.369 ( 1786.062 )
    244.63 ( 2906.763 )
    Notes
    [56] - Evaluable subjects in FAS
    [57] - Evaluable subjects in FAS
    [58] - Evaluable subjects in FAS
    [59] - Evaluable subjects in FAS
    [60] - Evaluable subjects in FAS
    No statistical analyses for this end point

    Other pre-specified: Change in biomarkers from baseline to week 12: ST2 (pg/mL)

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    End point title
    		 Change in biomarkers from baseline to week 12: ST2 (pg/mL)
    End point description
    ST2: suppression of tumorigenicity 2
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo BAY1021189 1.25 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Number of subjects analysed
    73 [61]
    69 [62]
    72 [63]
    67 [64]
    72 [65]
    Units: pg/mL
        arithmetic mean (standard deviation)
    9457.677 ( 54702.45 )
    1623.869 ( 25086.72 )
    -1217.77 ( 35166.41 )
    6933.941 ( 20747.71 )
    3681.668 ( 32293.77 )
    Notes
    [61] - Evaluable subjects in FAS
    [62] - Evaluable subjects in FAS
    [63] - Evaluable subjects in FAS
    [64] - Evaluable subjects in FAS
    [65] - Evaluable subjects in FAS
    No statistical analyses for this end point

    Other pre-specified: Change in biomarkers from baseline to week 12: Gal-3 (μg/mL)

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    End point title
    		 Change in biomarkers from baseline to week 12: Gal-3 (μg/mL)
    End point description
    Gal-3: Galectin-3
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo BAY1021189 1.25 milligram (mg) BAY1021189 2.5 mg BAY1021189 from 2.5 to 5 mg BAY1021189 from 2.5 to 10 mg
    Number of subjects analysed
    72 [66]
    68 [67]
    73 [68]
    64 [69]
    71 [70]
    Units: mcg/L
        arithmetic mean (standard deviation)
    0.802 ( 13.818 )
    0.233 ( 6.208 )
    -0.287 ( 3.729 )
    0.064 ( 5.64 )
    -0.38 ( 4.551 )
    Notes
    [66] - Evaluable subjects in FAS
    [67] - Evaluable subjects in FAS
    [68] - Evaluable subjects in FAS
    [69] - Evaluable subjects in FAS
    [70] - Evaluable subjects in 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 milligram (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 2.5mg 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 2.5mg 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 milligram (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
    30 / 92 (32.61%)
    26 / 91 (28.57%)
    26 / 90 (28.89%)
    20 / 91 (21.98%)
    25 / 91 (27.47%)
         number of deaths (all causes)
    6
    6
    5
    3
    4
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric cancer
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         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
    Intra-abdominal haemangioma
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 91 (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
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    0 / 91 (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
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Hypotension
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 91 (1.10%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Surgical and medical procedures
    Catheter placement
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 91 (1.10%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 91 (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 / 1
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    0 / 91 (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
    Oedema peripheral
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 91 (1.10%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    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
    Sudden death
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         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
    Device dislocation
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    0 / 91 (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, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 91 (1.10%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    0 / 91 (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
    Acute respiratory failure
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 91 (1.10%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 91 (1.10%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 91 (1.10%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Pulmonary congestion
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         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
    Pulmonary oedema
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    0 / 91 (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
    Investigations
    Transplant evaluation
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 91 (1.10%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 92 (2.17%)
    2 / 91 (2.20%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         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
    Contusion
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Incision site haemorrhage
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         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
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Atrial fibrillation
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    2 / 91 (2.20%)
         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
    Cardiac arrest
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    8 / 92 (8.70%)
    13 / 91 (14.29%)
    10 / 90 (11.11%)
    3 / 91 (3.30%)
    3 / 91 (3.30%)
         occurrences causally related to treatment / all
    1 / 14
    0 / 14
    0 / 11
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiac failure chronic
         subjects affected / exposed
    5 / 92 (5.43%)
    2 / 91 (2.20%)
    5 / 90 (5.56%)
    3 / 91 (3.30%)
    4 / 91 (4.40%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 5
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 92 (1.09%)
    2 / 91 (2.20%)
    3 / 90 (3.33%)
    2 / 91 (2.20%)
    3 / 91 (3.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 3
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    0 / 91 (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
    Ventricular tachycardia
         subjects affected / exposed
    1 / 92 (1.09%)
    1 / 91 (1.10%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    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
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 91 (1.10%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 91 (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
    Acute left ventricular failure
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    0 / 91 (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
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 91 (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
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         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
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 91 (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
    Headache
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         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
    Syncope
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 92 (1.09%)
    1 / 91 (1.10%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         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
    Thrombocytopenia
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Abdominal pain
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 91 (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
    Diarrhoea
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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 haemorrhage
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    0 / 91 (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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 91 (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
    Mechanical ileus
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Incarcerated umbilical hernia
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Cholangitis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         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
    Rash pruritic
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    1 / 91 (1.10%)
         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
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 91 (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 retention
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 91 (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
    Acute kidney injury
         subjects affected / exposed
    3 / 92 (3.26%)
    4 / 91 (4.40%)
    2 / 90 (2.22%)
    1 / 91 (1.10%)
    3 / 91 (3.30%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 91 (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
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 91 (1.10%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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 / 92 (1.09%)
    1 / 91 (1.10%)
    0 / 90 (0.00%)
    2 / 91 (2.20%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 91 (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 / 92 (0.00%)
    1 / 91 (1.10%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 91 (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 / 1
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Gout
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Hyperglycaemia
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Hyperkalaemia
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Hypoglycaemia
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 91 (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
    Hypokalaemia
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 91 (1.10%)
    2 / 90 (2.22%)
    0 / 91 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 91 (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
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 91 (0.00%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    0 / 91 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo BAY1021189 1.25 milligram (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
    24 / 92 (26.09%)
    25 / 91 (27.47%)
    20 / 90 (22.22%)
    23 / 91 (25.27%)
    28 / 91 (30.77%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    6 / 92 (6.52%)
    5 / 91 (5.49%)
    5 / 90 (5.56%)
    4 / 91 (4.40%)
    14 / 91 (15.38%)
         occurrences all number
    6
    5
    6
    4
    17
    Cardiac disorders
    Cardiac failure chronic
         subjects affected / exposed
    4 / 92 (4.35%)
    1 / 91 (1.10%)
    5 / 90 (5.56%)
    2 / 91 (2.20%)
    0 / 91 (0.00%)
         occurrences all number
    5
    1
    5
    2
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 92 (5.43%)
    3 / 91 (3.30%)
    2 / 90 (2.22%)
    2 / 91 (2.20%)
    5 / 91 (5.49%)
         occurrences all number
    6
    3
    2
    2
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 92 (3.26%)
    0 / 91 (0.00%)
    2 / 90 (2.22%)
    5 / 91 (5.49%)
    2 / 91 (2.20%)
         occurrences all number
    3
    0
    2
    5
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 92 (2.17%)
    5 / 91 (5.49%)
    1 / 90 (1.11%)
    1 / 91 (1.10%)
    0 / 91 (0.00%)
         occurrences all number
    2
    6
    1
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 91 (1.10%)
    0 / 90 (0.00%)
    1 / 91 (1.10%)
    5 / 91 (5.49%)
         occurrences all number
    0
    1
    0
    1
    7
    Nausea
         subjects affected / exposed
    3 / 92 (3.26%)
    5 / 91 (5.49%)
    3 / 90 (3.33%)
    1 / 91 (1.10%)
    1 / 91 (1.10%)
         occurrences all number
    4
    6
    3
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    5 / 92 (5.43%)
    1 / 91 (1.10%)
    3 / 90 (3.33%)
    2 / 91 (2.20%)
    4 / 91 (4.40%)
         occurrences all number
    5
    1
    3
    3
    4
    Cough
         subjects affected / exposed
    6 / 92 (6.52%)
    8 / 91 (8.79%)
    4 / 90 (4.44%)
    4 / 91 (4.40%)
    4 / 91 (4.40%)
         occurrences all number
    7
    8
    4
    4
    4
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 91 (0.00%)
    2 / 90 (2.22%)
    5 / 91 (5.49%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    2
    5
    0
    Hypokalaemia
         subjects affected / exposed
    3 / 92 (3.26%)
    5 / 91 (5.49%)
    2 / 90 (2.22%)
    2 / 91 (2.20%)
    5 / 91 (5.49%)
         occurrences all number
    3
    5
    2
    2
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jul 2013
    The purpose of this global amendment was to implement clarifications (primarily in exclusion criteria and study procedures): Exclusion criteria were clarified to facilitate enrollment of appropriate subjects, to prevent over-interpretation and exclusion of eligible subjects, and to minimize protocol deviations: -The exclusion criterion “IV inotropes at any time after hospitalization” was revised to “IV inotropes at any time between hospitalization and randomization” to clarify that there was no prohibition of inotropes after randomization (if HF re-hospitalization occurred). -The exclusion criterion “…valvular heart disease with severe aortic or mitral regurgitation…”was revised to “…valvular heart disease with severe aortic or primary mitral regurgitation…” to clarify that secondary (functional) mitral regurgitation was not excluded. -The exclusion criterion “ ..or CABG within 60 days prior to randomization; or indication for percutaneous coronary intervention (PCI) or CABG” was revised to “…or CABG within 60 days prior to randomization. Current indication for PCI or CABG (at time of randomization)” to clarify that no 60-day lag time was required after elective PCI. -Excluded BMI was changed from >40 kg/m^2 to >45 kg/m^2 to adapt the upper range of eligible BMI to the observed clinical characteristics at participating sites in order to recruit a population that was representative, including those with high BMI. The additional mandatory criterion of NT-ProBNP/BNP ensured the presence of HF in those subjects with very high BMI. Study procedures were clarified to minimize protocol deviations. The protocol was clarified in that there was only one committee, the Clinical Events Committee (CEC), and only one manual, the CEC manual, to adjudicate events. IV vasodilators were included as indicative of worsening chronic heart failure (WCHF) to be consistent with the CEC manual. The protocol was clarified in that HR was also measured during echocardiography.

    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.
    Endpoints of "Change in ‘health-related quality of life’, ‘Composite Congestion Score’, ‘NYHA function class’, and ‘background heart failure therapies’ were assessed as exploratory. “Incidence of atrial fibrillation” is reported in AE summary.
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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
    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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