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    Clinical Trial Results:
    A multicenter, randomized, placebo-controlled, parallel group, double blind, dose-finding Phase II trial to study the efficacy, safety, pharmacokinetics and pharmacodynamic effects of the oral partial adenosine A1 receptor agonist neladenoson bialanate over 20 weeks in patients with chronic heart failure and preserved ejection fraction

    Summary
    EudraCT number
    		 2016-004062-26
    Trial protocol
    		 BE   DE   ES   BG   PT   GR   AT   IT  
    Global end of trial date
    20 Jun 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jul 2019
    First version publication date
    05 Jul 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BAY1067197/17582
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03098979
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    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
    20 Jun 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jun 2018
    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 neladenoson bialanate for the Phase 3 trial by detecting and characterizing a significant dose-response relationship in the primary efficacy endpoint, absolute change from baseline in 6-minute walking distance (6MWD) at 20 weeks, in subjects with heart failure with preserved ejection fraction (HFpEF), and by characterizing the safety, tolerability and pharmacodynamic effects of the compound when given in addition to appropriate therapy for specific co-morbidities.
    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 Council for Harmonisation (ICH) guideline E6: Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 May 2017
    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
    Japan: 32
    Country: Number of subjects enrolled
    Bulgaria: 49
    Country: Number of subjects enrolled
    Poland: 58
    Country: Number of subjects enrolled
    United States: 16
    Country: Number of subjects enrolled
    Austria: 31
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Greece: 26
    Country: Number of subjects enrolled
    Israel: 17
    Country: Number of subjects enrolled
    Italy: 36
    Country: Number of subjects enrolled
    Portugal: 8
    Worldwide total number of subjects
    305
    EEA total number of subjects
    240
    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)
    41
    From 65 to 84 years
    236
    85 years and over
    28

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted at 76 study centers in 12 countries, between 10 May 2017 (first patient first visit) and 20 June 2018 (last patient last visit)

    Pre-assignment
    Screening details
    		 A total of 339 subjects entered the screening period, of whom 34 withdrew before randomization. The remaining 305 subjects were randomized and received at least one dose of study drug

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo matched to neladenoson bialanate tablets orally for 20 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to neladenoson bialanate tablets.

    Arm title
    		 Neladenoson Bialanate 5 mg
    Arm description
    		 Subjects received 5 milligrams (mg) of neladenoson bialanate tablets orally for 20 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Neladenoson Bialanate
    Investigational medicinal product code
    BAY1067197
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received neladenoson bialanate tablets orally.

    Arm title
    		 Neladenoson Bialanate 10 mg
    Arm description
    		 Subjects received 10 mg of neladenoson bialanate tablets orally for 20 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Neladenoson Bialanate
    Investigational medicinal product code
    BAY1067197
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received neladenoson bialanate tablets orally.

    Arm title
    		 Neladenoson Bialanate 20 mg
    Arm description
    		 Subjects received 20 mg of neladenoson bialanate tablets orally for 20 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Neladenoson Bialanate
    Investigational medicinal product code
    BAY1067197
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received neladenoson bialanate tablets orally.

    Arm title
    		 Neladenoson Bialanate 30 mg
    Arm description
    		 Subjects received 30 mg of neladenoson bialanate tablets orally for 20 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Neladenoson Bialanate
    Investigational medicinal product code
    BAY1067197
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received neladenoson bialanate tablets orally.

    Arm title
    		 Neladenoson Bialanate 40 mg
    Arm description
    		 Subjects received 40 mg of neladenoson bialanate tablets orally for 20 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Neladenoson Bialanate
    Investigational medicinal product code
    BAY1067197
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received neladenoson bialanate tablets orally.

    Number of subjects in period 1
    		Placebo Neladenoson Bialanate 5 mg Neladenoson Bialanate 10 mg Neladenoson Bialanate 20 mg Neladenoson Bialanate 30 mg Neladenoson Bialanate 40 mg
    Started
    76
    27
    50
    51
    50
    51
    Completed
    70
    25
    46
    46
    41
    47
    Not completed
    6
    2
    4
    5
    9
    4
         Adverse event, serious fatal
    1
    -
    2
    -
    1
    -
         Consent withdrawn by subject
    2
    1
    1
    1
    2
    1
         Physician decision
    2
    1
    -
    -
    -
    -
         Adverse event, non-fatal
    1
    -
    1
    4
    6
    1
         Non-compliance
    -
    -
    -
    -
    -
    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 neladenoson bialanate tablets orally for 20 weeks

    Reporting group title
    Neladenoson Bialanate 5 mg
    Reporting group description
    		 Subjects received 5 milligrams (mg) of neladenoson bialanate tablets orally for 20 weeks

    Reporting group title
    Neladenoson Bialanate 10 mg
    Reporting group description
    		 Subjects received 10 mg of neladenoson bialanate tablets orally for 20 weeks

    Reporting group title
    Neladenoson Bialanate 20 mg
    Reporting group description
    		 Subjects received 20 mg of neladenoson bialanate tablets orally for 20 weeks

    Reporting group title
    Neladenoson Bialanate 30 mg
    Reporting group description
    		 Subjects received 30 mg of neladenoson bialanate tablets orally for 20 weeks

    Reporting group title
    Neladenoson Bialanate 40 mg
    Reporting group description
    		 Subjects received 40 mg of neladenoson bialanate tablets orally for 20 weeks

    Reporting group values
    		 Placebo Neladenoson Bialanate 5 mg Neladenoson Bialanate 10 mg Neladenoson Bialanate 20 mg Neladenoson Bialanate 30 mg Neladenoson Bialanate 40 mg Total
    Number of subjects
    		 76 27 50 51 50 51 305
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 73.1 ± 8.0 74.3 ± 9.3 73.5 ± 9.9 71.4 ± 6.8 76 ± 9.4 73.7 ± 8.3 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 36 16 26 21 32 29 160
        Male
    		 40 11 24 30 18 22 145
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0
        Asian
    		 9 3 6 5 5 5 33
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0
        Black or African American
    		 3 0 0 1 0 1 5
        White
    		 64 24 44 45 45 45 267
        More than one race
    		 0 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 0 0 0 0 0 2
        Not Hispanic or Latino
    		 73 27 49 51 50 50 300
        Unknown or Not Reported
    		 1 0 1 0 0 1 3
    NYHA class
    NYHA classes: I: No limitation of physical activity (PA). Ordinary PA does not cause undue fatigue, palpitation, dyspnea, or anginal pain II: Slight limitation of PA; comfortable at rest. Ordinary PA results in fatigue, palpitation, dyspnea, or anginal pain III: Marked limitation of PA; comfortable at rest. Less than ordinary PA causes fatigue, palpitation, dyspnea, or anginal pain IV: Inability to carry on any PA without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any PA is undertaken, discomfort is increased
    Units: Subjects
        Class II
    		 61 23 37 41 31 39 232
        Class III/IV
    		 15 4 13 10 19 12 73
    Medical history: diabetes
    Subjects with medical history of Type 2 diabetes mellitus
    Units: Subjects
        Medical history: diabetes
    		 36 7 23 20 22 21 129
        Medical history: no diabetes
    		 40 20 27 31 28 30 176
    Medical history: Atrial fibrillation
    Subjects with medical history of Atrial fibrillation
    Units: Subjects
        Medical history: Atrial fibrillation
    		 28 10 18 19 20 21 116
        Medical history: no Atrial fibrillation
    		 48 17 32 32 30 30 189
    Medical history: hypertension
    Subjects with medical history of hypertension
    Units: Subjects
        Medical history: hypertension
    		 66 25 45 45 46 42 269
        Medical history: no hypertension
    		 10 2 5 6 4 9 36
    LVEF
    Left ventricular ejection fraction (LVEF) is defined as the fraction of blood being pumped out of the left ventricle of the heart with each contraction.
    Units: percentage
        arithmetic mean (standard deviation)
    		 57.09 ± 8.68 56.54 ± 9.62 53.78 ± 11.6 57.3 ± 10.4 59.43 ± 8.72 52.3 ± 12.76 -
    NT-proBNP
    N-terminal pro-hormone b-type natriuretic peptide
    Units: pg/ml
        median (full range (min-max))
    		 882.0 (54 to 3034) 1013.0 (136 to 5709) 1000.0 (116 to 3547) 834.5 (173 to 6003) 626.0 (78 to 3043) 886.5 (60 to 8170) -
    eGFR
    eGFR = estimated glomerular filtration rate
    Units: mL/min/1.73 square meter
        arithmetic mean (standard deviation)
    		 62.0 ± 17.9 52.6 ± 17.1 61.0 ± 24.2 57.1 ± 17.3 57.5 ± 18.2 60.0 ± 17.5 -
    6MWD
    6MWD = six-minute walking distance
    Units: meter
        arithmetic mean (standard deviation)
    		 322.8 ± 97.1 311.6 ± 108.2 295.8 ± 110.4 324.5 ± 105 321.1 ± 93.4 347.2 ± 94.5 -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to neladenoson bialanate tablets orally for 20 weeks

    Reporting group title
    Neladenoson Bialanate 5 mg
    Reporting group description
    		 Subjects received 5 milligrams (mg) of neladenoson bialanate tablets orally for 20 weeks

    Reporting group title
    Neladenoson Bialanate 10 mg
    Reporting group description
    		 Subjects received 10 mg of neladenoson bialanate tablets orally for 20 weeks

    Reporting group title
    Neladenoson Bialanate 20 mg
    Reporting group description
    		 Subjects received 20 mg of neladenoson bialanate tablets orally for 20 weeks

    Reporting group title
    Neladenoson Bialanate 30 mg
    Reporting group description
    		 Subjects received 30 mg of neladenoson bialanate tablets orally for 20 weeks

    Reporting group title
    Neladenoson Bialanate 40 mg
    Reporting group description
    		 Subjects received 40 mg of neladenoson bialanate tablets orally for 20 weeks

    Primary: Absolute change from baseline in 6-minute walking distance (6MWD) after 20 weeks of treatment

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    End point title
    		 Absolute change from baseline in 6-minute walking distance (6MWD) after 20 weeks of treatment
    End point description
    The 6MWD test is designed to evaluate a subject’s exercise capacity while performing an everyday activity.
    End point type
    Primary
    End point timeframe
    Up to 20 weeks of treatment
    End point values
    		 Placebo Neladenoson Bialanate 5 mg Neladenoson Bialanate 10 mg Neladenoson Bialanate 20 mg Neladenoson Bialanate 30 mg Neladenoson Bialanate 40 mg
    Number of subjects analysed
    65
    22
    44
    41
    34
    37
    Units: meter
    arithmetic mean (standard deviation)
        Value at baseline
    329 ± 95
    306 ± 117
    300 ± 109
    328 ± 105
    321 ± 101
    363 ± 83
        Change from baseline to Week 20
    1.89 ± 49.5
    24.8 ± 72.4
    27.2 ± 90.0
    14.6 ± 54.1
    16.3 ± 55.4
    10.7 ± 60.2
    Statistical analysis title
    		 Linear: Dose response test
    Comparison groups
    Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5183 [1]
    Method
    		 MCP-Mod method
    Confidence interval
    Notes
    [1] - Linear dose-response shape: The multiple comparison procedures (MCP) approach was applied to calculate the adjusted one-sided p-values of the contrast test.
    Statistical analysis title
    		 Sigmoidal Emax 1: Dose response test
    Comparison groups
    Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33 [2]
    Method
    		 MCP-Mod method
    Confidence interval
    Notes
    [2] - Sigmoidal Emax 1 dose-response shape: The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.
    Statistical analysis title
    		 Sigmoidal Emax 2: Dose response test
    Comparison groups
    Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6232 [3]
    Method
    		 MCP-Mod method
    Confidence interval
    Notes
    [3] - Sigmoidal Emax 2 dose-response shape: The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.
    Statistical analysis title
    		 Emax: Dose response test
    Comparison groups
    Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0918 [4]
    Method
    		 MCP-Mod method
    Confidence interval
    Notes
    [4] - Emax dose-response shape: The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.
    Statistical analysis title
    		 Quadratic: Dose response test
    Comparison groups
    Placebo v Neladenoson Bialanate 5 mg v Neladenoson Bialanate 10 mg v Neladenoson Bialanate 20 mg v Neladenoson Bialanate 30 mg v Neladenoson Bialanate 40 mg
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2701 [5]
    Method
    		 MCP-Mod method
    Confidence interval
    Notes
    [5] - Quadratic dose-response shape: The MCP approach was applied to calculate the adjusted one-sided p-values of the contrast test.

    Secondary: Reported values and absolute change in AVIVO activity intensity from baseline to 20 weeks

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    End point title
    		 Reported values and absolute change in AVIVO activity intensity from baseline to 20 weeks
    End point description
    AVIVO™ Mobile Patient Management System, a wearable wireless device worn by the subject, was used to monitor subjects’ cardiovascular status. The patient’s everyday physical activity e.g. duration, intensity, was also tracked by the AVIVO device
    End point type
    Secondary
    End point timeframe
    Up to 20 weeks of treatment
    End point values
    		 Placebo Neladenoson Bialanate 5 mg Neladenoson Bialanate 10 mg Neladenoson Bialanate 20 mg Neladenoson Bialanate 30 mg Neladenoson Bialanate 40 mg
    Number of subjects analysed
    56
    20
    39
    35
    32
    33
    Units: % of weekly average activity intensity
    arithmetic mean (standard deviation)
        Value at visit Baseline
    2.83 ± 1.03
    2.76 ± 0.72
    2.83 ± 0.95
    2.51 ± 0.91
    2.61 ± 0.94
    2.43 ± 0.57
        Change from baseline at Week 20
    -0.19 ± 0.58
    -0.25 ± 0.51
    -0.12 ± 0.58
    -0.08 ± 0.67
    -0.18 ± 0.57
    -0.14 ± 0.57
    No statistical analyses for this end point

    Secondary: Measured values (log transformed) and absolute change in NT-proBNP from baseline to 20 weeks

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    End point title
    		 Measured values (log transformed) and absolute change in NT-proBNP from baseline to 20 weeks
    End point description
    NT-proBNP = N-terminal pro-hormone b-type natriuretic peptide
    End point type
    Secondary
    End point timeframe
    Up to 20 weeks of treatment
    End point values
    		 Placebo Neladenoson Bialanate 5 mg Neladenoson Bialanate 10 mg Neladenoson Bialanate 20 mg Neladenoson Bialanate 30 mg Neladenoson Bialanate 40 mg
    Number of subjects analysed
    62
    21
    44
    39
    33
    36
    Units: log (pg/ml)
    median (full range (min-max))
        Value at baseline
    6.80 (4.0 to 8.0)
    6.78 (4.9 to 8.1)
    6.81 (4.8 to 8.2)
    6.73 (5.2 to 8.7)
    6.68 (4.5 to 8.0)
    6.64 (4.1 to 8.8)
        Absolute change from baseline to Week 20
    -0.07 (-1.3 to 1.6)
    0.08 (-3.0 to 0.9)
    0.13 (-1.7 to 1.6)
    0.06 (-1.2 to 2.3)
    0.09 (-1.3 to 0.9)
    0.19 (-1.0 to 2.9)
    No statistical analyses for this end point

    Secondary: Measured values (log-transformed) and absolute change in High sensitivity troponin T (hs-TNT) from baseline to 20 weeks

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    End point title
    		 Measured values (log-transformed) and absolute change in High sensitivity troponin T (hs-TNT) from baseline to 20 weeks
    End point description
    High sensitivity troponin T (hs-TNT) was measured
    End point type
    Secondary
    End point timeframe
    Up to 20 weeks of treatment
    End point values
    		 Placebo Neladenoson Bialanate 5 mg Neladenoson Bialanate 10 mg Neladenoson Bialanate 20 mg Neladenoson Bialanate 30 mg Neladenoson Bialanate 40 mg
    Number of subjects analysed
    63
    22
    44
    38
    33
    37
    Units: log(pg/mL)
    median (full range (min-max))
        Value at baseline
    2.92 (1.9 to 4.4)
    3.25 (1.9 to 4.7)
    2.95 (1.9 to 4.7)
    2.76 (1.9 to 4.2)
    2.73 (1.9 to 3.9)
    2.76 (1.9 to 4.8)
        Absolute change from baseline to Week 20
    0.00 (-1.4 to 1.6)
    0.02 (-0.9 to 0.9)
    0.00 (-0.7 to 1.1)
    0.12 (-0.8 to 1.5)
    0.13 (-0.4 to 1.2)
    0.01 (-0.8 to 0.9)
    No statistical analyses for this end point

    Secondary: Measured values and absolute change in 3 scores from Kansas City cardiomyopathy questionnaire (KCCQ) from baseline to 20 weeks: Overall Summary Score, Physical Limitation Score and Total Symptom Score

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    End point title
    		 Measured values and absolute change in 3 scores from Kansas City cardiomyopathy questionnaire (KCCQ) from baseline to 20 weeks: Overall Summary Score, Physical Limitation Score and Total Symptom Score
    End point description
    The KCCQ is the leading health-related quality-of-life measure for patients with chronic heart failure (CHF). It is a 23-item questionnaire that independently measures the impact of patient’s heart failure (HF), or its treatment, on 7 distinct domains: 1) Symptom Frequency 2) Symptom Burden 3) Physical Limitation 4) Quality of Life 5) Social Limitations 6) Self-efficacy 7) Symptoms Stability. Summary scores are a combination of these domains: Overall summary score: symptom frequency + symptom burden+ physical limitation + quality of life + social limitation Total symptom score: symptom frequency + symptom burden. Positive change means improvement and negative change means deterioration.
    End point type
    Secondary
    End point timeframe
    Up to 20 weeks of treatment
    End point values
    		 Placebo Neladenoson Bialanate 5 mg Neladenoson Bialanate 10 mg Neladenoson Bialanate 20 mg Neladenoson Bialanate 30 mg Neladenoson Bialanate 40 mg
    Number of subjects analysed
    65
    22
    44
    41
    34
    37
    Units: score
    arithmetic mean (standard deviation)
        Overall Summary Score Baseline
    69.19 ± 18.02
    64.75 ± 23.99
    66.42 ± 21.21
    64.57 ± 20.73
    63.67 ± 17.76
    64.65 ± 18.07
        Overall Summary Score Change from baseline
    3.38 ± 13.55
    7.04 ± 17.24
    -1.33 ± 20.61
    3.73 ± 13.03
    0.27 ± 14.83
    2.25 ± 14.25
        Physical Limitation Score Baseline
    69.07 ± 19.43
    63.18 ± 25.24
    68.03 ± 22.79
    69.35 ± 22.64
    64.53 ± 22.47
    63.12 ± 23.44
        Physical Limitation Score Change from baseline
    2.18 ± 17.54
    1.40 ± 17.62
    -1.34 ± 22.56
    0.92 ± 14.65
    -3.75 ± 22.10
    2.17 ± 17.32
        Total Symptom Score Baseline
    76.78 ± 19.64
    72.25 ± 21.73
    68.99 ± 23.13
    69.99 ± 20.18
    68.00 ± 20.09
    71.03 ± 18.80
        Total Symptom Score Change from baseline
    2.96 ± 15.85
    5.82 ± 17.51
    0.14 ± 19.08
    3.56 ± 14.04
    2.54 ± 16.79
    2.62 ± 16.04
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration up to 26 weeks
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to neladenoson bialanate tablets orally for 20 weeks.

    Reporting group title
    Neladenoson bialanate 5mg
    Reporting group description
    		 Subjects received 5 mg of neladenoson bialanate tablets orally for 20 weeks.

    Reporting group title
    Neladenoson bialanate 10mg
    Reporting group description
    		 Subjects received 10 mg of neladenoson bialanate tablets orally for 20 weeks.

    Reporting group title
    Neladenoson bialanate 20mg
    Reporting group description
    		 Subjects received 20 mg of neladenoson bialanate tablets orally for 20 weeks.

    Reporting group title
    Neladenoson bialanate 30mg
    Reporting group description
    		 Subjects received 30 mg of neladenoson bialanate tablets orally for 20 weeks.

    Reporting group title
    Neladenoson bialanate 40mg
    Reporting group description
    		 Subjects received 40 mg of neladenoson bialanate tablets orally for 20 weeks.

    Serious adverse events
    		 Placebo Neladenoson bialanate 5mg Neladenoson bialanate 10mg Neladenoson bialanate 20mg Neladenoson bialanate 30mg Neladenoson bialanate 40mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 76 (27.63%)
    9 / 27 (33.33%)
    11 / 50 (22.00%)
    11 / 51 (21.57%)
    14 / 50 (28.00%)
    16 / 51 (31.37%)
         number of deaths (all causes)
    2
    0
    2
    1
    1
    1
         number of deaths resulting from adverse events
    1
    0
    2
    1
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 27 (3.70%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 27 (3.70%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia repair
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Insertion of ambulatory peritoneal catheter
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 27 (3.70%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hysterosalpingectomy
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 27 (3.70%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Arteriogram coronary
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza A virus test positive
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 76 (2.63%)
    2 / 27 (7.41%)
    3 / 50 (6.00%)
    4 / 51 (7.84%)
    2 / 50 (4.00%)
    7 / 51 (13.73%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 3
    0 / 4
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 27 (3.70%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinoatrial block
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 27 (3.70%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    2 / 50 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal ganglia haemorrhage
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 27 (3.70%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    2 / 51 (3.92%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 27 (3.70%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 27 (3.70%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 27 (3.70%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Neladenoson bialanate 5mg Neladenoson bialanate 10mg Neladenoson bialanate 20mg Neladenoson bialanate 30mg Neladenoson bialanate 40mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 76 (31.58%)
    13 / 27 (48.15%)
    14 / 50 (28.00%)
    22 / 51 (43.14%)
    17 / 50 (34.00%)
    24 / 51 (47.06%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    4 / 51 (7.84%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    0
    4
    2
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 27 (3.70%)
    0 / 50 (0.00%)
    4 / 51 (7.84%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    0
    6
    1
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    5 / 76 (6.58%)
    0 / 27 (0.00%)
    3 / 50 (6.00%)
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    4 / 51 (7.84%)
         occurrences all number
    5
    0
    3
    1
    1
    6
    Cardiac failure
         subjects affected / exposed
    5 / 76 (6.58%)
    2 / 27 (7.41%)
    3 / 50 (6.00%)
    6 / 51 (11.76%)
    1 / 50 (2.00%)
    3 / 51 (5.88%)
         occurrences all number
    5
    3
    3
    9
    1
    3
    Ventricular tachycardia
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
    4 / 51 (7.84%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    5
    0
    1
    4
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 27 (3.70%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    3 / 50 (6.00%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    0
    0
    3
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    2 / 51 (3.92%)
    3 / 50 (6.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    2
    4
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 27 (0.00%)
    2 / 50 (4.00%)
    1 / 51 (1.96%)
    5 / 50 (10.00%)
    1 / 51 (1.96%)
         occurrences all number
    3
    0
    2
    1
    6
    1
    Diarrhoea
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    3 / 51 (5.88%)
    3 / 50 (6.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    0
    3
    3
    2
    Nausea
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
    3 / 50 (6.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    1
    1
    1
    3
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
    4 / 50 (8.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    1
    0
    4
    0
    Dyspnoea
         subjects affected / exposed
    3 / 76 (3.95%)
    2 / 27 (7.41%)
    2 / 50 (4.00%)
    5 / 51 (9.80%)
    3 / 50 (6.00%)
    3 / 51 (5.88%)
         occurrences all number
    3
    2
    2
    6
    3
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
    3 / 51 (5.88%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    2
    1
    1
    3
    0
    0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    5 / 51 (9.80%)
         occurrences all number
    1
    1
    1
    1
    2
    5
    Chronic kidney disease
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 27 (7.41%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    2
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 27 (3.70%)
    0 / 50 (0.00%)
    4 / 51 (7.84%)
    2 / 50 (4.00%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    0
    4
    3
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 76 (6.58%)
    1 / 27 (3.70%)
    3 / 50 (6.00%)
    3 / 51 (5.88%)
    2 / 50 (4.00%)
    4 / 51 (7.84%)
         occurrences all number
    6
    1
    3
    3
    3
    5
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    3 / 76 (3.95%)
    2 / 27 (7.41%)
    0 / 50 (0.00%)
    0 / 51 (0.00%)
    3 / 50 (6.00%)
    3 / 51 (5.88%)
         occurrences all number
    3
    2
    0
    0
    4
    4
    Hyperuricaemia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    1
    0
    1
    1
    0
    3
    Hypokalaemia
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 27 (0.00%)
    0 / 50 (0.00%)
    2 / 51 (3.92%)
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences all number
    5
    0
    0
    2
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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