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    Clinical Trial Results:
    A multicenter, randomized, double-blind, placebo-controlled phase III study to evaluate the efficacy, safety and tolerability of Serelaxin when added to standard therapy in acute heart failure patients

    Summary
    EudraCT number
    		 2013-001498-25
    Trial protocol
    		 SK   BE   SE   IE   BG   HU   PT   LT   IT   CZ   AT   EE   DK   ES   LV   NL   GR   GB   PL   NO  
    Global end of trial date
    01 Feb 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    28 Apr 2018
    First version publication date
    07 Feb 2018
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    The titles of end points 1, 2, 3 and 5 have been updated.

    Trial information

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    Trial identification
    Sponsor protocol code
    CRLX030A2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01870778
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    01 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were: • To demonstrate that serelaxin was superior to placebo in reducing cardiovascular (CV) death in acute heart failure (AHF) patients during a follow-up period of 180 days. • To demonstrate that serelaxin was superior to placebo in reducing worsening heart failure (WHF) through Day 5.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Oct 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
    Australia: 45
    Country: Number of subjects enrolled
    Argentina: 493
    Country: Number of subjects enrolled
    Austria: 72
    Country: Number of subjects enrolled
    Belgium: 53
    Country: Number of subjects enrolled
    Brazil: 87
    Country: Number of subjects enrolled
    Bulgaria: 472
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    Colombia: 9
    Country: Number of subjects enrolled
    Czech Republic: 413
    Country: Number of subjects enrolled
    Denmark: 18
    Country: Number of subjects enrolled
    France: 138
    Country: Number of subjects enrolled
    Germany: 641
    Country: Number of subjects enrolled
    United Kingdom: 138
    Country: Number of subjects enrolled
    Greece: 97
    Country: Number of subjects enrolled
    Hungary: 351
    Country: Number of subjects enrolled
    Ireland: 18
    Country: Number of subjects enrolled
    Israel: 256
    Country: Number of subjects enrolled
    Italy: 266
    Country: Number of subjects enrolled
    Mexico: 46
    Country: Number of subjects enrolled
    Netherlands: 150
    Country: Number of subjects enrolled
    Peru: 1
    Country: Number of subjects enrolled
    Poland: 450
    Country: Number of subjects enrolled
    Portugal: 59
    Country: Number of subjects enrolled
    Romania: 466
    Country: Number of subjects enrolled
    Russian Federation: 420
    Country: Number of subjects enrolled
    Slovakia: 258
    Country: Number of subjects enrolled
    South Africa: 30
    Country: Number of subjects enrolled
    Spain: 239
    Country: Number of subjects enrolled
    Sweden: 27
    Country: Number of subjects enrolled
    Switzerland: 42
    Country: Number of subjects enrolled
    Turkey: 88
    Country: Number of subjects enrolled
    United States: 687
    Worldwide total number of subjects
    6545
    EEA total number of subjects
    4326
    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)
    1411
    From 65 to 84 years
    4210
    85 years and over
    924

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were randomized in a 1:1 ratio to Serelaxin or matching placebo.

    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, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Serelaxin (RLX030)
    Arm description
    		 Participants received continuous intravenous infusion of serelaxin 30 ug/kg/day for 48 hours.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Serelaxin
    Investigational medicinal product code
    RLX030
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received continuous intravenous infusion of serelaxin 30 ug/kg/day for 48 hours.

    Arm title
    		 Placebo
    Arm description
    		 Participants received continuous intravenous infusion of matching placebo to serelaxin for 48 hours.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received continuous intravenous infusion of matching placebo to serelaxin for 48 hours.

    Number of subjects in period 1
    		Serelaxin (RLX030) Placebo
    Started
    3274
    3271
    Safety set
    3257 [1]
    3248 [2]
    Full analysis set
    3274
    3271
    Biomarker analysis set
    521 [3]
    510 [4]
    Completed
    3266
    3262
    Not completed
    8
    9
         Consent withdrawn by subject
    8
    7
         Lost to follow-up
    -
    2
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The numbers are correct.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The numbers are correct.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The numbers are correct.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The numbers are correct.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Serelaxin (RLX030)
    Reporting group description
    		 Participants received continuous intravenous infusion of serelaxin 30 ug/kg/day for 48 hours.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received continuous intravenous infusion of matching placebo to serelaxin for 48 hours.

    Reporting group values
    		 Serelaxin (RLX030) Placebo Total
    Number of subjects
    		 3274 3271 6545
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 686 725 1411
        From 65-84 years
    		 2106 2104 4210
        85 years and over
    		 482 442 924
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 73.1 ± 11.24 72.8 ± 11.17 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 1296 1341 2637
        Male
    		 1978 1930 3908

    End points

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    End points reporting groups
    Reporting group title
    Serelaxin (RLX030)
    Reporting group description
    		 Participants received continuous intravenous infusion of serelaxin 30 ug/kg/day for 48 hours.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received continuous intravenous infusion of matching placebo to serelaxin for 48 hours.

    Primary: Percentage of participants with confirmed cardiovascular (CV) death through day 180

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    End point title
    		 Percentage of participants with confirmed cardiovascular (CV) death through day 180
    End point description
    The percentage of participants with an adjudicated CV death through day 180 was assessed.
    End point type
    Primary
    End point timeframe
    180 days
    End point values
    		 Serelaxin (RLX030) Placebo
    Number of subjects analysed
    3274
    3271
    Units: Percentage of participants
        number (not applicable)
    8.7
    8.9
    Statistical analysis title
    		 Time to confirmed CV death
    Comparison groups
    Placebo v Serelaxin (RLX030)
    Number of subjects included in analysis
    6545
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3857 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.15
    Notes
    [1] - Adjusted alpha p-value based on multiple testing procedure.

    Primary: Percentage of participants with worsening of heart failure (WHF) through day 5

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    End point title
    		 Percentage of participants with worsening of heart failure (WHF) through day 5
    End point description
    The percentage of participants with WHF through day 5 was assessed.
    End point type
    Primary
    End point timeframe
    Day 5
    End point values
    		 Serelaxin (RLX030) Placebo
    Number of subjects analysed
    3274
    3271
    Units: Percentage of participants
        number (not applicable)
    6.9
    7.7
    Statistical analysis title
    		 Time to WHF
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    6545
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0968 [2]
    Method
    		 Gehan's generalized Wilcoxon test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.07
    Notes
    [2] - Adjusted p-value based on multiple testing procedure

    Secondary: Percentage of participants with all-cause death through day 180

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    End point title
    		 Percentage of participants with all-cause death through day 180
    End point description
    The percentage of participants with all-cause death through day 180 was assessed.
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Serelaxin (RLX030) Placebo
    Number of subjects analysed
    3274
    3271
    Units: Percentage of participants
        number (not applicable)
    11.2
    11.9
    Statistical analysis title
    		 Time to all cause death
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    6545
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.389
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.08

    Secondary: Length of total hospital stay (LOS) during the index acute heart failure (AHF) hospitalization

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    End point title
    		 Length of total hospital stay (LOS) during the index acute heart failure (AHF) hospitalization
    End point description
    Length of stay was defined as the index hospitalization discharge date and time minus the baseline date and time plus 1 day.
    End point type
    Secondary
    End point timeframe
    180 days (Participants still in the hospital at Day 60 were censored at Day 60)
    End point values
    		 Serelaxin (RLX030) Placebo
    Number of subjects analysed
    3274
    3271
    Units: days
        arithmetic mean (standard deviation)
    9.362 ± 9.3581
    9.545 ± 9.6739
    Statistical analysis title
    		 LOS during the index AHF hospitalization
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    6545
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2204 [3]
    Method
    		 Wilcoxon rank sum test
    Confidence interval
    Notes
    [3] - Based on multiple testing procedure

    Secondary: Percentage of participants with first occurrence of adjudicated CV death or adjudicated re-hospitalization

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    End point title
    		 Percentage of participants with first occurrence of adjudicated CV death or adjudicated re-hospitalization
    End point description
    The percentage of participants with adjudicated CV death or adjudicated re-hospitalization through day 180 was assessed.
    End point type
    Secondary
    End point timeframe
    180 days
    End point values
    		 Serelaxin (RLX030) Placebo
    Number of subjects analysed
    3274
    3271
    Units: Percentage of participants
        number (not applicable)
    24.3
    24.9
    Statistical analysis title
    		 Time to 1st occ. of adj. CV death or adj. re-hosp.
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    6545
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2744 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.07
    Notes
    [4] - Adjusted p-value based on multiple testing procedure

    Secondary: Length of Intensive Care Unit (ICU) and/or Coronary care unit (CCU) stay for the index AHF hospitalization

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    End point title
    		 Length of Intensive Care Unit (ICU) and/or Coronary care unit (CCU) stay for the index AHF hospitalization
    End point description
    Length of stay was defined as the hospitalization discharge date and the time minus the baseline date and time plus 1 day.
    End point type
    Secondary
    End point timeframe
    180 days (Patients still in the hospital at Day 60 were censored at Day 60)
    End point values
    		 Serelaxin (RLX030) Placebo
    Number of subjects analysed
    3274
    3271
    Units: days
        arithmetic mean (standard deviation)
    3.8 ± 8.29
    4.1 ± 8.77
    Statistical analysis title
    		 Length of ICU and/or CCU stay for index AHF hosp.
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    6545
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2103
    Method
    		 Wilcoxon rank sum test
    Confidence interval

    Secondary: Percentage of participants with first impovement since baseline in congestive signs and symptoms of heart failure

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    End point title
    		 Percentage of participants with first impovement since baseline in congestive signs and symptoms of heart failure
    End point description
    The percentage of participants with first improvement since baseline in congestive signs and symptoms of heart failure was assessed. The signs and symptoms included exertional dyspnea, orthopnea, rales, jugular venous pressure and peripheral edema/pre-sacral edema.
    End point type
    Secondary
    End point timeframe
    From baseline to Day 5
    End point values
    		 Serelaxin (RLX030) Placebo
    Number of subjects analysed
    3044
    3039
    Units: Percentage of participants
    number (not applicable)
        Exertinal dyspnea (n=3044,3039)
    94.1
    92.6
        Orthopnea (n=2937,2967)
    92.9
    91.2
        Rales (n=2888,2877)
    94.1
    93.7
        Jugular venous pressure (n=2054,2034)
    90.4
    88.0
        Peripheral/pre-sacral edema (n=2597,2622)
    91.6
    90.7
    Statistical analysis title
    		 First improvement in exertional dyspnea
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    6083
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 1.14
    Statistical analysis title
    		 First improvement in orthopnea
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    6083
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0051 [5]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 1.14
    Notes
    [5] - 2-sided p-value
    Statistical analysis title
    		 First improvement in rales
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    6083
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9962 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.05
    Notes
    [6] - 2-sided p-value
    Statistical analysis title
    		 First improvement in jugular venous pressure
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    6083
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0196 [7]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 1.15
    Notes
    [7] - 2-sided p-value
    Statistical analysis title
    		 First improvement in peripheral/pre-sacral edema
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    6083
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2158 [8]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 1.1
    Notes
    [8] - 2-sided p-value

    Secondary: Change from baseline in hsTroponin T biomarker

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    End point title
    		 Change from baseline in hsTroponin T biomarker
    End point description
    Blood samples were collected to assess the change from baseline in hsTroponin T. The geometric least square mean (LSM) of the ratio of the post-baseline value to the baseline value is presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2, Day 5 and Day 14
    End point values
    		 Serelaxin (RLX030) Placebo
    Number of subjects analysed
    521
    510
    Units: ug/L
    least squares mean (confidence interval 95%)
        Day 2 (n=464,459)
    0.9808 (0.9452 to 1.0177)
    1.0432 (1.0052 to 1.0827)
        Day 5 (n=458,449)
    0.9589 (0.9116 to 1.0087)
    1.0678 (1.0148 to 1.1237)
        Day 14 (n=436,418)
    0.7813 (0.7374 to 0.8278)
    0.8611 (0.8119 to 0.9132)
    Statistical analysis title
    		 Change from baseline in hsTroponin T biomarker
    Statistical analysis description
    Day 2
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    1031
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0209
    Method
    		 Repeated measure model
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8921
         upper limit
    		 0.9907
    Statistical analysis title
    		 Change from baseline in hsTroponin T biomarker
    Statistical analysis description
    Day 5
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    1031
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0034
    Method
    		 Repeated measures model
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8358
         upper limit
    		 0.9649
    Statistical analysis title
    		 Change from baseline in hsTroponin T biomarker
    Statistical analysis description
    Day 14
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    1031
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0209
    Method
    		 Repeated measures model
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8355
         upper limit
    		 0.9854

    Secondary: Change from baseline in NT-proBNP biomarker

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    End point title
    		 Change from baseline in NT-proBNP biomarker
    End point description
    Blood samples were collected to assess the change from baseline in NT-proBNP. The ratio of the post-baseline value to the baseline value is presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2, Day 5 and Day 14
    End point values
    		 Serelaxin (RLX030) Placebo
    Number of subjects analysed
    521
    510
    Units: pg/mL
    least squares mean (confidence interval 95%)
        Day 2 (n=472,465)
    0.4902 (0.4609 to 0.5214)
    0.5702 (0.5358 to 0.6068)
        Day 5 (n=465,455)
    0.4249 (0.3950 to 0.4570)
    0.4454 (0.4138 to 0.4794)
        Day 14 (n=446,429)
    0.4265 (0.3957 to 0.4596)
    0.4469 (0.4143 to 0.4822)
    Statistical analysis title
    		 Change from baseline in NT-proBNP biomarker
    Statistical analysis description
    Day 2
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    1031
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0007
    Method
    		 Repeated measures model
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7876
         upper limit
    		 0.9385
    Statistical analysis title
    		 Change from baseline in NT-proBNP biomarker
    Statistical analysis description
    Day 5
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    1031
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3709
    Method
    		 Repeated measures model
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.0579
    Statistical analysis title
    		 Change from baseline in NT-proBNP biomarker
    Statistical analysis description
    Day 14
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    1031
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3893
    Method
    		 Repeated measures model
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8578
         upper limit
    		 1.0617

    Secondary: Change from baseline in Cystatin C biomarker

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    End point title
    		 Change from baseline in Cystatin C biomarker
    End point description
    Blood samples were collected to assess the change from baseline in Cystatin C. The ratio of the post-baseline value to the baseline value is presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2, Day 5 and Day 14
    End point values
    		 Serelaxin (RLX030) Placebo
    Number of subjects analysed
    521
    510
    Units: mg/L
    least squares mean (confidence interval 95%)
        Day 2 (n=474,465)
    1.0261 (1.0119 to 1.0406)
    1.0648 (1.0499 to 1.0799)
        Day 5 (n=467,456)
    1.1171 (1.0976 to 1.1369)
    1.1259 (1.1061 to 1.1461)
        Day 14 (n=445,432)
    1.1186 (1.0949 to 1.1429)
    1.1342 (1.1098 to 1.1591)
    Statistical analysis title
    		 Change from baseline in Cystatin C biomarker
    Statistical analysis description
    Day 2
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    1031
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0003
    Method
    		 Repeated measures model
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9447
         upper limit
    		 0.983
    Statistical analysis title
    		 Change from baseline in Cystatin C biomarker
    Statistical analysis description
    Day 5
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    1031
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5361
    Method
    		 Repeated measures model
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9677
         upper limit
    		 1.0172
    Statistical analysis title
    		 Change from baseline in Cystatin C biomarker
    Statistical analysis description
    Day 14
    Comparison groups
    Serelaxin (RLX030) v Placebo
    Number of subjects included in analysis
    1031
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.375
    Method
    		 Repeated measures model
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9567
         upper limit
    		 1.0169

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    RLX030 30 ug/kg/day
    Reporting group description
    		 RLX030 30 ug/kg/day

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 RLX030 30 ug/kg/day Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    412 / 3257 (12.65%)
    424 / 3248 (13.05%)
         number of deaths (all causes)
    363
    386
         number of deaths resulting from adverse events
    6
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon neoplasm
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal adenocarcinoma
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 3257 (0.03%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Lung adenocarcinoma metastatic
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mesothelioma
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinum neoplasm
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to liver
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic gastric cancer
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ovarian neoplasm
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Waldenstrom's macroglobulinaemia
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm rupture
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Arterial stenosis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    0 / 3257 (0.00%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 3257 (0.03%)
    3 / 3248 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    3 / 3257 (0.09%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    14 / 3257 (0.43%)
    9 / 3248 (0.28%)
         occurrences causally related to treatment / all
    5 / 14
    3 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Iliac artery embolism
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subclavian steal syndrome
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cardioversion
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toe amputation
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery bypass
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cardiac death
         subjects affected / exposed
    0 / 3257 (0.00%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Asthenia
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extravasation
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug effect increased
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site phlebitis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    4 / 3257 (0.12%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 3257 (0.06%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular stent occlusion
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sudden cardiac death
         subjects affected / exposed
    3 / 3257 (0.09%)
    6 / 3248 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 3
    0 / 6
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Acquired phimosis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    5 / 3257 (0.15%)
    5 / 3248 (0.15%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    3 / 3257 (0.09%)
    3 / 3248 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Bronchitis chronic
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    5 / 3257 (0.15%)
    7 / 3248 (0.22%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchospasm
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 3257 (0.18%)
    5 / 3248 (0.15%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 3257 (0.03%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Interstitial lung disease
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 3257 (0.00%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    5 / 3257 (0.15%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary cavitation
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 3257 (0.15%)
    7 / 3248 (0.22%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 7
         deaths causally related to treatment / all
    1 / 5
    0 / 2
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pulmonary hypertension
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    3 / 3257 (0.09%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary mass
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory depression
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    7 / 3257 (0.21%)
    10 / 3248 (0.31%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 11
         deaths causally related to treatment / all
    0 / 3
    0 / 4
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    2 / 3257 (0.06%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    2 / 3257 (0.06%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium tremens
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device battery issue
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device leakage
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 3257 (0.06%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure decreased
         subjects affected / exposed
    0 / 3257 (0.00%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 3257 (0.03%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac output decreased
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    2 / 3257 (0.06%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    3 / 3257 (0.09%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular resistance pulmonary increased
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Aortic restenosis
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac valve replacement complication
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery restenosis
         subjects affected / exposed
    2 / 3257 (0.06%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural myocardial infarction
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    2 / 3257 (0.06%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    2 / 3257 (0.06%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 3257 (0.00%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rib fracture
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 3257 (0.00%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 3257 (0.03%)
    3 / 3248 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 3257 (0.03%)
    7 / 3248 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    14 / 3257 (0.43%)
    12 / 3248 (0.37%)
         occurrences causally related to treatment / all
    1 / 14
    1 / 12
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 3257 (0.03%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    2 / 3257 (0.06%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    4 / 3257 (0.12%)
    9 / 3248 (0.28%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 3257 (0.00%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    10 / 3257 (0.31%)
    13 / 3248 (0.40%)
         occurrences causally related to treatment / all
    0 / 10
    1 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Arteriosclerosis coronary artery
         subjects affected / exposed
    2 / 3257 (0.06%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 3257 (0.06%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    5 / 3257 (0.15%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular dissociation
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    4 / 3257 (0.12%)
    4 / 3248 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    4 / 3257 (0.12%)
    9 / 3248 (0.28%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 9
         deaths causally related to treatment / all
    0 / 4
    0 / 7
    Cardiac failure
         subjects affected / exposed
    62 / 3257 (1.90%)
    68 / 3248 (2.09%)
         occurrences causally related to treatment / all
    5 / 62
    2 / 69
         deaths causally related to treatment / all
    2 / 20
    0 / 22
    Cardiac failure acute
         subjects affected / exposed
    14 / 3257 (0.43%)
    8 / 3248 (0.25%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 9
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Cardiac failure chronic
         subjects affected / exposed
    2 / 3257 (0.06%)
    3 / 3248 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cardiac failure congestive
         subjects affected / exposed
    12 / 3257 (0.37%)
    9 / 3248 (0.28%)
         occurrences causally related to treatment / all
    1 / 12
    0 / 9
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 3257 (0.06%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Cardiogenic shock
         subjects affected / exposed
    5 / 3257 (0.15%)
    6 / 3248 (0.18%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 6
         deaths causally related to treatment / all
    1 / 3
    0 / 6
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiorenal syndrome
         subjects affected / exposed
    1 / 3257 (0.03%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chordae tendinae rupture
         subjects affected / exposed
    2 / 3257 (0.06%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 3257 (0.00%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    17 / 3257 (0.52%)
    12 / 3248 (0.37%)
         occurrences causally related to treatment / all
    0 / 18
    0 / 12
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery perforation
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    5 / 3257 (0.15%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Defect conduction intraventricular
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    2 / 3257 (0.06%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    5 / 3257 (0.15%)
    5 / 3248 (0.15%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 3257 (0.06%)
    3 / 3248 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve stenosis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 3257 (0.09%)
    4 / 3248 (0.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Sinus node dysfunction
         subjects affected / exposed
    1 / 3257 (0.03%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 3257 (0.03%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pericarditis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 3257 (0.03%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Torsade de pointes
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    4 / 3257 (0.12%)
    6 / 3248 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 5
    Ventricular tachycardia
         subjects affected / exposed
    14 / 3257 (0.43%)
    11 / 3248 (0.34%)
         occurrences causally related to treatment / all
    1 / 14
    2 / 12
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain stem stroke
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Carotid artery stenosis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid sinus syndrome
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral artery embolism
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 3257 (0.06%)
    3 / 3248 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cognitive disorder
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Epilepsy
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercapnic coma
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    11 / 3257 (0.34%)
    16 / 3248 (0.49%)
         occurrences causally related to treatment / all
    1 / 11
    0 / 16
         deaths causally related to treatment / all
    0 / 2
    0 / 6
    Muscle contractions involuntary
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 3257 (0.06%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 3257 (0.06%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    5 / 3257 (0.15%)
    3 / 3248 (0.09%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    6 / 3257 (0.18%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular encephalopathy
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 3257 (0.21%)
    7 / 3248 (0.22%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia macrocytic
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 3257 (0.06%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diarrhoea
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroduodenal ulcer
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 3257 (0.06%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematochezia
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 3257 (0.06%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal stenosis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Melaena
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subileus
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Alcoholic liver disease
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic congestion
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    2 / 3257 (0.06%)
    3 / 3248 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hepatic function abnormal
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    2 / 3257 (0.06%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panniculitis
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 3257 (0.00%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    20 / 3257 (0.61%)
    25 / 3248 (0.77%)
         occurrences causally related to treatment / all
    4 / 20
    3 / 28
         deaths causally related to treatment / all
    0 / 1
    1 / 5
    Anuria
         subjects affected / exposed
    2 / 3257 (0.06%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Azotaemia
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    4 / 3257 (0.12%)
    3 / 3248 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    0 / 3257 (0.00%)
    6 / 3248 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal artery stenosis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    13 / 3257 (0.40%)
    9 / 3248 (0.28%)
         occurrences causally related to treatment / all
    1 / 13
    1 / 9
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Renal failure
         subjects affected / exposed
    10 / 3257 (0.31%)
    16 / 3248 (0.49%)
         occurrences causally related to treatment / all
    1 / 10
    2 / 16
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal mass
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Facial asymmetry
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    2 / 3257 (0.06%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Arthritis bacterial
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergilloma
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    9 / 3257 (0.28%)
    4 / 3248 (0.12%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cholecystitis infective
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic hepatitis B
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis bacterial
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    3 / 3257 (0.09%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis bacterial
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 3257 (0.06%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 3257 (0.06%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nosocomial infection
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    34 / 3257 (1.04%)
    32 / 3248 (0.99%)
         occurrences causally related to treatment / all
    1 / 34
    0 / 32
         deaths causally related to treatment / all
    0 / 6
    0 / 4
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    6 / 3257 (0.18%)
    8 / 3248 (0.25%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    Septic shock
         subjects affected / exposed
    4 / 3257 (0.12%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Staphylococcal bacteraemia
         subjects affected / exposed
    2 / 3257 (0.06%)
    3 / 3248 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    13 / 3257 (0.40%)
    5 / 3248 (0.15%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 3257 (0.03%)
    3 / 3248 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 3257 (0.09%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    3 / 3257 (0.09%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 3257 (0.03%)
    2 / 3248 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 3257 (0.03%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 3257 (0.03%)
    0 / 3248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic alkalosis
         subjects affected / exposed
    0 / 3257 (0.00%)
    1 / 3248 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.5%
    Non-serious adverse events
    		 RLX030 30 ug/kg/day Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1336 / 3257 (41.02%)
    1277 / 3248 (39.32%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    23 / 3257 (0.71%)
    37 / 3248 (1.14%)
         occurrences all number
    24
    37
    Hypotension
         subjects affected / exposed
    69 / 3257 (2.12%)
    58 / 3248 (1.79%)
         occurrences all number
    69
    58
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    31 / 3257 (0.95%)
    41 / 3248 (1.26%)
         occurrences all number
    31
    41
    Non-cardiac chest pain
         subjects affected / exposed
    12 / 3257 (0.37%)
    20 / 3248 (0.62%)
         occurrences all number
    13
    20
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    6 / 3257 (0.18%)
    17 / 3248 (0.52%)
         occurrences all number
    8
    17
    Epistaxis
         subjects affected / exposed
    19 / 3257 (0.58%)
    14 / 3248 (0.43%)
         occurrences all number
    19
    14
    Dyspnoea
         subjects affected / exposed
    17 / 3257 (0.52%)
    15 / 3248 (0.46%)
         occurrences all number
    17
    15
    Cough
         subjects affected / exposed
    41 / 3257 (1.26%)
    36 / 3248 (1.11%)
         occurrences all number
    41
    36
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    16 / 3257 (0.49%)
    30 / 3248 (0.92%)
         occurrences all number
    17
    31
    Insomnia
         subjects affected / exposed
    42 / 3257 (1.29%)
    48 / 3248 (1.48%)
         occurrences all number
    42
    48
    Confusional state
         subjects affected / exposed
    25 / 3257 (0.77%)
    28 / 3248 (0.86%)
         occurrences all number
    25
    28
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    36 / 3257 (1.11%)
    49 / 3248 (1.51%)
         occurrences all number
    36
    49
    Blood potassium decreased
         subjects affected / exposed
    15 / 3257 (0.46%)
    20 / 3248 (0.62%)
         occurrences all number
    15
    21
    Blood pressure decreased
         subjects affected / exposed
    36 / 3257 (1.11%)
    23 / 3248 (0.71%)
         occurrences all number
    37
    23
    Blood urea increased
         subjects affected / exposed
    24 / 3257 (0.74%)
    25 / 3248 (0.77%)
         occurrences all number
    24
    25
    Blood pressure systolic decreased
         subjects affected / exposed
    29 / 3257 (0.89%)
    24 / 3248 (0.74%)
         occurrences all number
    29
    24
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    17 / 3257 (0.52%)
    15 / 3248 (0.46%)
         occurrences all number
    17
    15
    Aortic valve stenosis
         subjects affected / exposed
    23 / 3257 (0.71%)
    13 / 3248 (0.40%)
         occurrences all number
    23
    13
    Aortic valve incompetence
         subjects affected / exposed
    21 / 3257 (0.64%)
    25 / 3248 (0.77%)
         occurrences all number
    21
    25
    Cardiac failure
         subjects affected / exposed
    162 / 3257 (4.97%)
    185 / 3248 (5.70%)
         occurrences all number
    164
    191
    Bradycardia
         subjects affected / exposed
    23 / 3257 (0.71%)
    22 / 3248 (0.68%)
         occurrences all number
    23
    22
    Atrial fibrillation
         subjects affected / exposed
    46 / 3257 (1.41%)
    45 / 3248 (1.39%)
         occurrences all number
    47
    47
    Mitral valve incompetence
         subjects affected / exposed
    52 / 3257 (1.60%)
    47 / 3248 (1.45%)
         occurrences all number
    52
    47
    Ventricular tachycardia
         subjects affected / exposed
    37 / 3257 (1.14%)
    24 / 3248 (0.74%)
         occurrences all number
    38
    25
    Tricuspid valve incompetence
         subjects affected / exposed
    30 / 3257 (0.92%)
    21 / 3248 (0.65%)
         occurrences all number
    30
    21
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    27 / 3257 (0.83%)
    17 / 3248 (0.52%)
         occurrences all number
    27
    17
    Headache
         subjects affected / exposed
    74 / 3257 (2.27%)
    92 / 3248 (2.83%)
         occurrences all number
    76
    95
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    48 / 3257 (1.47%)
    47 / 3248 (1.45%)
         occurrences all number
    48
    47
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    18 / 3257 (0.55%)
    19 / 3248 (0.58%)
         occurrences all number
    18
    19
    Constipation
         subjects affected / exposed
    70 / 3257 (2.15%)
    57 / 3248 (1.75%)
         occurrences all number
    70
    57
    Diarrhoea
         subjects affected / exposed
    44 / 3257 (1.35%)
    52 / 3248 (1.60%)
         occurrences all number
    44
    52
    Nausea
         subjects affected / exposed
    59 / 3257 (1.81%)
    51 / 3248 (1.57%)
         occurrences all number
    59
    51
    Vomiting
         subjects affected / exposed
    30 / 3257 (0.92%)
    24 / 3248 (0.74%)
         occurrences all number
    31
    24
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    20 / 3257 (0.61%)
    20 / 3248 (0.62%)
         occurrences all number
    20
    20
    Renal failure
         subjects affected / exposed
    42 / 3257 (1.29%)
    46 / 3248 (1.42%)
         occurrences all number
    42
    46
    Acute kidney injury
         subjects affected / exposed
    35 / 3257 (1.07%)
    34 / 3248 (1.05%)
         occurrences all number
    35
    34
    Renal impairment
         subjects affected / exposed
    48 / 3257 (1.47%)
    55 / 3248 (1.69%)
         occurrences all number
    49
    55
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    22 / 3257 (0.68%)
    26 / 3248 (0.80%)
         occurrences all number
    22
    26
    Muscle spasms
         subjects affected / exposed
    79 / 3257 (2.43%)
    49 / 3248 (1.51%)
         occurrences all number
    82
    50
    Arthralgia
         subjects affected / exposed
    25 / 3257 (0.77%)
    21 / 3248 (0.65%)
         occurrences all number
    25
    22
    Pain in extremity
         subjects affected / exposed
    27 / 3257 (0.83%)
    32 / 3248 (0.99%)
         occurrences all number
    27
    33
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    17 / 3257 (0.52%)
    22 / 3248 (0.68%)
         occurrences all number
    17
    22
    Cystitis
         subjects affected / exposed
    18 / 3257 (0.55%)
    7 / 3248 (0.22%)
         occurrences all number
    18
    7
    Bronchitis
         subjects affected / exposed
    30 / 3257 (0.92%)
    47 / 3248 (1.45%)
         occurrences all number
    30
    47
    Urinary tract infection
         subjects affected / exposed
    58 / 3257 (1.78%)
    68 / 3248 (2.09%)
         occurrences all number
    58
    68
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    16 / 3257 (0.49%)
    28 / 3248 (0.86%)
         occurrences all number
    16
    28
    Hyperkalaemia
         subjects affected / exposed
    40 / 3257 (1.23%)
    36 / 3248 (1.11%)
         occurrences all number
    40
    36
    Hyperglycaemia
         subjects affected / exposed
    25 / 3257 (0.77%)
    17 / 3248 (0.52%)
         occurrences all number
    25
    17
    Hyperuricaemia
         subjects affected / exposed
    25 / 3257 (0.77%)
    21 / 3248 (0.65%)
         occurrences all number
    25
    21
    Hypoglycaemia
         subjects affected / exposed
    29 / 3257 (0.89%)
    22 / 3248 (0.68%)
         occurrences all number
    29
    24
    Hypokalaemia
         subjects affected / exposed
    263 / 3257 (8.07%)
    241 / 3248 (7.42%)
         occurrences all number
    268
    250
    Hyponatraemia
         subjects affected / exposed
    19 / 3257 (0.58%)
    13 / 3248 (0.40%)
         occurrences all number
    19
    13

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Aug 2013
    Amendment 1 introduced the following changes in order to comply with Health Authority requests stemming from the Volunteer Harmonization Procedure: • A criterion was added excluding patients with hematocrit < 25%, or a history of blood transfusion within the 14 days prior to Screening, or active life-threatening gastrointestinal bleeding. • ECG assessments were included at Screening and at Day 5 or Discharge, whichever occurred first. • An echocardiogram was included. The echocardiogram had to be performed during the index hospitalization, to determine a patient’s ejection fraction which was used to classify the type of HF for subgroup analysis. The echocardiogram was to be performed as soon as possible post randomization, and prior to Discharge. • The follow up period was changed from a minimum of 14 days to 180 days for the case the study was concluded early for efficacy following the interim analysis. • A minor clarification was made to the timing of the ECG sub-study: the first sub-study ECG was to be performed at Baseline, not at Screening. • A minor clarification was made to the Laboratory sub-study urine assessment: the data was to be maintained in the source documents only and not in the database.
    23 Sep 2013
    Amendment 2 introduced the following changes: • In the original protocol, all-cause death through Day 180 was not included in the multiple testing procedure of the key secondary efficacy variables, i.e., only the other 3 key secondary efficacy variables were included. As per feedback from FDA, all 4 key secondary efficacy variables were included in the multiple testing procedure, so the overall type I error including all-cause death and other 3 key efficacy variables was controlled at 5% alpha level. • In addition, a minor change was made to the Physician assessment of signs and symptoms criteria. NA, not evaluable, was removed from the assessments for exertional dyspnea and orthopnea. This was done to avoid confusion during data collection between when the evaluation was not evaluable (patient was immobile) and when the evaluation was simply not done.
    06 Jan 2014
    Amendment 3 introduced the following changes: • Exclusion criterion #8 was amended criteria to exclude current treatment within 2 hours prior to randomization (and not at Screening) in order to improve patient recruitment. • Additional information about 5% dextrose infusion bags and materials which can be used during preparation of study treatment was included. • Filter name was updated based on the availability of a new brand name. • The timing of the physical examination was clarified due to inconsistency with the assessment schedule. • The summary of Amendment 2 was updated to remove the requirement for IRB/EC protocol approval prior to implementation since this was not valid in select countries. • Schedule of assessments table was updated to clarify the intervals for collection of WHF assessment (at hours 24, 48, 72, 96 and 120) as part of the physician assessment of HF signs and symptoms. • The safety set definition was updated to clarify a statement that any patient who has received serelaxin was included as part of the serelaxin treatment group. • Time-to-event was changed to be defined as randomization to the event. • Length of stay definition was changed to index hospitalization discharge date and time minus the randomization date and time.
    09 Sep 2014
    Amendment 4 introduced the changes to improve the overall clarity of the study inclusion and exclusion criteria: Some of the changes included: Inclusion criteria: • The criteria for hospitalization due to AHF were enhanced to read: hospitalized for AHF with the anticipated requirement of i.v. therapy (including i.v. diuretics) for at least 48 hours. • The dyspnea at rest criteria was enhanced to read: persistent dyspnea at rest or with minimal exertion at screening and at the time of randomization, despite standard background therapy for AHF including the protocol required i.v. furosemide of at least 40 mg total (or equivalent). • The BNP and NT proBNP criteria were increased to BNP ≥ 500 pg/mL or NT-proBNP ≥ 2,000 pg/mL. The following BNP and NT proBNP criteria were also added: for patients ≥ 75 years of age or with current atrial fibrillation (at the time of randomization), BNP ≥ 750 pg/mL or NT-proBNP ≥ 3,000 pg/mL. • The inclusion criteria for i.v. furosemide were updated to add the following criteria: Time from presentation to start of furosemide administration was to be less than 6 hours.
    18 Feb 2015
    Amendment 5 introduced the following changes: • The reduction of WHF events through Day 5 was added as an additional primary endpoint. • The target number of CV deaths and the sample size was increased to adjust for the alpha-split required to accommodate the additional primary objective. • Minor changes to provide some clarity and flexibility around the conduct and timing of the study visits and visit procedures.

    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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