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    Clinical Trial Results:
    A Multicenter, International, Phase 3, Double-Blind, Placebo-Controlled, Randomized Study to Evaluate the Efficacy, Safety, and Tolerability of Daily Oral Dosing of Tafamidis Meglumine (PF-06291826) 20 mg or 80 mg in Comparison to Placebo in Subjects Diagnosed With Transthyretin Cardiomyopathy (TTR-CM)

    Summary
    EudraCT number
    2012-002465-35
    Trial protocol
    GB   IT   ES   DE   SE   CZ   NL   BE  
    Global end of trial date
    07 Feb 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    01 May 2019
    First version publication date
    16 Feb 2019
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    B3461028
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01994889
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    ATTR-ACT: Other Identifier: Alias Study Number
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of an oral dose of 20 milligrams (mg) or 80 mg tafamidis meglumine soft-gel capsules based on all-cause mortality and on frequency of cardiovascular-related hospitalizations as well as to assess safety and tolerability in comparison to placebo.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Dec 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
    Belgium: 2
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    France: 28
    Country: Number of subjects enrolled
    Germany: 49
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Japan: 17
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 279
    Worldwide total number of subjects
    441
    EEA total number of subjects
    142
    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)
    42
    From 65 to 84 years
    377
    85 years and over
    22

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Pooled analysis of the tafamidis treatment groups 20 mg and 80 mg was performed in comparison to placebo group.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Tafamidis 20 mg
    Arm description
    Subjects with variant transthyretin cardiomyopathy (TTR-CM) genotype or wild-type TTRCM genotype received one tafamidis 20 milligram (mg) capsule + 3 placebo capsules (matched to tafamidis) orally once daily for 30 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Tafamidis meglumine
    Investigational medicinal product code
    PF-06291826
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    One tafamidis 20 mg capsule + 3 placebo capsules (matched to tafamidis), orally once daily for 30 months.

    Arm title
    Tafamidis 80 mg
    Arm description
    Subjects with variant TTR-CM genotype or wild-type TTR-CM genotype received tafamidis 80 mg (4 capsules of 20 mg each) orally once daily for 30 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Tafamidis meglumine
    Investigational medicinal product code
    PF-06291826
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Tafamidis 80 mg (4 capsules of 20 mg each), orally once daily for 30 months.

    Arm title
    Placebo
    Arm description
    Subjects with variant TTR-CM genotype or wild-type TTR-CM genotype received 4 placebo capsules matched to tafamidis orally once daily for 30 months.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Four placebo capsules (matched to tafamidis), orally once daily for 30 months.

    Number of subjects in period 1
    Tafamidis 20 mg Tafamidis 80 mg Placebo
    Started
    88
    176
    177
    Completed
    60
    113
    85
    Not completed
    28
    63
    92
         Protocol deviation
    -
    1
    1
         Death
    14
    25
    38
         Organ Transplantation
    1
    5
    5
         Cardiac Device Implantation
    -
    2
    -
         Adverse event, serious fatal
    5
    8
    7
         Adverse event, serious non fatal
    -
    3
    3
         Adverse event, non-fatal
    -
    1
    1
         No longer willing to participate
    8
    17
    37
         Lost to follow-up
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tafamidis 20 mg
    Reporting group description
    Subjects with variant transthyretin cardiomyopathy (TTR-CM) genotype or wild-type TTRCM genotype received one tafamidis 20 milligram (mg) capsule + 3 placebo capsules (matched to tafamidis) orally once daily for 30 months.

    Reporting group title
    Tafamidis 80 mg
    Reporting group description
    Subjects with variant TTR-CM genotype or wild-type TTR-CM genotype received tafamidis 80 mg (4 capsules of 20 mg each) orally once daily for 30 months.

    Reporting group title
    Placebo
    Reporting group description
    Subjects with variant TTR-CM genotype or wild-type TTR-CM genotype received 4 placebo capsules matched to tafamidis orally once daily for 30 months.

    Reporting group values
    Tafamidis 20 mg Tafamidis 80 mg Placebo Total
    Number of subjects
    88 176 177 441
    Age categorical
    The intent-to-treat (ITT) analysis set included all subjects in the safety population (all randomized subjects who received at least 1 dose of double-blind medication) who had at least 1 post baseline efficacy evaluation ( post baseline hospitalization, study visit, or date of death).
    Units: Subjects
        Adults (18-64 years)
    11 16 15 42
        From 65-84 years
    74 148 155 377
        85 years and over
    3 12 7 22
    Age Continuous
    The ITT analysis set included all subjects in the safety population (all randomized subjects who received at least 1 dose of double-blind medication) who had at least 1 post baseline efficacy evaluation ( post baseline hospitalization, study visit, or date of death).
    Units: years
        arithmetic mean (standard deviation)
    73.3 ± 7.07 75.2 ± 7.24 74.1 ± 6.69 -
    Sex: Female, Male
    The ITT analysis set included all subjects in the safety population (all randomized subjects who received at least 1 dose of double-blind medication) who had at least 1 post baseline efficacy evaluation ( post baseline hospitalization, study visit, or date of death).
    Units: Subjects
        Female
    5 18 20 43
        Male
    83 158 157 398
    Race (NIH/OMB)
    The ITT analysis set included all subjects in the safety population (all randomized subjects who received at least 1 dose of double-blind medication) who had at least 1 post baseline efficacy evaluation ( post baseline hospitalization, study visit, or date of death).
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    2 11 5 18
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    11 26 26 63
        White
    75 136 146 357
        More than one race
    0 0 0 0
        Unknown or Not Reported
    0 3 0 3
    Ethnicity (NIH/OMB)
    The ITT analysis set included all subjects in the safety population (all randomized subjects who received at least 1 dose of double-blind medication) who had at least 1 post baseline efficacy evaluation ( post baseline hospitalization, study visit, or date of death).
    Units: Subjects
        Hispanic or Latino
    3 4 7 14
        Not Hispanic or Latino
    84 171 170 425
        Unknown or Not Reported
    1 1 0 2

    End points

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    End points reporting groups
    Reporting group title
    Tafamidis 20 mg
    Reporting group description
    Subjects with variant transthyretin cardiomyopathy (TTR-CM) genotype or wild-type TTRCM genotype received one tafamidis 20 milligram (mg) capsule + 3 placebo capsules (matched to tafamidis) orally once daily for 30 months.

    Reporting group title
    Tafamidis 80 mg
    Reporting group description
    Subjects with variant TTR-CM genotype or wild-type TTR-CM genotype received tafamidis 80 mg (4 capsules of 20 mg each) orally once daily for 30 months.

    Reporting group title
    Placebo
    Reporting group description
    Subjects with variant TTR-CM genotype or wild-type TTR-CM genotype received 4 placebo capsules matched to tafamidis orally once daily for 30 months.

    Subject analysis set title
    Tafamidis
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects with variant TTR-CM genotype or wild-type TTR-CM genotype received one tafamidis 20 mg + 3 placebo capsules (matched to tafamidis) or 80 mg (4 capsules of 20 mg each) capsule orally once daily for 30 months.

    Primary: Hierarchical Combination of All-Cause Mortality and Frequency of Cardiovascular (CV)-Related Hospitalizations

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    End point title
    Hierarchical Combination of All-Cause Mortality and Frequency of Cardiovascular (CV)-Related Hospitalizations [1]
    End point description
    All-cause mortality and frequency of CV hospitalization were analyzed using Finkelstein-Schoenfeld method, which combines in a hierarchical fashion using all-cause mortality first. The method compares every subject with every other subject within strata, assigning a +1 to the “better” subject and a -1 to the “worse” subject and 0 if they are “tied”. Subjects who discontinued for transplantation (heart transplantation and combined heart and liver transplantation) or for implantation of a cardiac mechanical assist device, were handled in the same manner as death. 'Win' represents a subject doing better based on hierarchical comparison. The reported unit is the total ‘wins’ for each treatment group from performing such a hierarchical comparison across all 4 strata in the study. Analysis done on ITT analysis set. Pre-specified intent of study was to compare results between tafamidis with placebo,irrespective of tafamidis doses. Analysis based on pooled dose groups,as per study protocol.
    End point type
    Primary
    End point timeframe
    Baseline up to Month 30
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All patients receiving active medication (Tafamidis 20mg and Tafamidis 80 mg) are included in the pooled analysis
    End point values
    Placebo Tafamidis
    Number of subjects analysed
    177
    264
    Units: wins
        number (not applicable)
    5071
    8595
    Statistical analysis title
    Tafamidis Vs. Placebo
    Comparison groups
    Placebo v Tafamidis
    Number of subjects included in analysis
    441
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006
    Method
    Finkelstein-Schoenfeld Method
    Confidence interval

    Secondary: All-Cause Mortality

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    End point title
    All-Cause Mortality [2]
    End point description
    Number of deaths during the study due to any cause was analyzed. Subjects who discontinued for transplantation (heart transplantation and combined heart and liver transplantation) or for implantation of a cardiac mechanical assist device were handled in the same manner as death. The ITT analysis set included all subjects in the safety population (all randomized subjects who received at least 1 dose of double-blind medication) who had at least 1 post baseline efficacy evaluation (post baseline hospitalization, study visit, or date of death). The pre-specified intent of this study was to compare the results between tafamidis with placebo, irrespective of the tafamidis doses. Therefore, this analysis was based on the pooled dose groups, as per the study protocol.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 30
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All patients receiving active medication (Tafamidis 20mg and Tafamidis 80 mg) are included in the pooled analysis
    End point values
    Placebo Tafamidis
    Number of subjects analysed
    177
    264
    Units: subjects
        Deaths (all causes)
    72
    69
        Heart transplants
    4
    7
        Cardiac Mechanical Assist Devices
    0
    2
    Statistical analysis title
    Tafamidis Vs. Placebo
    Statistical analysis description
    Hazard ratio from a Cox proportional hazards model with treatment, TTR genotype (variant and wild-type) and New York Heart Association (NYHA) baseline classification (NYHA Classes I and II combined and NYHA Class III) in the model.
    Comparison groups
    Placebo v Tafamidis
    Number of subjects included in analysis
    441
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0259
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.698
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.508
         upper limit
    0.958

    Secondary: Frequency of Cardiovascular-Related Hospitalizations

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    End point title
    Frequency of Cardiovascular-Related Hospitalizations [3]
    End point description
    CV related hospitalizations per year is calculated as subject’s number of CV related hospitalizations upon duration on study in years. The ITT analysis set included all subjects in the safety population (all randomized subjects who received at least 1 dose of double-blind medication) who had at least 1 post baseline efficacy evaluation (post baseline hospitalization, study visit, or date of death). The pre-specified intent of this study was to compare the results between tafamidis with placebo, irrespective of the tafamidis doses. Therefore, this analysis was based on the pooled dose groups, as per the study protocol.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 30
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All patients receiving active medication (Tafamidis 20mg and Tafamidis 80 mg) are included in the pooled analysis
    End point values
    Placebo Tafamidis
    Number of subjects analysed
    177
    264
    Units: CV hospitalization per year
        arithmetic mean (standard deviation)
    0.884 ± 1.2032
    0.999 ± 2.2777
    Statistical analysis title
    Tafamidis Vs. Placebo
    Comparison groups
    Placebo v Tafamidis
    Number of subjects included in analysis
    441
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    Poisson regression analysis
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.6761
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5639
         upper limit
    0.8107
    Notes
    [4] - Poisson regression analysis with treatment, TTR Genotype, NYHA Baseline classification, treatment-by-TTR genotype interaction, and treatment-by-NYHA Baseline classification interaction terms as factors adjusted for treatment duration.

    Secondary: Change From Baseline in the Total Distance Walked During 6 Minute Walk Test (6MWT) at Month 30

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    End point title
    Change From Baseline in the Total Distance Walked During 6 Minute Walk Test (6MWT) at Month 30 [5]
    End point description
    6MWT is the total distance that a subject could walk in 6 minutes. Subjects were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. The ITT analysis set included all subjects in the safety population (all randomized subjects who received at least 1 dose of double-blind medication) who had at least 1 post baseline efficacy evaluation (post baseline hospitalization, study visit, or date of death). The pre-specified intent of this study was to compare the results between tafamidis with placebo, irrespective of the tafamidis doses. Therefore, this analysis was based on the pooled dose groups, as per the study protocol. Here, ‘n’ = Subjects evaluable for this end point at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 30
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All patients receiving active medication (Tafamidis 20mg and Tafamidis 80 mg) are included in the pooled analysis
    End point values
    Placebo Tafamidis
    Number of subjects analysed
    177
    264
    Units: meters
    arithmetic mean (standard deviation)
        Baseline (n=177, 264)
    353.26 ± 125.983
    350.55 ± 121.296
        Change at Month 30 (n=70, 155)
    -89.67 ± 105.159
    -30.46 ± 87.886
    Statistical analysis title
    Tafamidis Vs. Placebo
    Statistical analysis description
    L.S. means are from an ANCOVA (MMRM) model with an unstructured covariance matrix; center and subject within center as random effects; treatment, visit, TTR genotype (variant and wild-type), and visit by treatment interaction, as fixed effects and baseline score as covariate.
    Comparison groups
    Placebo v Tafamidis
    Number of subjects included in analysis
    441
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed Model Repeated Measures ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    75.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    57.56
         upper limit
    93.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.236

    Secondary: Change from Baseline in Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) at Month 30

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    End point title
    Change from Baseline in Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) at Month 30 [6]
    End point description
    KCCQ: 23-item subject-completed questionnaire that assesses health status and health-related quality of life in subjects with heart failure. Eight domain scores were calculated: Physical limitation, Social limitation, Quality of life, Self-efficacy, Symptom stability, Symptom frequency, Symptom burden, and Total symptoms (calculated as the mean of Symptom frequency and Symptom burden scores). Two summary scores were calculated: Clinical Summary (calculated as mean of Physical limitation and Total symptom scores) and Overall Summary (calculated as mean of Physical limitation, Social limitation, Total symptoms, and Quality of life scores). Domain and summary scores ranged from 0 (minimum) to 100 (maximum); higher scores represent better health status. Analysis done on ITT analysis set. Pre-specified intent of study was to compare results between tafamidis with placebo,irrespective of tafamidis doses. Here, ‘n’ = Subjects evaluable for this end point at specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 30
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All patients receiving active medication (Tafamidis 20mg and Tafamidis 80 mg) are included in the pooled analysis
    End point values
    Placebo Tafamidis
    Number of subjects analysed
    177
    264
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=177, 264)
    65.898 ± 21.7357
    67.274 ± 21.3561
        Change at Month 30 (n=84,170)
    -14.637 ± 21.4078
    -3.855 ± 19.3075
    Statistical analysis title
    Tafamidis Vs. Placebo
    Statistical analysis description
    Change at Month 30: Overall Summary
    Comparison groups
    Placebo v Tafamidis
    Number of subjects included in analysis
    441
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed Model Repeated Measures ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    13.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.48
         upper limit
    17.83
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.13

    Secondary: Number of Subjects With Cardiovascular-Related Mortality

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    End point title
    Number of Subjects With Cardiovascular-Related Mortality [7]
    End point description
    Deaths adjudicated as CV-related and indeterminate are reported. Subjects who discontinued for transplantation (heart transplantation and combined heart and liver transplantation) or for implantation of a cardiac mechanical assist device, were handled in the same manner as death. The ITT analysis set included all subjects in the safety population (all randomized subjects who received at least 1 dose of double-blind medication) who had at least 1 post baseline efficacy evaluation (post baseline hospitalization, study visit, or date of death). The pre-specified intent of this study was to compare the results between tafamidis with placebo, irrespective of the tafamidis doses. Therefore, this analysis was based on the pooled dose groups, as per the study protocol.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 30
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All patients receiving active medication (Tafamidis 20mg and Tafamidis 80 mg) are included in the pooled analysis
    End point values
    Placebo Tafamidis
    Number of subjects analysed
    177
    264
    Units: subjects
    63
    64
    Statistical analysis title
    Tafamidis Vs.Placebo
    Statistical analysis description
    Hazard ratio from a Cox proportional hazards model with treatment, TTR genotype (variant and wild-type) and NYHA baseline classification (NYHA Classes I and II combined and NYHA Class III) in the model.
    Comparison groups
    Placebo v Tafamidis
    Number of subjects included in analysis
    441
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0383
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.691
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.488
         upper limit
    0.98

    Secondary: Percentage of Subjects With Stabilized Transthyretin (TTR) at Month 1

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    End point title
    Percentage of Subjects With Stabilized Transthyretin (TTR) at Month 1 [8]
    End point description
    TTR stabilization is a measure of the degree of stabilization afforded the TTR molecule by tafamidis. The ITT analysis set included all subjects in the safety population (all randomized subjects who received at least 1 dose of double-blind medication) who had at least 1 post baseline efficacy evaluation (post baseline hospitalization, study visit, or date of death). The pre-specified intent of this study was to compare the results between tafamidis with placebo, irrespective of the tafamidis doses. Therefore, this analysis was based on the pooled dose groups, as per the study protocol. Here, ‘Number analyzed’ = Subjects evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Month 1
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All patients receiving active medication (Tafamidis 20mg and Tafamidis 80 mg) are included in the pooled analysis
    End point values
    Placebo Tafamidis
    Number of subjects analysed
    170
    245
    Units: percentage of subjects
        number (not applicable)
    3.5
    86.1
    Statistical analysis title
    Tafamidis Vs.Placebo
    Comparison groups
    Placebo v Tafamidis
    Number of subjects included in analysis
    415
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 28 days after last dose of study drug (Month 31)
    Adverse event reporting additional description
    Same event may appear as both an adverse event (AE) and serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another, or a subject may have experienced both a serious and non-serious event. Analysis performed on safety population.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Tafamidis 20 mg
    Reporting group description
    Participants with variant transthyretin cardiomyopathy (TTR-CM) genotype or wild-type TTRCM genotype received one tafamidis 20 milligram (mg) capsule orally once daily for 30 months.

    Reporting group title
    Tafamidis 80 mg
    Reporting group description
    Participants with variant TTR-CM genotype or wild-type TTR-CM genotype received tafamidis 80 mg (4 capsules of 20 mg each) orally once daily for 30 months.

    Reporting group title
    Placebo
    Reporting group description
    Participants with variant TTR-CM genotype or wild-type TTR-CM genotype received 4 placebo capsules matched to tafamidis orally once daily for 30 months.

    Serious adverse events
    Tafamidis 20 mg Tafamidis 80 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    66 / 88 (75.00%)
    133 / 176 (75.57%)
    140 / 177 (79.10%)
         number of deaths (all causes)
    23
    49
    72
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gallbladder adenocarcinoma
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraductal papilloma of breast
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Oesophageal adenocarcinoma
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal adenoma
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Testicular neoplasm
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma metastatic
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Amyloidosis
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 88 (2.27%)
    4 / 176 (2.27%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 88 (1.14%)
    4 / 176 (2.27%)
    3 / 177 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 11
    0 / 9
    General physical health deterioration
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Medical device site haematoma
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 88 (0.00%)
    4 / 176 (2.27%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sudden death
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    9 / 88 (10.23%)
    24 / 176 (13.64%)
    34 / 177 (19.21%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 24
    0 / 34
         deaths causally related to treatment / all
    0 / 9
    0 / 24
    0 / 34
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Confusional state
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    4 / 177 (2.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Stress
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spermatocele
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    5 / 88 (5.68%)
    9 / 176 (5.11%)
    5 / 177 (2.82%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 11
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Femoral neck fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 176 (1.70%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    2 / 88 (2.27%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    2 / 88 (2.27%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle strain
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal foreign body
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 176 (1.70%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Skin abrasion
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 176 (1.70%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasoplegia syndrome
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Anticoagulation drug level above therapeutic
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anticoagulation drug level below therapeutic
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood potassium decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood sodium decreased
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcus test positive
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    3 / 177 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    2 / 88 (2.27%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    7 / 88 (7.95%)
    11 / 176 (6.25%)
    8 / 177 (4.52%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 12
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 88 (2.27%)
    4 / 176 (2.27%)
    5 / 177 (2.82%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 88 (1.14%)
    4 / 176 (2.27%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 88 (1.14%)
    5 / 176 (2.84%)
    5 / 177 (2.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac amyloidosis
         subjects affected / exposed
    2 / 88 (2.27%)
    3 / 176 (1.70%)
    5 / 177 (2.82%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    0 / 3
    Cardiac arrest
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 176 (1.14%)
    6 / 177 (3.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 6
    Cardiac failure
         subjects affected / exposed
    16 / 88 (18.18%)
    34 / 176 (19.32%)
    39 / 177 (22.03%)
         occurrences causally related to treatment / all
    0 / 25
    0 / 50
    0 / 61
         deaths causally related to treatment / all
    0 / 4
    0 / 6
    0 / 6
    Cardiac failure acute
         subjects affected / exposed
    4 / 88 (4.55%)
    23 / 176 (13.07%)
    17 / 177 (9.60%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 30
    0 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Cardiac failure chronic
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 176 (1.14%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    15 / 88 (17.05%)
    20 / 176 (11.36%)
    32 / 177 (18.08%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 31
    0 / 46
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    0 / 3
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    3 / 88 (3.41%)
    2 / 176 (1.14%)
    4 / 177 (2.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiomyopathy
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiorenal syndrome
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic left ventricular failure
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Conduction disorder
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 88 (1.14%)
    3 / 176 (1.70%)
    6 / 177 (3.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial depression
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nodal rhythm
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systolic dysfunction
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    3 / 177 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Ventricular tachycardia
         subjects affected / exposed
    2 / 88 (2.27%)
    2 / 176 (1.14%)
    7 / 177 (3.95%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Familial amyloidosis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    4 / 177 (2.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Asthma
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Choking
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 88 (2.27%)
    3 / 176 (1.70%)
    4 / 177 (2.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    5 / 88 (5.68%)
    6 / 176 (3.41%)
    4 / 177 (2.26%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 176 (1.70%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary toxicity
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Microcytic anaemia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophilia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 176 (1.14%)
    4 / 177 (2.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 88 (2.27%)
    0 / 176 (0.00%)
    5 / 177 (2.82%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolic cerebral infarction
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 88 (0.00%)
    6 / 176 (3.41%)
    10 / 177 (5.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    3 / 88 (3.41%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uraemic encephalopathy
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 88 (3.41%)
    1 / 176 (0.57%)
    3 / 177 (1.69%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    3 / 88 (3.41%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroduodenal ulcer
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 176 (1.14%)
    3 / 177 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tongue disorder
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    9 / 88 (10.23%)
    13 / 176 (7.39%)
    15 / 177 (8.47%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 14
    0 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Azotaemia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 176 (1.14%)
    4 / 177 (2.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 176 (1.14%)
    3 / 177 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cardiac cirrhosis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic hepatitis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathic ulcer
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Urticaria
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device connection issue
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    4 / 177 (2.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    6 / 177 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    2 / 88 (2.27%)
    2 / 176 (1.14%)
    6 / 177 (3.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Fluid retention
         subjects affected / exposed
    2 / 88 (2.27%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 176 (1.70%)
    4 / 177 (2.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 176 (1.14%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 88 (0.00%)
    4 / 176 (2.27%)
    4 / 177 (2.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 88 (2.27%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 88 (3.41%)
    2 / 176 (1.14%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Influenza
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Necrotising soft tissue infection
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 88 (6.82%)
    13 / 176 (7.39%)
    12 / 177 (6.78%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 14
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Pneumonia legionella
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 88 (3.41%)
    1 / 176 (0.57%)
    2 / 177 (1.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    Septic arthritis staphylococcal
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Serratia infection
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 88 (2.27%)
    1 / 176 (0.57%)
    5 / 177 (2.82%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Tafamidis 20 mg Tafamidis 80 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    86 / 88 (97.73%)
    170 / 176 (96.59%)
    171 / 177 (96.61%)
    Injury, poisoning and procedural complications
    Abdominal injury
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Animal bite
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Arthropod bite
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Arthropod sting
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Back injury
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Bone fissure
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Bursa injury
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    2
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    1
    0
    1
    Chest injury
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Compression fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Contusion
         subjects affected / exposed
    6 / 88 (6.82%)
    11 / 176 (6.25%)
    5 / 177 (2.82%)
         occurrences all number
    6
    14
    6
    Craniocerebral injury
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    1
    0
    2
    Electric shock
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Excoriation
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Eye contusion
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Face injury
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Facial bones fracture
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    1
    1
    0
    Fall
         subjects affected / exposed
    24 / 88 (27.27%)
    38 / 176 (21.59%)
    40 / 177 (22.60%)
         occurrences all number
    36
    50
    69
    Femoral neck fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Femur fracture
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    0
    Foot fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Hand fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    2 / 177 (1.13%)
         occurrences all number
    0
    1
    2
    Head injury
         subjects affected / exposed
    1 / 88 (1.14%)
    5 / 176 (2.84%)
    2 / 177 (1.13%)
         occurrences all number
    1
    5
    2
    Hip fracture
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    1
    0
    1
    Incision site erythema
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Incision site pain
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    2
    1
    Injury
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    1
    1
    0
    Joint injury
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 176 (1.70%)
    1 / 177 (0.56%)
         occurrences all number
    0
    3
    1
    Laceration
         subjects affected / exposed
    3 / 88 (3.41%)
    6 / 176 (3.41%)
    3 / 177 (1.69%)
         occurrences all number
    3
    6
    3
    Ligament injury
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Ligament sprain
         subjects affected / exposed
    2 / 88 (2.27%)
    1 / 176 (0.57%)
    2 / 177 (1.13%)
         occurrences all number
    2
    1
    2
    Limb injury
         subjects affected / exposed
    2 / 88 (2.27%)
    1 / 176 (0.57%)
    4 / 177 (2.26%)
         occurrences all number
    2
    1
    4
    Lip injury
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Lower limb fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    0
    Meniscus injury
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    1
    1
    0
    Metal poisoning
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle injury
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    1
    0
    1
    Muscle rupture
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Muscle strain
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences all number
    0
    0
    2
    Overdose
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Pelvic fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Periorbital haemorrhage
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Post procedural haematoma
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    2 / 177 (1.13%)
         occurrences all number
    0
    1
    2
    Post procedural swelling
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    2 / 177 (1.13%)
         occurrences all number
    0
    2
    4
    Rib fracture
         subjects affected / exposed
    2 / 88 (2.27%)
    2 / 176 (1.14%)
    3 / 177 (1.69%)
         occurrences all number
    2
    2
    4
    Scar
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences all number
    0
    2
    0
    Seroma
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Skeletal injury
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Skin abrasion
         subjects affected / exposed
    1 / 88 (1.14%)
    5 / 176 (2.84%)
    5 / 177 (2.82%)
         occurrences all number
    1
    5
    5
    Skin injury
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    0
    Spinal column injury
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Spinal compression fracture
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences all number
    1
    0
    2
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Subdural haematoma
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    3
    0
    Sunburn
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Suture related complication
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    0
    Thermal burn
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    2
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Tooth fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Upper limb fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Wound
         subjects affected / exposed
    0 / 88 (0.00%)
    4 / 176 (2.27%)
    1 / 177 (0.56%)
         occurrences all number
    0
    4
    1
    Wrist fracture
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Skin wound
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Anticoagulation drug level above therapeutic
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    4 / 177 (2.26%)
         occurrences all number
    0
    1
    4
    Anticoagulation drug level below therapeutic
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    1
    1
    0
    Arterial bruit
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 176 (1.70%)
    1 / 177 (0.56%)
         occurrences all number
    0
    3
    1
    Bence Jones protein urine present
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Blood albumin decreased
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    1
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    2 / 177 (1.13%)
         occurrences all number
    0
    1
    2
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    4 / 88 (4.55%)
    3 / 176 (1.70%)
    1 / 177 (0.56%)
         occurrences all number
    4
    4
    1
    Blood chloride decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Blood creatine increased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Blood creatinine abnormal
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    3 / 88 (3.41%)
    9 / 176 (5.11%)
    8 / 177 (4.52%)
         occurrences all number
    4
    9
    8
    Blood glucose increased
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    1 / 177 (0.56%)
         occurrences all number
    0
    2
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Blood lactic acid increased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Blood potassium abnormal
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences all number
    0
    0
    2
    Blood potassium decreased
         subjects affected / exposed
    1 / 88 (1.14%)
    4 / 176 (2.27%)
    5 / 177 (2.82%)
         occurrences all number
    1
    4
    5
    Blood potassium increased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    4 / 177 (2.26%)
         occurrences all number
    0
    0
    4
    Blood pressure decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences all number
    0
    0
    2
    Blood pressure increased
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    0
    Blood pressure systolic decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Blood sodium decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    5 / 177 (2.82%)
         occurrences all number
    0
    1
    5
    Blood urea increased
         subjects affected / exposed
    3 / 88 (3.41%)
    8 / 176 (4.55%)
    5 / 177 (2.82%)
         occurrences all number
    3
    8
    5
    Blood uric acid increased
         subjects affected / exposed
    3 / 88 (3.41%)
    8 / 176 (4.55%)
    5 / 177 (2.82%)
         occurrences all number
    3
    8
    5
    Blood urine present
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences all number
    0
    2
    0
    Body temperature decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences all number
    0
    2
    0
    Breath sounds abnormal
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    3 / 177 (1.69%)
         occurrences all number
    0
    1
    3
    C-reactive protein increased
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac murmur
         subjects affected / exposed
    2 / 88 (2.27%)
    3 / 176 (1.70%)
    4 / 177 (2.26%)
         occurrences all number
    2
    3
    4
    Crystal urine present
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Drug level above therapeutic
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    5 / 177 (2.82%)
         occurrences all number
    0
    2
    5
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 88 (3.41%)
    9 / 176 (5.11%)
    11 / 177 (6.21%)
         occurrences all number
    3
    9
    11
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Heart rate decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Heart rate increased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences all number
    0
    0
    2
    Heart rate irregular
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Human epidermal growth factor receptor decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Human rhinovirus test positive
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Inflammatory marker increased
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    0
    International normalised ratio decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    International normalised ratio increased
         subjects affected / exposed
    5 / 88 (5.68%)
    4 / 176 (2.27%)
    4 / 177 (2.26%)
         occurrences all number
    6
    4
    4
    Liver function test abnormal
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences all number
    0
    0
    2
    Liver function test increased
         subjects affected / exposed
    2 / 88 (2.27%)
    5 / 176 (2.84%)
    2 / 177 (1.13%)
         occurrences all number
    2
    5
    2
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    1 / 177 (0.56%)
         occurrences all number
    0
    2
    1
    Occult blood positive
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences all number
    0
    0
    2
    Optic nerve cup/disc ratio increased
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    0
    Oxygen saturation abnormal
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    2 / 177 (1.13%)
         occurrences all number
    0
    2
    2
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    2
    Platelet count decreased
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    2 / 177 (1.13%)
         occurrences all number
    1
    1
    2
    Prostatic specific antigen increased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences all number
    0
    0
    2
    Protein urine present
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Prothrombin time prolonged
         subjects affected / exposed
    3 / 88 (3.41%)
    3 / 176 (1.70%)
    1 / 177 (0.56%)
         occurrences all number
    3
    3
    1
    Pulmonary function test decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Pulse absent
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Red blood cell count decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Thyroid function test abnormal
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Thyroxine decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Transaminases increased
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    3 / 177 (1.69%)
         occurrences all number
    0
    2
    4
    Troponin increased
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 176 (1.14%)
    4 / 177 (2.26%)
         occurrences all number
    1
    2
    4
    Urobilinogen urine increased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Venous pressure jugular abnormal
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Venous pressure jugular increased
         subjects affected / exposed
    4 / 88 (4.55%)
    4 / 176 (2.27%)
    9 / 177 (5.08%)
         occurrences all number
    5
    4
    12
    Vitamin D decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    2 / 177 (1.13%)
         occurrences all number
    0
    2
    2
    Waist circumference increased
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences all number
    0
    2
    0
    Weight decreased
         subjects affected / exposed
    6 / 88 (6.82%)
    8 / 176 (4.55%)
    18 / 177 (10.17%)
         occurrences all number
    6
    8
    19
    Weight increased
         subjects affected / exposed
    7 / 88 (7.95%)
    13 / 176 (7.39%)
    12 / 177 (6.78%)
         occurrences all number
    8
    20
    12
    White blood cell count decreased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Cardiac disorders
    Accelerated idioventricular rhythm
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Acute myocardial infarction
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Angina pectoris
         subjects affected / exposed
    2 / 88 (2.27%)
    3 / 176 (1.70%)
    1 / 177 (0.56%)
         occurrences all number
    2
    3
    1
    Aortic valve incompetence
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    2 / 177 (1.13%)
         occurrences all number
    0
    1
    2
    Aortic valve stenosis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences all number
    0
    0
    2
    Arrhythmia
         subjects affected / exposed
    0 / 88 (0.00%)
    5 / 176 (2.84%)
    1 / 177 (0.56%)
         occurrences all number
    0
    5
    1
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    3 / 177 (1.69%)
         occurrences all number
    0
    5
    6
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    13 / 88 (14.77%)
    28 / 176 (15.91%)
    31 / 177 (17.51%)
         occurrences all number
    17
    35
    49
    Atrial flutter
         subjects affected / exposed
    5 / 88 (5.68%)
    8 / 176 (4.55%)
    12 / 177 (6.78%)
         occurrences all number
    7
    11
    16
    Atrial tachycardia
         subjects affected / exposed
    3 / 88 (3.41%)
    6 / 176 (3.41%)
    7 / 177 (3.95%)
         occurrences all number
    5
    6
    8
    Atrial thrombosis
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    4 / 177 (2.26%)
         occurrences all number
    1
    1
    4
    Atrioventricular block
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    1
    1
    0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    3 / 177 (1.69%)
         occurrences all number
    0
    2
    3
    Atrioventricular block first degree
         subjects affected / exposed
    2 / 88 (2.27%)
    3 / 176 (1.70%)
    2 / 177 (1.13%)
         occurrences all number
    2
    3
    2
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences all number
    1
    2
    0
    Bradyarrhythmia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Bradycardia
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 176 (1.14%)
    3 / 177 (1.69%)
         occurrences all number
    2
    2
    3
    Bundle branch block right
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    2 / 177 (1.13%)
         occurrences all number
    0
    1
    2
    Cardiac amyloidosis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac aneurysm
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Cardiac disorder
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Cardiac failure
         subjects affected / exposed
    18 / 88 (20.45%)
    20 / 176 (11.36%)
    33 / 177 (18.64%)
         occurrences all number
    35
    29
    62
    Cardiac failure acute
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 176 (1.70%)
    2 / 177 (1.13%)
         occurrences all number
    0
    3
    6
    Cardiac failure chronic
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    3
    Cardiac failure congestive
         subjects affected / exposed
    2 / 88 (2.27%)
    3 / 176 (1.70%)
    4 / 177 (2.26%)
         occurrences all number
    2
    3
    5
    Cardiogenic shock
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Cardiomegaly
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiomyopathy
         subjects affected / exposed
    2 / 88 (2.27%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    2
    0
    1
    Cardiorenal syndrome
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Coronary artery disease
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    0 / 177 (0.00%)
         occurrences all number
    0
    2
    0
    Cyanosis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    3 / 177 (1.69%)
         occurrences all number
    0
    1
    3
    Diastolic dysfunction
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Hepatojugular reflux
         subjects affected / exposed
    2 / 88 (2.27%)
    3 / 176 (1.70%)
    1 / 177 (0.56%)
         occurrences all number
    2
    4
    1
    Intracardiac thrombus
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    1
    1
    0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Left ventricular failure
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    2 / 177 (1.13%)
         occurrences all number
    0
    1
    2
    Low cardiac output syndrome
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    2 / 177 (1.13%)
         occurrences all number
    0
    0
    2
    Mitral valve incompetence
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 176 (1.14%)
    6 / 177 (3.39%)
         occurrences all number
    1
    2
    7
    Palpitations
         subjects affected / exposed
    2 / 88 (2.27%)
    4 / 176 (2.27%)
    8 / 177 (4.52%)
         occurrences all number
    2
    4
    11
    Pericardial effusion
         subjects affected / exposed
    2 / 88 (2.27%)
    2 / 176 (1.14%)
    2 / 177 (1.13%)
         occurrences all number
    2
    2
    2
    Pulmonary valve incompetence
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Rhythm idioventricular
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    0
    Right ventricular failure
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    1
    1
    0
    Sinus arrest
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    1
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 176 (0.57%)
    0 / 177 (0.00%)
         occurrences all number
    1
    1
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 176 (0.00%)
    1 / 177 (0.56%)
         occurrences all number
    0
    0
    1
    Sinus node dysfunction
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    3 / 177 (1.69%)
         occurrences all number
    0
    1
    3
    Tachyarrhythmia
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    2
    0
    0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 176 (1.14%)
    1 / 177 (0.56%)
         occurrences all number
    0
    2
    1
    Tachycardia
         subjects affected / exposed
    3 / 88 (3.41%)
    6 / 176 (3.41%)
    1 / 177 (0.56%)
         occurrences all number
    3
    6
    1
    Tricuspid valve incompetence
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 176 (1.14%)
    4 / 177 (2.26%)
         occurrences all number
    1
    2
    4
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 176 (0.57%)
    1 / 177 (0.56%)
         occurrences all number
    0
    1
    1
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 176 (1.70%)
    3 / 177 (1.69%)
         occurrences all number
    0
    3
    3
    Ventricular fibrillation
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 176 (0.00%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    0
    Ventricular tachycardia