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    Clinical Trial Results:
    A 52-week treatment, multi-center, randomized, doubleblind, double dummy, parallel-group, active controlled study to compare the effect of QVA149 (indacaterol maleate / glycopyrronium bromide) with salmeterol/fluticasone on the rate of exacerbations in subjects with moderate to very severe COPD. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2012-004966-16
    Trial protocol
    		 SK   HU   SE   ES   AT   LT   NL   CZ   FI   DE   BE   IS   IT   PT   NO   PL   EE   DK   BG   LV   GR   GB   LU  
    Global end of trial date
    15 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jul 2018
    First version publication date
    12 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CQVA149A2318
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01782326
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that QVA149 (110/50 μg o.d.) was at least non-inferior to salmeterol/fluticasone (50/500 μg b.i.d.) in terms of rate of Chronic Obstructive Pulmonary Disease (COPD) exacerbations (mild/moderate/severe) during 52 weeks of treatment
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 180
    Country: Number of subjects enrolled
    Austria: 94
    Country: Number of subjects enrolled
    Belgium: 84
    Country: Number of subjects enrolled
    Bulgaria: 105
    Country: Number of subjects enrolled
    Canada: 51
    Country: Number of subjects enrolled
    Chile: 14
    Country: Number of subjects enrolled
    China: 295
    Country: Number of subjects enrolled
    Colombia: 29
    Country: Number of subjects enrolled
    Croatia: 36
    Country: Number of subjects enrolled
    Czech Republic: 167
    Country: Number of subjects enrolled
    Denmark: 60
    Country: Number of subjects enrolled
    Estonia: 31
    Country: Number of subjects enrolled
    Finland: 22
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    Germany: 525
    Country: Number of subjects enrolled
    United Kingdom: 41
    Country: Number of subjects enrolled
    Greece: 72
    Country: Number of subjects enrolled
    Guatemala: 49
    Country: Number of subjects enrolled
    Hong Kong: 5
    Country: Number of subjects enrolled
    Hungary: 73
    Country: Number of subjects enrolled
    Iceland: 21
    Country: Number of subjects enrolled
    India: 103
    Country: Number of subjects enrolled
    Italy: 98
    Country: Number of subjects enrolled
    Japan: 80
    Country: Number of subjects enrolled
    Korea, Republic of: 71
    Country: Number of subjects enrolled
    Latvia: 17
    Country: Number of subjects enrolled
    Lithuania: 57
    Country: Number of subjects enrolled
    Mexico: 32
    Country: Number of subjects enrolled
    Netherlands: 58
    Country: Number of subjects enrolled
    Norway: 26
    Country: Number of subjects enrolled
    Philippines: 35
    Country: Number of subjects enrolled
    Poland: 95
    Country: Number of subjects enrolled
    Portugal: 31
    Country: Number of subjects enrolled
    Romania: 172
    Country: Number of subjects enrolled
    Russian Federation: 94
    Country: Number of subjects enrolled
    Serbia: 69
    Country: Number of subjects enrolled
    Slovakia: 104
    Country: Number of subjects enrolled
    South Africa: 96
    Country: Number of subjects enrolled
    Spain: 87
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Taiwan: 16
    Country: Number of subjects enrolled
    Thailand: 8
    Country: Number of subjects enrolled
    Turkey: 25
    Worldwide total number of subjects
    3358
    EEA total number of subjects
    2106
    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)
    1650
    From 65 to 84 years
    1700
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This was a 52- week treatment, multi-center, randomized, double-blind, double-dummy, parallel-group, non-inferiority, active controlled study to evaluate the effect of QVA149 (110/50 μg o.d.) compared to salmeterol/fluticasone (50/500 μg b.i.d.) on exacerbations (mild/moderate/severe) in patients with moderate to very severe COPD.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QVA149
    Arm description
    		 QVA149 (110/50 μg) once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    indacaterol maleate / glycopyrronium bromide
    Investigational medicinal product code
    QVA149
    Other name
    indacaterol maleate / glycopyrronium bromide
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    110/50 μg capsules

    Arm title
    		 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Arm description
    		 Salmeterol/fluticasone (50/500μg) twice a day
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Salmeterol/fluticasone
    Investigational medicinal product code
    Other name
    Salmeterol/fluticasone
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    110/50 μg o.d powder for multi dose administration

    Number of subjects in period 1
    		QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Started
    1678
    1680
    Completed
    1400
    1360
    Not completed
    278
    320
         Adverse event, serious fatal
    129
    145
         Physician decision
    13
    16
         Technical problems
    -
    5
         Protocol deviation
    8
    7
         Lack of efficacy
    17
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QVA149
    Reporting group description
    		 QVA149 (110/50 μg) once daily

    Reporting group title
    Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Reporting group description
    		 Salmeterol/fluticasone (50/500μg) twice a day

    Reporting group values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS) Total
    Number of subjects
    		 1678 1680 3358
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 816 834 1650
        From 65-84 years
    		 860 840 1700
        85 years and over
    		 2 6 8
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.6 ± 7.89 64.5 ± 7.7 -
    Gender, Male/Female
    Units: Participants
        Female
    		 1297 1256 2553
        Male
    		 381 424 805

    End points

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    End points reporting groups
    Reporting group title
    QVA149
    Reporting group description
    		 QVA149 (110/50 μg) once daily

    Reporting group title
    Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Reporting group description
    		 Salmeterol/fluticasone (50/500μg) twice a day

    Primary: Rate of COPD exacerbations

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    End point title
    		 Rate of COPD exacerbations
    End point description
    COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event. Estimates are from a generalized linear model assuming a negative binomial distribution with terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. As the offset variable log(exposure time in years) was used.
    End point type
    Primary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1528
    1556
    Units: COPD Exacerbations/year
        least squares mean (confidence interval 95%)
    3.59 (3.28 to 3.94)
    4.03 (3.68 to 4.41)
    Statistical analysis title
    		 Rate of COPD exacerbations
    Comparison groups
    QVA149 v Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects included in analysis
    3084
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    		 Generalized linear model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 0.96
    Notes
    [1] - Study was designed to have >95% power to rule out a 1.15-fold increase in the rate exacerbations for QVA149 vs. salmeterol/fluticasone.
    Statistical analysis title
    		 Rate of COPD exacerbations
    Comparison groups
    QVA149 v Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects included in analysis
    3084
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Generalized linear method
    Parameter type
    		 Rate Ratio
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 0.96

    Secondary: Time to first COPD exacerbation.

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    End point title
    		 Time to first COPD exacerbation.
    End point description
    First COPD exacerbations starting between first dose and one day after last treatment are included. Cox regression model includes terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. 
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1675
    1679
    Units: Days
        median (confidence interval 95%)
    71 (60 to 82)
    51 (46 to 57)
    Statistical analysis title
    		 Time to first COPD exacerbation.
    Comparison groups
    QVA149 v Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects included in analysis
    3354
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 0.91

    Secondary: Rate of moderate to severe COPD exacerbations.

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    End point title
    		 Rate of moderate to severe COPD exacerbations.
    End point description
    COPD exacerbations starting between date of first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event with the worst severity. A COPD exacerbation of moderate severity meets the symptoms definition in the protocol and requires treatment with systemic corticosteroids and/or antibiotics. A severe COPD exacerbation requires hospitalization. Estimates are from a generalized linear model assuming a negative binomial distribution with terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. The offset variable log(exposure time in years) was used.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1651
    1656
    Units: COPD Exacerbation/year
        least squares mean (confidence interval 95%)
    0.98 (0.88 to 1.1)
    1.19 (1.07 to 1.32)
    Statistical analysis title
    		 Rate of moderate to severe COPD exacerbations
    Comparison groups
    QVA149 v Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects included in analysis
    3307
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Generalized linear model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 0.91

    Secondary: Time to first moderate to severe COPD exacerbation.

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    End point title
    		 Time to first moderate to severe COPD exacerbation.
    End point description
    First COPD exacerbations starting between first dose and one day after last treatment are included. Cox regression model includes terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region.
    End point type
    Secondary
    End point timeframe
    52 weeks.
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1675
    1679
    Units: Days
        median (confidence interval 95%)
    999 (99 to 9999)
    308 (283 to 352)
    Statistical analysis title
    		 Time to first moderate to severe COPD exacerbation
    Comparison groups
    QVA149 v Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects included in analysis
    3354
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 0.86

    Secondary: Rate of moderate to severe COPD exacerbations requiring treatment with systemic corticosteroids

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    End point title
    		 Rate of moderate to severe COPD exacerbations requiring treatment with systemic corticosteroids
    End point description
    COPD exacerbations starting between date of first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event with the worst severity. Estimates are from a generalized linear model assuming a negative binomial distribution with fixed effects of treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. The offset variable log(exposure time in years) was used.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1651
    1656
    Units: COPD Exacerbation/year
        least squares mean (confidence interval 95%)
    0.18 (0.14 to 0.22)
    0.18 (0.14 to 0.23)
    No statistical analyses for this end point

    Secondary: Rate of moderate to severe COPD exacerbations requiring treatment with antibiotics

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    End point title
    		 Rate of moderate to severe COPD exacerbations requiring treatment with antibiotics
    End point description
    Estimates are from a generalized linear model assuming a negative binomial distribution with terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. The offset variable log(exposure time in years) was used. COPD exacerbations starting between first dose and one day after last treatment are included .
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1651
    1656
    Units: COPD Exacerbation/year
        least squares mean (confidence interval 95%)
    0.17 (0.13 to 0.22)
    0.22 (0.17 to 0.28)
    No statistical analyses for this end point

    Secondary: Rate of moderate to severe COPD exacerbations requiring hospitalization. COPD exacerbations starting between first dose and one day after last treatment are included.

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    End point title
    		 Rate of moderate to severe COPD exacerbations requiring hospitalization. COPD exacerbations starting between first dose and one day after last treatment are included.
    End point description
    All exacerbations requiring hospitalization are considered severe according to protocol definitions so this is the rate of severe COPD exacerbations only. Note - an ER visit of longer than 24 hours was considered a hospitalization.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1651
    1656
    Units: COPD Exacerbation/year
        least squares mean (confidence interval 95%)
    0.15 (0.11 to 0.19)
    0.17 (0.13 to 0.22)
    No statistical analyses for this end point

    Secondary: Rate of moderate to severe COPD exacerbations requiring re-hospitalization within 30 days

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    End point title
    		 Rate of moderate to severe COPD exacerbations requiring re-hospitalization within 30 days
    End point description
    Re-hospitalizations are defined as hospitalizations starting within the first 30 days after a severe COPD exacerbation and between first dose and one day after date of last treatment. Generalized linear model assuming a negative binomial distribution with terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. The offset variable log(exposure time in years) was used. COPD exacerbations starting between first dose and one day after last treatment are included.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1675
    1679
    Units: COPD Exacerbation/year
        arithmetic mean (standard deviation)
    0 ± 0.15
    0 ± 0.12
    No statistical analyses for this end point

    Secondary: Time to first moderate to severe COPD exacerbations requiring treatment with systemic corticosteroids

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    End point title
    		 Time to first moderate to severe COPD exacerbations requiring treatment with systemic corticosteroids
    End point description
    Cox regression model includes terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. COPD exacerbations starting between first dose and one day after date of last treatment are included.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1675
    1679
    Units: Days
        median (confidence interval 95%)
    999 (99 to 9999)
    999 (99 to 9999)
    Statistical analysis title
    		 Exacerbations requiring systemic corticosteroids
    Comparison groups
    QVA149 v Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects included in analysis
    3354
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.256
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.08

    Secondary: Time to first moderate to severe COPD exacerbations requiring treatment with antibiotics

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    End point title
    		 Time to first moderate to severe COPD exacerbations requiring treatment with antibiotics
    End point description
    Cox regression model includes terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. COPD exacerbations starting between first dose and one day after date of last treatment are included.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1675
    1679
    Units: Days
        median (confidence interval 95%)
    999 (99 to 9999)
    999 (99 to 9999)
    Statistical analysis title
    		 Exacerbations requiring treatment with antibiotics
    Comparison groups
    QVA149 v Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects included in analysis
    3354
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.008
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 0.95

    Secondary: Time to first moderate to severe COPD exacerbations requiring hospitalization

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    End point title
    		 Time to first moderate to severe COPD exacerbations requiring hospitalization
    End point description
    Cox regression model includes terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. COPD exacerbations starting between first dose and one day after date of last treatment are included.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1675
    1679
    Units: Days
        median (confidence interval 95%)
    999 (99 to 9999)
    999 (99 to 9999)
    Statistical analysis title
    		 Exacerbations requiring hospitalization
    Comparison groups
    QVA149 v Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects included in analysis
    3354
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.046
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1

    Secondary: Time to first moderate to severe COPD exacerbations requiring re-hospitalization within 30 days

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    End point title
    		 Time to first moderate to severe COPD exacerbations requiring re-hospitalization within 30 days
    End point description
    Cox regression model includes terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. COPD exacerbations starting between first dose and one day after date of last treatment are included.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1675
    1679
    Units: Days
        median (confidence interval 95%)
    999 (99 to 9999)
    999 (99 to 9999)
    Statistical analysis title
    		 Exacerbations requiring re-hospitalization
    Comparison groups
    QVA149 v Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects included in analysis
    3354
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.79
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 2.1

    Secondary: Forced expiratory volume in 1 second

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    End point title
    		 Forced expiratory volume in 1 second
    End point description
    Change from baseline. Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, airflow limitation severity, region, visit, treatment-by-visit interaction, and baseline FEV1-by-visit interaction.
    End point type
    Secondary
    End point timeframe
    Baseline, day 1 (30 min and one hour post dose)
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1675
    1679
    Units: Liters
    least squares mean (standard error)
        Day 1, 30 min post-dose (n=1659, 1663)
    0.121 ± 0.0049
    0.076 ± 0.0049
        Day 1, one hour post-dose (n=1657, 1664)
    0.147 ± 0.0054
    0.092 ± 0.0054
    No statistical analyses for this end point

    Secondary: Forced expiratory volume in 1 second

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    End point title
    		 Forced expiratory volume in 1 second
    End point description
    Change from baseline in trough value. Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, airflow limitation severity, visit, treatment-by-visit interaction, and baseline FEV1-by-visit interaction.
    End point type
    Secondary
    End point timeframe
    Baseline, 4 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1597
    1595
    Units: Liters
        least squares mean (standard error)
    0.079 ± 0.007
    0.006 ± 0.007
    No statistical analyses for this end point

    Secondary: Forced expiratory volume in 1 second

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    End point title
    		 Forced expiratory volume in 1 second
    End point description
    Change from baseline in trough value. Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, airflow limitation severity, visit, treatment-by-visit interaction, and baseline FEV1-by-visit interaction.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1597
    1595
    Units: Liters
        least squares mean (standard error)
    0.07 ± 0.0072
    -0.008 ± 0.0072
    No statistical analyses for this end point

    Secondary: Forced expiratory volume in 1 second

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    End point title
    		 Forced expiratory volume in 1 second
    End point description
    Change from baseline in trough value. Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, airflow limitation severity, visit, treatment-by-visit interaction, and baseline FEV1-by-visit interaction.
    End point type
    Secondary
    End point timeframe
    Baseline, 26 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1597
    1595
    Units: Liters
        least squares mean (standard error)
    0.049 ± 0.0073
    -0.037 ± 0.0074
    No statistical analyses for this end point

    Secondary: Forced expiratory volume in 1 second

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    End point title
    		 Forced expiratory volume in 1 second
    End point description
    Change from baseline in trough value. Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, airflow limitation severity, visit, treatment-by-visit interaction, and baseline FEV1-by-visit interaction.
    End point type
    Secondary
    End point timeframe
    Baseline, 38 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1597
    1595
    Units: Liters
        least squares mean (standard error)
    0.034 ± 0.0074
    -0.039 ± 0.0075
    No statistical analyses for this end point

    Secondary: Forced expiratory volume in 1 second

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    End point title
    		 Forced expiratory volume in 1 second
    End point description
    Change from baseline in trough value. Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, airflow limitation severity, visit, treatment-by-visit interaction, and baseline FEV1-by-visit interaction.
    End point type
    Secondary
    End point timeframe
    Baseline, 52 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1597
    1595
    Units: Liters
        least squares mean (standard error)
    0.015 ± 0.0075
    -0.048 ± 0.0076
    No statistical analyses for this end point

    Secondary: Change from baseline in Forced expiratory volume in 1 second AUC (0-12h)

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    End point title
    		 Change from baseline in Forced expiratory volume in 1 second AUC (0-12h)
    End point description
    Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time”
    End point type
    Secondary
    End point timeframe
    Baseline, 52 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    279
    277
    Units: Liters
        least squares mean (standard error)
    0.078 ± 0.0174
    -0.032 ± 0.0176
    No statistical analyses for this end point

    Secondary: Change from baseline in total St. George's Respiratory Questionnaire score

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    End point title
    		 Change from baseline in total St. George's Respiratory Questionnaire score
    End point description
    The St. George Respiratory Questionnaire C (SGRQ-C) is a disease-specific measure of health status for use in COPD that was used to provide the health status measurements in this study. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline SGRQ-C total score, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, airflow limitation severity, visit, treatment*visit Interaction, baseline SGRQ-C total score*visit + region. lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, 4 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1602
    1593
    Units: Score on a scale
        least squares mean (standard error)
    -2.3 ± 0.36
    -2.3 ± 0.36
    No statistical analyses for this end point

    Secondary: Change from baseline in total St. George's Respiratory Questionnaire score

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    End point title
    		 Change from baseline in total St. George's Respiratory Questionnaire score
    End point description
    The St. George Respiratory Questionnaire C (SGRQ-C) is a disease-specific measure of health status for use in COPD that was used to provide the health status measurements in this study. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline SGRQ-C total score, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, airflow limitation severity, visit, treatment*visit Interaction, baseline SGRQ-C total score*visit + region. lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1602
    1593
    Units: Score on a scale
        least squares mean (standard error)
    -3.2 ± 0.38
    -1.9 ± 0.38
    No statistical analyses for this end point

    Secondary: Change from baseline in total St. George's Respiratory Questionnaire score

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    End point title
    		 Change from baseline in total St. George's Respiratory Questionnaire score
    End point description
    The St. George Respiratory Questionnaire C (SGRQ-C) is a disease-specific measure of health status for use in COPD that was used to provide the health status measurements in this study. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline SGRQ-C total score, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, airflow limitation severity, visit, treatment*visit Interaction, baseline SGRQ-C total score*visit + region. lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, 26 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1602
    1593
    Units: Score on a scale
        least squares mean (standard error)
    -3.5 ± 0.39
    -2.3 ± 0.39
    No statistical analyses for this end point

    Secondary: Change from baseline in total St. George's Respiratory Questionnaire score

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    End point title
    		 Change from baseline in total St. George's Respiratory Questionnaire score
    End point description
    The St. George Respiratory Questionnaire C (SGRQ-C) is a disease-specific measure of health status for use in COPD that was used to provide the health status measurements in this study. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline SGRQ-C total score, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, airflow limitation severity, visit, treatment*visit Interaction, baseline SGRQ-C total score*visit + region. lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, 38 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1602
    1593
    Units: Score on a scale
        least squares mean (standard error)
    -3.5 ± 0.4
    -1.7 ± 0.4
    No statistical analyses for this end point

    Secondary: Change from baseline in total St. George's Respiratory Questionnaire score

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    End point title
    		 Change from baseline in total St. George's Respiratory Questionnaire score
    End point description
    The St. George Respiratory Questionnaire C (SGRQ-C) is a disease-specific measure of health status for use in COPD that was used to provide the health status measurements in this study. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline SGRQ-C total score, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, airflow limitation severity, visit, treatment*visit Interaction, baseline SGRQ-C total score*visit + region. lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, 52 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1602
    1593
    Units: Score on a scale
        least squares mean (standard error)
    -3.1 ± 0.41
    -1.9 ± 0.41
    No statistical analyses for this end point

    Secondary: Change from baseline in the number of puffs of rescue medication

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    End point title
    		 Change from baseline in the number of puffs of rescue medication
    End point description
    A linear mixed model (LMM) was used for this analysis Change from baseline in mean number of puffs. LMM including: treatment, baseline value, smoking status at screening, ICS use at screening, airflow limitation severity, region and random effect of center nested within region.
    End point type
    Secondary
    End point timeframe
    Baseline, 52 weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1675
    1679
    Units: Number of puffs per day
        least squares mean (standard error)
    -1.01 ± 0.097
    -0.76 ± 0.097
    No statistical analyses for this end point

    Secondary: Change from baseline in the safety of QVA149 ((110/50 μg o.d.) vs fluticasone/salmeterol (500/50μg bid) in terms of HPA axis function, as determined by collection of 24-hour urine cortisol.

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    End point title
    		 Change from baseline in the safety of QVA149 ((110/50 μg o.d.) vs fluticasone/salmeterol (500/50μg bid) in terms of HPA axis function, as determined by collection of 24-hour urine cortisol.
    End point description
    Urine cortisol/creatinine ratio
    End point type
    Secondary
    End point timeframe
    Baseline, 52 Weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    162
    154
    Units: ng/mL
        median (full range (min-max))
    5.615 (-96.93 to 509.17)
    -10.39 (-97.76 to 4444.65)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Forced Vital Capacity

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    End point title
    		 Change From Baseline in Forced Vital Capacity
    End point description
    Change from baseline in trough value (average of values measured 45 and 15 minutes prior to the morning dose). Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FVC was defined as the average of the pre-dose FVC measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FVC measurements, smoking status at screening, screening inhaled corticosteroid (ICS) use, region, baseline FVC * visit interaction, and visit, treatment * visit interaction
    End point type
    Secondary
    End point timeframe
    4 Weeks, 12 Weeks, 26 Weeks, 38 Weeks, 52 Weeks
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1597
    1595
    Units: Liters
    least squares mean (standard error)
        4 weeks
    0.146 ± 0.0127
    -0.032 ± 0.0128
        12 weeks
    0.134 ± 0.0131
    -0.071 ± 0.0131
        26 weeks
    0.088 ± 0.0135
    -0.121 ± 0.0136
        38 weeks
    0.071 ± 0.0137
    -0.111 ± 0.0137
        52 weeks
    0.022 ± 0.0139
    -0.138 ± 0.014
    No statistical analyses for this end point

    Secondary: Number of patients with adverse events, serious adverse events, and death

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    End point title
    		 Number of patients with adverse events, serious adverse events, and death
    End point description
    The overall rate of adverse events reported from initiation through 30 days post last dose.
    End point type
    Secondary
    End point timeframe
    52 weeks of treatment + 30 days
    End point values
    		 QVA149 Long acting B2 agonist (LABA) and inhaled corticosteroid (ICS)
    Number of subjects analysed
    1678
    1680
    Units: Number of participants
        Patients with at least one SAEs
    308
    334
        Patients with at least one AE
    1459
    1498
        Death
    24
    24
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    QVA149
    Reporting group description
    		 QVA149

    Reporting group title
    Salm/Flut
    Reporting group description
    		 Salm/Flut

    Serious adverse events
    		 QVA149 Salm/Flut
    Total subjects affected by serious adverse events
         subjects affected / exposed
    308 / 1678 (18.36%)
    334 / 1680 (19.88%)
         number of deaths (all causes)
    24
    24
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ACUTE MYELOID LEUKAEMIA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ADENOCARCINOMA GASTRIC
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ADENOCARCINOMA OF COLON
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    ADRENAL GLAND CANCER
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-CELL LYMPHOMA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BASAL CELL CARCINOMA
         subjects affected / exposed
    2 / 1678 (0.12%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BREAST CANCER
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHIAL CARCINOMA
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CHRONIC MYELOID LEUKAEMIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLON CANCER
         subjects affected / exposed
    1 / 1678 (0.06%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    DIFFUSE LARGE B-CELL LYMPHOMA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    GASTRIC CANCER
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC CANCER
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOPHARYNGEAL CANCER
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    LARGE INTESTINE BENIGN NEOPLASM
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARYNGEAL CANCER
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARYNGEAL SQUAMOUS CELL CARCINOMA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG ADENOCARCINOMA METASTATIC
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG NEOPLASM MALIGNANT
         subjects affected / exposed
    3 / 1678 (0.18%)
    6 / 1680 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MALIGNANT MESENCHYMOMA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METASTASES TO LIVER
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYELOID LEUKAEMIA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEOPLASM MALIGNANT
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    NON-HODGKIN'S LYMPHOMA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NON-SMALL CELL LUNG CANCER
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OESOPHAGEAL CARCINOMA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PENILE NEOPLASM
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLASMA CELL MYELOMA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROSTATE CANCER
         subjects affected / exposed
    4 / 1678 (0.24%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RECTAL ADENOCARCINOMA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RECTAL CANCER
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL CANCER
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL CELL CARCINOMA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL CELL LUNG CANCER
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SQUAMOUS CELL CARCINOMA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA OF LUNG
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TONGUE NEOPLASM MALIGNANT STAGE UNSPECIFIED
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URETHRAL CANCER
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    AORTIC ANEURYSM
         subjects affected / exposed
    2 / 1678 (0.12%)
    3 / 1680 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AORTIC ANEURYSM RUPTURE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    AORTIC CALCIFICATION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTERIOSCLEROSIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CIRCULATORY COLLAPSE
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    2 / 1678 (0.12%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EMBOLISM ARTERIAL
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    3 / 1678 (0.18%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    2 / 1678 (0.12%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LERICHE SYNDROME
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORTHOSTATIC HYPOTENSION
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
         subjects affected / exposed
    4 / 1678 (0.24%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL EMBOLISM
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TEMPORAL ARTERITIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOPHLEBITIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOSIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VARICOSE ULCERATION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENOUS THROMBOSIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    LOCAL SWELLING
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MULTI-ORGAN FAILURE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 1678 (0.06%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUDDEN CARDIAC DEATH
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    SUDDEN DEATH
         subjects affected / exposed
    1 / 1678 (0.06%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Immune system disorders
    FOOD ALLERGY
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    BENIGN PROSTATIC HYPERPLASIA
         subjects affected / exposed
    0 / 1678 (0.00%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TESTICULAR TORSION
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UTERINE POLYP
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE PULMONARY OEDEMA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    5 / 1678 (0.30%)
    4 / 1680 (0.24%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    ASTHMA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS CHRONIC
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    BRONCHOPLEURAL FISTULA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHOSPASM
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    182 / 1678 (10.85%)
    207 / 1680 (12.32%)
         occurrences causally related to treatment / all
    5 / 237
    8 / 264
         deaths causally related to treatment / all
    0 / 10
    0 / 13
    CHRONIC RESPIRATORY FAILURE
         subjects affected / exposed
    4 / 1678 (0.24%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    COUGH
         subjects affected / exposed
    0 / 1678 (0.00%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    8 / 1678 (0.48%)
    4 / 1680 (0.24%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    EMPHYSEMA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPISTAXIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOPTYSIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOTHORAX
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERCAPNIA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARYNGEAL OEDEMA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG CONSOLIDATION
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PLEURISY
         subjects affected / exposed
    2 / 1678 (0.12%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PNEUMONITIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    2 / 1678 (0.12%)
    5 / 1680 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX SPONTANEOUS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    4 / 1678 (0.24%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    PULMONARY HAEMORRHAGE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PULMONARY HILAR ENLARGEMENT
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY HYPERTENSION
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY OEDEMA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    RESPIRATORY ACIDOSIS
         subjects affected / exposed
    2 / 1678 (0.12%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    11 / 1678 (0.66%)
    6 / 1680 (0.36%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 7
         deaths causally related to treatment / all
    0 / 3
    0 / 4
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COMPLETED SUICIDE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    DELIRIUM TREMENS
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEPRESSION
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HALLUCINATION
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SLEEP DISORDER
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 1678 (0.06%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    BLOOD POTASSIUM INCREASED
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ANAEMIA POSTOPERATIVE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANKLE FRACTURE
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRAIN HERNIATION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CARBON MONOXIDE POISONING
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CLAVICLE FRACTURE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COMPRESSION FRACTURE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEAD INJURY
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    2 / 1678 (0.12%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HUMERUS FRACTURE
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIMB INJURY
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENISCUS INJURY
         subjects affected / exposed
    0 / 1678 (0.00%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OVERDOSE
         subjects affected / exposed
    2 / 1678 (0.12%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PATELLA FRACTURE
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PELVIC FRACTURE
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POSTOPERATIVE WOUND COMPLICATION
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROCEDURAL INTESTINAL PERFORATION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RIB FRACTURE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL COMPRESSION FRACTURE
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL FRACTURE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TIBIA FRACTURE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND DECOMPOSITION
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    PROGRESSIVE CEREBELLAR DEGENERATION
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    1 / 1678 (0.06%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    4 / 1678 (0.24%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    ANGINA PECTORIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANGINA UNSTABLE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARRHYTHMIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    5 / 1678 (0.30%)
    7 / 1680 (0.42%)
         occurrences causally related to treatment / all
    4 / 5
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    2 / 1678 (0.12%)
    3 / 1680 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL TACHYCARDIA
         subjects affected / exposed
    2 / 1678 (0.12%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRADYCARDIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    5 / 1678 (0.30%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 1
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    5 / 1678 (0.30%)
    7 / 1680 (0.42%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 7
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    CARDIAC FAILURE ACUTE
         subjects affected / exposed
    0 / 1678 (0.00%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    1 / 1678 (0.06%)
    3 / 1680 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CARDIAC TAMPONADE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CARDIO-RESPIRATORY ARREST
         subjects affected / exposed
    1 / 1678 (0.06%)
    3 / 1680 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    CARDIOVASCULAR DISORDER
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONGESTIVE CARDIOMYOPATHY
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COR PULMONALE
         subjects affected / exposed
    0 / 1678 (0.00%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COR PULMONALE CHRONIC
         subjects affected / exposed
    0 / 1678 (0.00%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    2 / 1678 (0.12%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CORONARY ARTERY STENOSIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ISCHAEMIC CARDIOMYOPATHY
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEFT VENTRICULAR DYSFUNCTION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEFT VENTRICULAR FAILURE
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    6 / 1678 (0.36%)
    5 / 1680 (0.30%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    MYOCARDIAL ISCHAEMIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    MYOCARDIAL RUPTURE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PERICARDIAL EFFUSION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERICARDIAL HAEMORRHAGE
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RIGHT VENTRICULAR FAILURE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SINUS TACHYCARDIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENTRICULAR ARRHYTHMIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    BASAL GANGLIA STROKE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRAIN INJURY
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRAIN STEM HAEMORRHAGE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CAROTID ARTERIOSCLEROSIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CAROTID ARTERY OCCLUSION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CENTRAL NERVOUS SYSTEM LESION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBELLAR INFARCTION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL INFARCTION
         subjects affected / exposed
    2 / 1678 (0.12%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL ISCHAEMIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL THROMBOSIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 1678 (0.00%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLUSTER HEADACHE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEPRESSED LEVEL OF CONSCIOUSNESS
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPILEPSY
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEMIPARESIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYDROCEPHALUS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
         subjects affected / exposed
    2 / 1678 (0.12%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LACUNAR INFARCTION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    2 / 1678 (0.12%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIITH NERVE PARALYSIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPARIN-INDUCED THROMBOCYTOPENIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOCHROMIC ANAEMIA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    ANGLE CLOSURE GLAUCOMA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OPHTHALMOPLEGIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OPTIC ISCHAEMIC NEUROPATHY
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RETINAL DETACHMENT
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL DISTENSION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL HERNIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACID PEPTIC DISEASE
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASCITES
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DUODENAL ULCER
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPHAGIA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FAECALOMA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC ULCER
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 1678 (0.00%)
    3 / 1680 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATEMESIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ILEUS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ILEUS PARALYTIC
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INGUINAL HERNIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL PERFORATION
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL STENOSIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARGE INTESTINE POLYP
         subjects affected / exposed
    0 / 1678 (0.00%)
    4 / 1680 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OESOPHAGITIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    2 / 1678 (0.12%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PANCREATITIS ACUTE
         subjects affected / exposed
    1 / 1678 (0.06%)
    3 / 1680 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STOMATITIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UMBILICAL HERNIA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DRUG-INDUCED LIVER INJURY
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC CIRRHOSIS
         subjects affected / exposed
    2 / 1678 (0.12%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC CYST RUPTURED
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC FUNCTION ABNORMAL
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIVER DISORDER
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    LINEAR IGA DISEASE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARAPSORIASIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SWELLING FACE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URTICARIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CALCULUS URINARY
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC KIDNEY DISEASE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    URETHRAL STENOSIS
         subjects affected / exposed
    2 / 1678 (0.12%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY RETENTION
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    GOITRE
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTHROPATHY
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GROIN PAIN
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCLE HAEMORRHAGE
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOARTHRITIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOLYSIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOPOROTIC FRACTURE
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POLYMYALGIA RHEUMATICA
         subjects affected / exposed
    2 / 1678 (0.12%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL PAIN
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    ABSCESS JAW
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABSCESS LIMB
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATYPICAL MYCOBACTERIAL INFECTION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACTERAEMIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    4 / 1680 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS INFECTIVE
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYSTITIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    2 / 1678 (0.12%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ECZEMA INFECTED
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTEROCOLITIS INFECTIOUS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    0 / 1678 (0.00%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS ROTAVIRUS
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 INFLUENZA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    HERPES ZOSTER
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    INFECTED SKIN ULCER
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTIOUS PLEURAL EFFUSION
         subjects affected / exposed
    2 / 1678 (0.12%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTIVE ANEURYSM
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    8 / 1678 (0.48%)
    7 / 1680 (0.42%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION BACTERIAL
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION VIRAL
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG INFECTION
         subjects affected / exposed
    0 / 1678 (0.00%)
    3 / 1680 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    MENINGITIS VIRAL
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NASOPHARYNGITIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORAL VIRAL INFECTION
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OTITIS EXTERNA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OTITIS MEDIA CHRONIC
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PHARYNGITIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOCOCCAL INFECTION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    34 / 1678 (2.03%)
    54 / 1680 (3.21%)
         occurrences causally related to treatment / all
    0 / 36
    3 / 60
         deaths causally related to treatment / all
    0 / 4
    1 / 3
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PSEUDOMONAS INFECTION
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY SEPSIS
         subjects affected / exposed
    4 / 1678 (0.24%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    PULMONARY TUBERCULOSIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    2 / 1678 (0.12%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION BACTERIAL
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    SINUSITIS
         subjects affected / exposed
    2 / 1678 (0.12%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPUTUM PURULENT
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUBERCULOUS PLEURISY
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    2 / 1678 (0.12%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION BACTERIAL
         subjects affected / exposed
    9 / 1678 (0.54%)
    15 / 1680 (0.89%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URETERITIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIRAL INFECTION
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 1678 (0.06%)
    2 / 1680 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    ACIDOSIS
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CACHEXIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    1 / 1678 (0.06%)
    3 / 1680 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIET REFUSAL
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ELECTROLYTE IMBALANCE
         subjects affected / exposed
    1 / 1678 (0.06%)
    0 / 1680 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    1 / 1678 (0.06%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERKALAEMIA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 1678 (0.00%)
    1 / 1680 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 QVA149 Salm/Flut
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1285 / 1678 (76.58%)
    1351 / 1680 (80.42%)
    Respiratory, thoracic and mediastinal disorders
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    1262 / 1678 (75.21%)
    1331 / 1680 (79.23%)
         occurrences all number
    5182
    5694
    Infections and infestations
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    76 / 1678 (4.53%)
    91 / 1680 (5.42%)
         occurrences all number
    104
    115
    NASOPHARYNGITIS
         subjects affected / exposed
    197 / 1678 (11.74%)
    194 / 1680 (11.55%)
         occurrences all number
    274
    263
    UPPER RESPIRATORY TRACT INFECTION BACTERIAL
         subjects affected / exposed
    121 / 1678 (7.21%)
    157 / 1680 (9.35%)
         occurrences all number
    170
    220
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    131 / 1678 (7.81%)
    136 / 1680 (8.10%)
         occurrences all number
    210
    243

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 May 2013
    Issued when approximately 3000 patients had been screened and approximately 1350 patients had been randomized in 38 countries, was prepared to remove the Sub-Study Data Analysis and to include the collection of the CAT (COPD Assessment Test) score at Visit 1
    04 Mar 2014
    Issued to remove serum cortisol analyses from the study as data from a previous QVA149 clinical trial demonstrated that there were no clinically significant changes in serum cortisol levels, when QVA149 was compared to salmeterol/fluticasone, following 26 weeks of treatment. In addition, published data on the effect of inhaled corticosteroid therapy on serum cortisol levels has been varied, with minimal effects reported in most studies.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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