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    Clinical Trial Results:
    A 52-week, Double-Blind, Randomized, Placebo Controlled Parallel Group Study to Evaluate the Effect of Roflumilast 500 ug on Exacerbation Rate in Subjects with Chronic Obstructive Pulmonary Disease (COPD) Treated with a Fixed Dose Combination of Long-Acting Beta Agonist and Inhaled Corticosteroid (LABA/ICS)

    Summary
    EudraCT number
    		 2011-003606-24
    Trial protocol
    		 ES   IT  
    Global end of trial date
    24 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2016
    First version publication date
    15 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ROF-MD-07
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01443845
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Forest Laboratories, LLC, an Allergan affiliate
    Sponsor organisation address
    Harborside Financial Center Plaza V, Suite 1900, Jersey City, United States, 07311-4994
    Public contact
    Clinical Trial Registries Team, Forest Laboratories, LLC, an Allergan affiliate, +1 1-800-347-4500, IR-CTRegistration@allergan.com
    Scientific contact
    Therapeutic Area Head, Forest Laboratories, LLC, an Allergan affiliate, +1 1-800-347-4500, IR-CTRegistration@allergan.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Jan 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the additional benefit of roflumilast added on to fixed dose combination LABA/ICS (Advair® 250/50ug 1 puff b.i.d or Symbicort® 160/4.5ug 2 puffs b.i.d) in the reduction of exacerbations in subjects with severe to very severe COPD.
    Protection of trial subjects
    At each study center, the Investigator was responsible for ensuring that the investigation was conducted according to the signed Investigator agreement, the protocol, the study procedures manual, and Good Clinical Practice (GCP) guidelines; for protecting the rights, safety, and welfare of patients under the Investigator’s care; and for the control of drugs under investigation. The Investigator at each study center was responsible for the management of the study, which consisted of maintaining the study file and patient records, corresponding with the Institutional Review Board(IRB)/Independent Ethics Committee(IEC), and completing the electronic case report forms (eCRFs).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Sep 2011
    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
    Canada: 29
    Country: Number of subjects enrolled
    Malaysia: 13
    Country: Number of subjects enrolled
    Thailand: 34
    Country: Number of subjects enrolled
    Mexico: 44
    Country: Number of subjects enrolled
    Taiwan: 13
    Country: Number of subjects enrolled
    Colombia: 17
    Country: Number of subjects enrolled
    United States: 915
    Country: Number of subjects enrolled
    Ukraine: 190
    Country: Number of subjects enrolled
    Argentina: 396
    Country: Number of subjects enrolled
    Russian Federation: 154
    Country: Number of subjects enrolled
    Philippines: 261
    Country: Number of subjects enrolled
    Peru: 71
    Country: Number of subjects enrolled
    Romania: 109
    Country: Number of subjects enrolled
    Serbia: 94
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    2354
    EEA total number of subjects
    123
    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)
    1181
    From 65 to 84 years
    1154
    85 years and over
    19

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment occurred from September 2011 to October 2014 for a total of 380 study centers screened patients for the study: Italy, Spain, United States, Ukraine, Argentina, Russia, Philippines, Romania, Serbia, Canada, Malaysia, Thailand, Mexico, Peru and Taiwan

    Pre-assignment
    Screening details
    		 The study consisted of 2 weeks of single-blind placebo lead-in with fixed-dose combination (FDC) long-acting β2-agonist(s) (LABA)/inhaled corticosteroid(s) (ICS) treatment followed by 52 weeks of double-blind treatment in addition to maintenance FDC LABA/ICS.

    Pre-assignment period milestones
    Number of subjects started
    		 2354
    Number of subjects completed
    		 2352

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Adverse event, non-fatal: 1
    Reason: Number of subjects
    		 Protocol deviation: 1
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    During the double-blind treatment period, all parties involved in the study (e.g., patients, Investigators, site personnel, Regional Site Managers [RSMs], clinical research assistants, and the Sponsor) were blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Dose-matched placebo, oral administration, once per day.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration, once per day

    Arm title
    		 Roflumilast
    Arm description
    		 Roflumilast 500 µg, oral administration, once per day
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Daxas, Daliresp
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 500 microgram (μg) tablet, oral administration, once per day.

    Number of subjects in period 1 [1]
    		Placebo Roflumilast
    Started
    1174
    1178
    Completed
    922
    841
    Not completed
    252
    337
         Adverse event, serious fatal
    25
    30
         Consent withdrawn by subject
    63
    67
         Deterioration in pulmonary function
    1
    4
         Other reasons, including COPD exacerbations
    44
    44
         Adverse event, non-fatal
    38
    108
         Site terminated by Sponsor- e.g. military conflict
    20
    21
         Lost to follow-up
    9
    13
         Lack of efficacy
    10
    5
         Protocol deviation
    42
    45
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The safety population (numbering 2352 patients) of the trial does not include 2 patients from the enrolled population (numbering 2354 patients), due to a protocol deviation for one patient and an adverse event for a second patient.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Dose-matched placebo, oral administration, once per day.

    Reporting group title
    Roflumilast
    Reporting group description
    		 Roflumilast 500 µg, oral administration, once per day

    Reporting group values
    		 Placebo Roflumilast Total
    Number of subjects
    		 1174 1178 2352
    Age categorical
    Units: Subjects
        Adults 40-65 years
    		 634 640 1274
        Adults over 65 years
    		 540 538 1078
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.5 ( 8.4 ) 64.4 ( 8.8 ) -
    Gender categorical
    Units: Subjects
        Male
    		 794 821 1615
        Female
    		 380 357 737
    Race
    Units: Subjects
        White
    		 944 935 1879
        Black or African American
    		 27 35 62
        Asian
    		 170 167 337
        American Indian or Alaska Native
    		 6 16 22
        Native Hawaiian or Other Pacific Islander
    		 0 2 2
        Other
    		 27 23 50
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 272 268 540
        Not Hispanic or Latino
    		 902 910 1812
    ICS/LABA Therapy
    Patients long-acting β2-agonist(s) (LABA)/inhaled corticosteroid(s) (ICS) therapy
    Units: Subjects
        Advair
    		 766 768 1534
        Symbicort
    		 408 410 818
    Long-acting muscarinic antagonist(s) (LAMA) use
    Pateints using LAMA medication
    Units: Subjects
        LAMA
    		 546 548 1094
        No-LAMA
    		 628 630 1258
    BMI Category
    Body-Mass Index Category.
    Units: Subjects
        Under weight: < 18.5
    		 95 100 195
        Normal weight: >= 18.5 to < 25
    		 480 468 948
        Over weight: >= 25 to < 30
    		 347 342 689
        Obese: >= 30
    		 252 268 520
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 72.57 ( 18.67 ) 73.63 ( 19.57 ) -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 167.53 ( 9.39 ) 167.8 ( 9.35 ) -
    BMI
    Body-Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 25.72 ( 5.72 ) 25.99 ( 5.91 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Dose-matched placebo, oral administration, once per day.

    Reporting group title
    Roflumilast
    Reporting group description
    		 Roflumilast 500 µg, oral administration, once per day

    Primary: Rate of moderate or severe COPD exacerbations per patient per year.

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    End point title
    		 Rate of moderate or severe COPD exacerbations per patient per year.
    End point description
    Rate of moderate or severe COPD exacerbations, defined as requiring oral or parenteral glucocorticosteroids (moderate) or requiring hospitalization and/or leading to death (severe), during the double-blind treatment period.
    End point type
    Primary
    End point timeframe
    Baseline to Week 52
    End point values
    		 Placebo Roflumilast
    Number of subjects analysed
    1174 [1]
    1178 [2]
    Units: COPD exacerbations per patient per year
        number (confidence interval 95%)
    1.27 (1.17 to 1.39)
    1.17 (1.06 to 1.28)
    Notes
    [1] - Intent-to-Treat Study Population
    [2] - Intent-to-Treat Study Population
    Statistical analysis title
    		 Rate ratio (Roflumilast/Placebo)
    Statistical analysis description
    A rate ratio < 1 represents a favorable outcome for the test treatment.
    Comparison groups
    Placebo v Roflumilast
    Number of subjects included in analysis
    2352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1634 [3]
    Method
    		 negative binomial regression
    Parameter type
    		 Rate Ratio
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.063
    Notes
    [3] - p-values are based on a negative binomial regression with factors Treatment and LAMA use.
    Statistical analysis title
    		 Subgroup Analysis - By Sex - Male
    Comparison groups
    Placebo v Roflumilast
    Number of subjects included in analysis
    2352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0195
    Method
    		 negative binomial regression
    Parameter type
    		 Rate Ratio
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 0.97
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.08
    Statistical analysis title
    		 Subgroup Analysis - By Sex - Female
    Comparison groups
    Placebo v Roflumilast
    Number of subjects included in analysis
    2352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3164
    Method
    		 negative binomial regression
    Parameter type
    		 Rate Ratio
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.101
    Statistical analysis title
    		 Subgroup Analysis - By LABA/ICS Thearapy - Advair
    Statistical analysis description
    Subgroup analysis between patients taking Advair verses patients taking Symbicort as LABA/ICS therapy.
    Comparison groups
    Placebo v Roflumilast
    Number of subjects included in analysis
    2352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0385
    Method
    		 negative binomial regression
    Parameter type
    		 Rate Ratio
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 0.99
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.076
    Statistical analysis title
    		 Subgroup Analysis -By LABA/ICS Thearapy -Symbicort
    Statistical analysis description
    Subgroup analysis between patients taking Advair verses patients taking Symbicort as LABA/ICS therapy.
    Comparison groups
    Placebo v Roflumilast
    Number of subjects included in analysis
    2352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6475
    Method
    		 negative binomial regression
    Parameter type
    		 Rate Ratio
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.114

    Secondary: Rate of COPD exacerbations that led to hospitalization or death (ie, severe COPD exacerbations)

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    End point title
    		 Rate of COPD exacerbations that led to hospitalization or death (ie, severe COPD exacerbations)
    End point description
    Rate of moderate or severe COPD exacerbations, defined as requiring hospitalization and/or leading to death (severe), during the double-blind treatment period.
    End point type
    Secondary
    End point timeframe
    Week 0 (Visit 2) to Week 52
    End point values
    		 Placebo Roflumilast
    Number of subjects analysed
    1174 [4]
    1178 [5]
    Units: COPD exacerbations per patient per year
        number (confidence interval 95%)
    0.29 (0.25 to 0.34)
    0.28 (0.23 to 0.33)
    Notes
    [4] - Intent-to Treat Population
    [5] - Intent-to-Treat Population
    Statistical analysis title
    		 Rate ratio (Roflumilast/Placebo)
    Statistical analysis description
    Rate ratio < 1 represents a favorable outcome for the test treatment.
    Comparison groups
    Roflumilast v Placebo
    Number of subjects included in analysis
    2352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6354 [6]
    Method
    		 negative binomial regression
    Parameter type
    		 Rate Ratio
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.118
    Notes
    [6] - p-values are based on a negative binomial regression with factors Treatment and LAMA use.

    Secondary: Rate of moderate or severe COPD exacerbations or COPD exacerbations treated with antibiotics

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    End point title
    		 Rate of moderate or severe COPD exacerbations or COPD exacerbations treated with antibiotics
    End point description
    Rate of moderate or severe COPD exacerbations treated with antibiotics during the double-blind treatment period.
    End point type
    Secondary
    End point timeframe
    Week 0 (Visit 2) to Week 52
    End point values
    		 Placebo Roflumilast
    Number of subjects analysed
    1174 [7]
    1178 [8]
    Units: COPD Exacerbations per Patient per Year
        number (confidence interval 95%)
    1.45 (1.34 to 1.57)
    1.31 (1.2 to 1.43)
    Notes
    [7] - Intent-to-Treat Population
    [8] - Intent-to-Treat Population
    Statistical analysis title
    		 Rate ratio (Roflumilast/Placebo)
    Statistical analysis description
    A rate ratio < 1 represents a favorable outcome for the test treatment.
    Comparison groups
    Roflumilast v Placebo
    Number of subjects included in analysis
    2352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0884 [9]
    Method
    		 negative binomial regression
    Parameter type
    		 Rate Ratio
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [9] - p-values are based on a negative binomial regression with factors Treatment and LAMA use.

    Secondary: Mean change from randomization (Visit 2) over 52 weeks of treatment in predose forced expiratory volume in 1 second (FEV1)

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    End point title
    		 Mean change from randomization (Visit 2) over 52 weeks of treatment in predose forced expiratory volume in 1 second (FEV1)
    End point description
    Mean change from randomization (Visit 2) over 52 weeks of treatment in predose forced expiratory volume in 1 second (FEV1)
    End point type
    Secondary
    End point timeframe
    Week 0 (Visit 2) to Week 52
    End point values
    		 Placebo Roflumilast
    Number of subjects analysed
    1105 [10]
    1054 [11]
    Units: Liters
        least squares mean (standard error)
    -0.0091 ( 0.0047 )
    0.0441 ( 0.0048 )
    Notes
    [10] - Intent-to-Treat Population who the completed 52-week treatment period
    [11] - Intent-to-Treat Population who the completed 52-week treatment period
    Statistical analysis title
    		 LS Mean difference (Roflumilast - Placebo)
    Comparison groups
    Placebo v Roflumilast
    Number of subjects included in analysis
    2159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.0532
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.0664
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0067
    Notes
    [12] - The MMRM analysis is based on all postbaseline observed data using a mixed model with terms for treatment, baseline, visit, LAMA use, treatment-by-visit and baseline-by-visit interactions.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Dose-matched placebo, oral administration, once per day.

    Reporting group title
    Roflumilast
    Reporting group description
    		 Roflumilast 500 µg, oral administration, once per day

    Serious adverse events
    		 Placebo Roflumilast
    Total subjects affected by serious adverse events
         subjects affected / exposed
    162 / 1174 (13.80%)
    180 / 1178 (15.28%)
         number of deaths (all causes)
    25
    30
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric cancer
         subjects affected / exposed
    0 / 1174 (0.00%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    3 / 1174 (0.26%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to liver
         subjects affected / exposed
    0 / 1174 (0.00%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenosquamous cell lung cancer
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer stage 0
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epithelioid mesothelioma
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung squamous cell carcinoma metastatic
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to spine
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spleen
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine carcinoma
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polycythaemia vera
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer limited stage
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung carcinoma cell type unspecified stage IV
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung squamous cell carcinoma stage III
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer stage III
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 1174 (0.17%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectosigmoid cancer
         subjects affected / exposed
    2 / 1174 (0.17%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (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
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (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 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (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
    0 / 1174 (0.00%)
    3 / 1178 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 1174 (0.17%)
    3 / 1178 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Angiodysplasia
         subjects affected / exposed
    0 / 1174 (0.00%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 1174 (0.00%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    3 / 1174 (0.26%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Femoral artery occlusion
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (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
    1 / 1174 (0.09%)
    0 / 1178 (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 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Accelerated hypertension
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 1174 (0.26%)
    6 / 1178 (0.51%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Sudden cardiac death
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Death
         subjects affected / exposed
    3 / 1174 (0.26%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Discomfort
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oedema peripheral
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peripheral swelling
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pyrexia
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Chest pain
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seasonal allergy
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Adnexa uteri mass
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adnexal torsion
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    6 / 1174 (0.51%)
    7 / 1178 (0.59%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    Respiratory failure
         subjects affected / exposed
    5 / 1174 (0.43%)
    7 / 1178 (0.59%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Pneumothorax
         subjects affected / exposed
    2 / 1174 (0.17%)
    4 / 1178 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 1174 (0.00%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Dyspnoea
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Laryngeal granuloma
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         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
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory muscle weakness
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 1174 (0.26%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (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 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nasal polyps
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obliterative bronchiolitis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (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
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bullous lung disease
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hydrothorax
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperventilation
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinus congestion
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sputum retention
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cough
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 1174 (0.00%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Confusional state
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Depression
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Major depression
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mental status changes
         subjects affected / exposed
    2 / 1174 (0.17%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Insomnia
         subjects affected / exposed
    2 / 1174 (0.17%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    2 / 2
    1 / 2
    Investigations
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tinea pedis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nutritional condition abnormal
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Weight increased
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 1174 (0.34%)
    3 / 1178 (0.25%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Femoral neck fracture
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heat stroke
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary contusion
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         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
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Road traffic accident
         subjects affected / exposed
    3 / 1174 (0.26%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye injury
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    2 / 1174 (0.17%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    2 / 1174 (0.17%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (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
    Hydrocele
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Choledochal cyst
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertrophic cardiomyopathy
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (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 myocardial infarction
         subjects affected / exposed
    1 / 1174 (0.09%)
    7 / 1178 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    0 / 1174 (0.00%)
    5 / 1178 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 5
    Atrial fibrillation
         subjects affected / exposed
    5 / 1174 (0.43%)
    4 / 1178 (0.34%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 5
    Angina pectoris
         subjects affected / exposed
    1 / 1174 (0.09%)
    3 / 1178 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    3 / 1174 (0.26%)
    3 / 1178 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Cardiogenic shock
         subjects affected / exposed
    0 / 1174 (0.00%)
    3 / 1178 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 1174 (0.00%)
    3 / 1178 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 1174 (0.09%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 1174 (0.26%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Myocardial infarction
         subjects affected / exposed
    1 / 1174 (0.09%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute coronary syndrome
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Arrhythmia
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    4 / 1174 (0.34%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiomyopathy
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    2 / 1174 (0.17%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cor pulmonale acute
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Coronary artery insufficiency
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Left ventricular failure
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial rupture
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tachycardia
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiomegaly
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    2 / 1174 (0.17%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 1174 (0.17%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cervical radiculopathy
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic transformation stroke
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral ventricle dilatation
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hydrocephalus
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    2 / 1174 (0.17%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 1174 (0.00%)
    3 / 1178 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Vascular encephalopathy
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Drooling
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 1174 (0.00%)
    4 / 1178 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 1174 (0.00%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Anaemia macrocytic
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyphaema
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratitis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mydriasis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 1174 (0.09%)
    5 / 1178 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    0 / 1174 (0.00%)
    3 / 1178 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Colitis ischaemic
         subjects affected / exposed
    0 / 1174 (0.00%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 1174 (0.17%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 1174 (0.00%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 1174 (0.00%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal hernia
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Abdominal strangulated hernia
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal angiodysplasia
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal hypertensive gastropathy
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 1174 (0.17%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 1174 (0.17%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Dyspepsia
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Erosive duodenitis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal ulcer haemorrhage
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 1174 (0.17%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (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 / 1174 (0.09%)
    3 / 1178 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Abdominal pain upper
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Faeces soft
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal discomfort
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Salivary hypersecretion
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 1174 (0.17%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    3 / 1174 (0.26%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Erythema
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Night sweats
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pruritus
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematuria
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pollakiuria
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary retention
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Azotaemia
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 1174 (0.09%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patellofemoral pain syndrome
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Osteochondrosis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Muscle spasms
         subjects affected / exposed
    2 / 1174 (0.17%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Muscular weakness
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neck pain
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Periarthritis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Osteopenia
         subjects affected / exposed
    2 / 1174 (0.17%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    45 / 1174 (3.83%)
    47 / 1178 (3.99%)
         occurrences causally related to treatment / all
    2 / 48
    0 / 52
         deaths causally related to treatment / all
    0 / 5
    0 / 11
    Sepsis
         subjects affected / exposed
    4 / 1174 (0.34%)
    3 / 1178 (0.25%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    1 / 1174 (0.09%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Pneumonia bacterial
         subjects affected / exposed
    0 / 1174 (0.00%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 1174 (0.17%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Amoebic dysentery
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    2 / 1174 (0.17%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    7 / 1174 (0.60%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mycobacterium avium complex infection
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subcutaneous abscess
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tooth infection
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         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 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Urosepsis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Viral infection
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic hepatitis C
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (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
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    2 / 1174 (0.17%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    2 / 1174 (0.17%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Systemic candida
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis viral
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchitis bacterial
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Candida infection
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fungal infection
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Furuncle
         subjects affected / exposed
    1 / 1174 (0.09%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nasopharyngitis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Onychomycosis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin infection
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tracheitis
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pharyngitis
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 1174 (0.09%)
    3 / 1178 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 3
    Hyponatraemia
         subjects affected / exposed
    0 / 1174 (0.00%)
    2 / 1178 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cachexia
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Decreased appetite
         subjects affected / exposed
    3 / 1174 (0.26%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    2 / 3
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fluid imbalance
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gout
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperglycaemia
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 1174 (0.00%)
    1 / 1178 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyslipidaemia
         subjects affected / exposed
    1 / 1174 (0.09%)
    0 / 1178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Roflumilast
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    188 / 1174 (16.01%)
    317 / 1178 (26.91%)
    Investigations
    Weight decreased
         subjects affected / exposed
    27 / 1174 (2.30%)
    91 / 1178 (7.72%)
         occurrences all number
    28
    91
    Nervous system disorders
    Headache
         subjects affected / exposed
    48 / 1174 (4.09%)
    80 / 1178 (6.79%)
         occurrences all number
    56
    96
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    36 / 1174 (3.07%)
    119 / 1178 (10.10%)
         occurrences all number
    38
    137
    Nausea
         subjects affected / exposed
    30 / 1174 (2.56%)
    62 / 1178 (5.26%)
         occurrences all number
    32
    71
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    66 / 1174 (5.62%)
    60 / 1178 (5.09%)
         occurrences all number
    103
    75

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Aug 2011
    • Per FDA request, an MMRM would be used for the secondary efficacy parameter. The dependent variable would be the change from randomization (Visit 2) to each scheduled post-randomization visit (encompassing all available measurements in a patient) during the treatment period • Stratification up to 60% of patients on LAMA added onto ICS/LABA • As per FDA request, changed the inclusion criterion for FEV1 predicted from < 60% to ≤ 50% • Defined counting and merging exacerbations occurring within 10 days of each other as a single exacerbation • Added urine pregnancy testing to Visit 4, 5, 6, 7, and 8 for women of childbearing potential • Per FDA request, added follow-up visit assessments for patients discontinuing, including FEV1, exacerbation, safety, and concomitant medication data collection • Decreased the washout period for theophylline from 3 months to 1 month prior to enrollment
    02 Feb 2012
    • MACE and the specified subcategories of MACE would be presented by treatment group • MACE would be evaluated according to pre-defined criteria by a MACE Adjudication Committee • Provided a clarification of the assessments to be performed in patients who discontinued double-blind investigational product • Provided clarifications to the inclusion and exclusion criteria and the schedule of evaluations • Provided additional information on the C-SSRS and administration of the eC-SSRS • Provided additional information on the sensitivity analyses to be performed for the primary and secondary efficacy parameters
    15 May 2013
    • With respect to FEV1 measurements, changed the term prebronchodilator to predose • Clarified how to handle missed and skipped visits • Added guidance on how to prepare a patient for the screening visit • Updated the MACE section that reflected what was written in the Committee Charter • Updated drug dispensing table • Clarified the reading of ECGs
    02 Apr 2014
    • COPD exacerbations that met criteria for an SAE were recorded in the COPD exacerbation section of the EDC as soon as possible after their occurrence and were subject to on-going safety monitoring and evaluation • Examples of acceptable qualifying documentation for COPD exacerbations were added to the inclusion criteria, while a patient interview was removed as an acceptable method of documentation • An offset variable in the negative binomial model for COPD exacerbations was added to exclude the days during which new exacerbations could not occur; ie, the days when the patient was experiencing existing moderate or severe exacerbations and 10 days after each moderate or severe exacerbation • Additional telephone contacts were added so patients were assessed for COPD exacerbations every 4 weeks between visits • PK sampling instructions were clarified and updated in text and in Appendix IV • Appendices VII (Daliresp package insert), VIII (Advair package insert), and IX (Symbicort package insert) of the protocol were updated
    06 Aug 2015
    Added 2 secondary efficacy endpoints (rate of COPD exacerbations that led to hospitalization or death [ie, severe COPD exacerbations] and rate of moderate or severe COPD exacerbations or COPD exacerbations treated with antibiotics), which were previously identified as additional efficacy parameters • Replaced the Poisson regression with Pearson Chi-square correction for scale with the Poisson regression with robust variance estimate using the sandwich method, for consistency with statistical methods for other exacerbation endpoints • Required the assessment of Hy’s Law criteria as a laboratory assessment and described how the data would be summarized

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

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