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    Clinical Trial Results:
    A 12-month, open label, randomised, effectiveness study to evaluate fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) Inhalation Powder delivered once daily via a Novel Dry Powder Inhaler (NDPI) compared with the existing COPD maintenance therapy alone in subjects with Chronic Obstructive Pulmonary Disease (COPD).

    Summary
    EudraCT number
    2011-002452-13
    Trial protocol
    GB  
    Global end of trial date
    24 Nov 2015

    Results information
    Results version number
    v2(current)
    This version publication date
    10 Jun 2017
    First version publication date
    21 Sep 2016
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    95% CIs additionally presented for the LS mean annual rate.

    Trial information

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    Trial identification
    Sponsor protocol code
    HZC115151
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    Clincial Trials Helpdesk, GlaxoSmithKline Research & Development Ltd, +44 0208990 44 66, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clincial Trials Helpdesk, GlaxoSmithKline Research & Development Ltd, +44 0208990 44 66, GSKClinicalSupportHD@gsk.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
    23 May 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
    The objective of the study is to compare the effectiveness and safety of fluticasone furoate (FF)/vilanterol (VI) Inhalation Powder 100mcg/25mcg with other maintenance therapy over twelve months in a large UK primary care population of subjects with COPD. FF/VI will be administered once-daily (QD) in the morning via the Novel Dry Powder Inhaler (NDPI).
    Protection of trial subjects
    N/A
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Mar 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 3161
    Worldwide total number of subjects
    3161
    EEA total number of subjects
    3161
    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)
    1242
    From 65 to 84 years
    1804
    85 years and over
    115

    Subject disposition

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    Recruitment
    Recruitment details
    This was a multicenter, randomized, stratified, open-label study to evaluate the effectiveness and safety of fluticasone fuorate (FF)/vilanterol (VI) in participants (Par) followed in primary care who had a diagnosis of and received regular treatment for Chronic Obstructive Pulmonary Disease (COPD).

    Pre-assignment
    Screening details
    Participants (par.) were randomized 1:1 to receive 1 inhalation of FF/VI 100 microgram (mcg)/25 mcg once daily (QD) or continued their existing maintenance therapy for 12 months. 2802 par. were randomized (3 par. randomized to the FF/VI arm did not receive study medication). A total of 2799 par. comprised the Intent to Treat (ITT) Population.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Usual Care
    Arm description
    Participants continued their existing maintenance therapy that included one of the following: an inhaled corticosteroid (ICS) alone or Long Acting Beta Agonist (LABA) alone or Long Acting Muscarinic Antagonist (LAMA) alone or combination of any two (ICS+LABA/ ICS+LAMA/ LABA+LAMA) or triple therapy (ICS+LABA+LAMA) at the appropriate dosing schedule, for 12 months.
    Arm type
    Active comparator

    Investigational medicinal product name
    Usual Care (LABA or LABA/LAMA or ICS or ICS/LABA or LABA or ICS/LABA+LAMA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Inhaled corticosteroid alone or in combination with a long acting bronchodilator or, Long-acting bronchodilator alone or, triple maintenance therapy At appropriate dosing as instructed

    Arm title
    Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Arm description
    Participants were prescribed one inhalation of fluticasone fuorate /vilaneterol (FF/VI) 100 mcg/25 mcg via dry powder inhaler (DPI) once daily in the morning for 12 months in lieu of existing maintenance therapy. Participants on previous triple therapy received LAMA therapy additionally.
    Arm type
    Experimental

    Investigational medicinal product name
    FF 100 mcg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    It is available as dry white powder containing 100 mcg of Fluticasone Furoate blended with lactose per blister and was administered by DPI, once daily in the morning.

    Investigational medicinal product name
    VI 25 mcg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour, powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    It is available as dry white powder containing 25 mcg of Vilanterol micronized drug (as the 'M' salt triphenylacetate) blended with lactose and magnesium stearate per blister and was administered by DPI, once daily in the morning.

    Number of subjects in period 1 [1]
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Started
    1403
    1396
    Completed
    1309
    1291
    Not completed
    94
    105
         Protocol deviation
    5
    6
         Physician decision
    9
    3
         Lack of efficacy
    -
    1
         Met Protocol-defined stopping criteria
    8
    10
         Adverse event, serious fatal
    29
    43
         Consent withdrawn by subject
    14
    17
         Lost to follow-up
    29
    25
    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: There were a total of 3161 participants enrolled into this study and 2799 participants were included in the ITT population (all randomised participants who received a prescription of study medication).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Usual Care
    Reporting group description
    Participants continued their existing maintenance therapy that included one of the following: an inhaled corticosteroid (ICS) alone or Long Acting Beta Agonist (LABA) alone or Long Acting Muscarinic Antagonist (LAMA) alone or combination of any two (ICS+LABA/ ICS+LAMA/ LABA+LAMA) or triple therapy (ICS+LABA+LAMA) at the appropriate dosing schedule, for 12 months.

    Reporting group title
    Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Reporting group description
    Participants were prescribed one inhalation of fluticasone fuorate /vilaneterol (FF/VI) 100 mcg/25 mcg via dry powder inhaler (DPI) once daily in the morning for 12 months in lieu of existing maintenance therapy. Participants on previous triple therapy received LAMA therapy additionally.

    Reporting group values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg Total
    Number of subjects
    1403 1396 2799
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    66.7 ± 9.93 66.6 ± 9.9 -
    Gender categorical
    Units: Subjects
        Female
    671 698 1369
        Male
    732 698 1430
    Race
    Units: Subjects
        African American/African Heritage
    3 5 8
        Asian-Central/South Asian Heritage
    5 6 11
        Asian-East Asian Heritage
    1 0 1
        Asian-South East Asian Heritage
    1 0 1
        White-Arabic/North African Heritage
    1 3 4
        White-White/Caucasian/European Heritage
    1387 1376 2763
        Mixed Race
    5 5 10
        Unknown
    0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Usual Care
    Reporting group description
    Participants continued their existing maintenance therapy that included one of the following: an inhaled corticosteroid (ICS) alone or Long Acting Beta Agonist (LABA) alone or Long Acting Muscarinic Antagonist (LAMA) alone or combination of any two (ICS+LABA/ ICS+LAMA/ LABA+LAMA) or triple therapy (ICS+LABA+LAMA) at the appropriate dosing schedule, for 12 months.

    Reporting group title
    Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Reporting group description
    Participants were prescribed one inhalation of fluticasone fuorate /vilaneterol (FF/VI) 100 mcg/25 mcg via dry powder inhaler (DPI) once daily in the morning for 12 months in lieu of existing maintenance therapy. Participants on previous triple therapy received LAMA therapy additionally.

    Primary: Mean Annual Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations

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    End point title
    Mean Annual Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations
    End point description
    Mean annual rate of moderate or severe COPD exacerbations during treatment were assessed. Moderate exacerbation: participant received exacerbation-related prescription of oral corticosteroids and/ or antibiotic (with/without National Health Service [NHS] contact) not requiring hospitalisation. Severe exacerbation: an exacerbation-related hospitalisation. Analysis method was Generalised Linear Model (GLM) assuming the negative binomial distribution with a log-link function and logarithm of time on treatment as an offset variable, adjusted for randomized treatment, baseline COPD maintenance therapy per randomisation stratification, number of moderate/severe COPD exacerbations in previous year and smoking status at baseline. Intent to treat (ITT) population: all randomised participants who received a prescription of study medication. Primary Efficacy Analysis Population: all ITT participants who had at least one moderate/severe exacerbation in the year prior to randomization.
    End point type
    Primary
    End point timeframe
    Up to 54 weeks
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1134
    1135
    Units: Exacerbations per participant per year
        least squares mean (confidence interval 95%)
    1.9 (1.8 to 2.01)
    1.74 (1.65 to 1.84)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg v Usual Care
    Number of subjects included in analysis
    2269
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.025
    Method
    Generalized Linear Model
    Parameter type
    Adjusted treatment ratio
    Point estimate
    0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    0.99

    Secondary: Number of participants with serious adverse events (SAEs) of penumonia during the study

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    End point title
    Number of participants with serious adverse events (SAEs) of penumonia during the study
    End point description
    Incidence of SAE of pneumonia was defined for each randomized treatment group as the proportion (number) of participants in that group who experienced at least one SAE of pneumonia in the Pneumonia Adverse Event of Special Interest subgroup during the treatment period (from start date of exposure to stop date of exposure + 28 days). Non-inferiority is demonstrated if the upper limit of the two-sided 95% confidence interval for the incidence ratio is less than 2.
    End point type
    Secondary
    End point timeframe
    Up to 58 weeks
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403 [1]
    1396 [2]
    Units: Participants
        number (not applicable)
    83
    94
    Notes
    [1] - ITT Population
    [2] - ITT Population
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Estimation comments: Calculated as % of participants who had at least one SAE of pneumonia in the FF/VI group divided by the % of participants who had at least one SAE of pneumonia in the Usual Care group
    Comparison groups
    Usual Care v Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects included in analysis
    2799
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Parameter type
    Incidence ratio
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    1.5

    Secondary: Mean number of serious adverse events of pnuemonia during the study

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    End point title
    Mean number of serious adverse events of pnuemonia during the study
    End point description
    The mean number of SAE of pneumonia over the treatment period (from first date of exposure to last date of exposure + 28 days was calculated. Analysis was performed using a negative binomial regression model with covariates of randomized treatment and with logarithm of time on treatment as an offset variable.
    End point type
    Secondary
    End point timeframe
    Up to 58 weeks
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403
    1396
    Units: Mean Number of SAE
        least squares mean (confidence interval 95%)
    0.07 (0.06 to 0.09)
    0.08 (0.06 to 0.09)
    Statistical analysis title
    Statistical Ananlysis 1
    Comparison groups
    Usual Care v Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects included in analysis
    2799
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.632
    Method
    Generalized Linear Model
    Parameter type
    Adjusted treatment ratio
    Point estimate
    1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    1.47

    Secondary: Time to the first serious adverse event of pneumonia occuring in a year

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    End point title
    Time to the first serious adverse event of pneumonia occuring in a year
    End point description
    The analysis method was a Cox proportional hazards model adjusted for randomized treatment. Analyses included those on-treatment SAEs of pneumonia that had an onset over the first 364 days of exposure, as defined. Participants who did not have an SAE of pneumonia during the first 364 days of the treatment period (start date of exposure to end date of exposure + 28 days were considered censored.
    End point type
    Secondary
    End point timeframe
    Up to 52 weeks
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403 [3]
    1396 [4]
    Units: Participants
        number (not applicable)
    80
    89
    Notes
    [3] - ITT Population
    [4] - ITT Population
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Usual Care v Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects included in analysis
    2799
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.439
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.52

    Secondary: Number of COPD-related secondary care contacts expressed as Least Square Mean

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    End point title
    Number of COPD-related secondary care contacts expressed as Least Square Mean
    End point description
    A COPD-related secondary care contact was defined as an inpatient admission or a specialist outpatient visit or an accident & emergency (A&E) contact. A participant with an A&E contact and subsequent inpatient admission was considered to have had two healthcare contacts. Inpatient admissions recorded at two hospitals on the same day, this was counted as a single (inpatient admission) secondary care contact. COPD-related contacts were identified using predefined lists of ICD-10 codes, specialty descriptions and diagnosis codes recorded in the patients electronic health record (EHR). GLM assuming the negative binomial distribution with log-link function and logarithm of time on treatment as an offset variable and adjusted for randomised treatment, baseline COPD maintenance therapy per randomisation stratification, number of moderate/severe COPD exacerbations in the previous year to randomisation and smoking status at baseline.
    End point type
    Secondary
    End point timeframe
    Up to 54 weeks
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403
    1396
    Units: Contacts per participant per year
        least squares mean (confidence interval 95%)
    1.48 (1.3 to 1.67)
    1.57 (1.39 to 1.78)
    Statistical analysis title
    Statistical Ananlysis 1
    Comparison groups
    Usual Care v Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects included in analysis
    2799
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.488
    Method
    Generalized linear model
    Parameter type
    Adjusted treatment ratio
    Point estimate
    1.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.27

    Secondary: Number of COPD-related primary care contacts expressed using Least Square Mean

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    End point title
    Number of COPD-related primary care contacts expressed using Least Square Mean
    End point description
    A COPD-related primary care contact was defined as a primary care contact on a given calendar date with either a nurse, general physician (GP) or other healthcare professional that were considered as COPD-related, if the most prominent signs and symptoms the participant was presenting were as a direct result of the participant's COPD, as per Readcodes recorded in the patients electronic health record (EHR). The analysis method was General Linear Model assuming an underlying negative binomial distribution with a log-link function and logarithm of time on treatment as an offset variable and adjusted for randomised treatment, baseline COPD maintenance therapy per randomisation stratification, number of moderate/severe COPD exacerbations in the previous year to randomisation and smoking status at baseline.
    End point type
    Secondary
    End point timeframe
    Up to 54 weeks
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403
    1396
    Units: Contacts per participant per year
        least squares mean (confidence interval 95%)
    2.46 (2.34 to 2.58)
    2.42 (2.3 to 2.53)
    Statistical analysis title
    Statistical Ananlysis 1
    Comparison groups
    Usual Care v Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects included in analysis
    2799
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.622
    Method
    Generalized Linear Model
    Parameter type
    Adjusted treatment ratio
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.92
         upper limit
    1.05

    Secondary: Number of all secondary care contacts expressed using Least Square Mean

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    End point title
    Number of all secondary care contacts expressed using Least Square Mean
    End point description
    A secondary care contact was defined as an inpatient admission or a specialist outpatient visit or an A&E contact. A participant with an A&E contact and subsequent inpatient admission was considered to have had two healthcare contacts. In the situation where inpatient admissions were recorded at two hospitals on the same day, this was counted as a single secondary care contact. The analysis method was General Linear Model assuming an underlying negative binomial distribution with a log-link function and logarithm of time on treatment as an offset variable and adjusted for randomised treatment, baseline COPD maintenance therapy per randomization stratification, number of moderate/severe COPD exacerbations in the previous year to randomization and smoking status at baseline.
    End point type
    Secondary
    End point timeframe
    Up to 54 weeks
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403
    1396
    Units: Contacts per participant per year
        least squares mean (confidence interval 95%)
    9.36 (8.74 to 10.02)
    9.81 (9.17 to 10.51)
    Statistical analysis title
    Statistical Ananlysis 1
    Comparison groups
    Usual Care v Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects included in analysis
    2799
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.336
    Method
    Generalized Linear Model
    Parameter type
    Adjusted treatment ratio
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.95
         upper limit
    1.15

    Secondary: Number of all primary care contacts expressed using Least Square Mean

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    End point title
    Number of all primary care contacts expressed using Least Square Mean
    End point description
    A primary care contact was defined as contact with a either a nurse, general practitioner, or other healthcare professional. The analysis method was General Linear Model assuming an underlying negative binomial distribution with a log-link function and logarithm of time on treatment as an offset variable and adjusted for randomized treatment, baseline COPD maintenance therapy per randomization stratification, number of moderate/severe COPD exacerbations in the previous year to randomization and smoking status at baseline.
    End point type
    Secondary
    End point timeframe
    Up to 54 weeks
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403
    1396
    Units: Contacts per participant per year
        least squares mean (confidence interval 95%)
    18.88 (18.06 to 19.74)
    21.2 (20.27 to 22.16)
    Statistical analysis title
    Statistical Ananlysis 1
    Comparison groups
    Usual Care v Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects included in analysis
    2799
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Generalized Linear Model
    Parameter type
    Adjusted treatment ratio
    Point estimate
    1.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.05
         upper limit
    1.2

    Secondary: Time to an event of discontinuation of initial therapy occurring in a year

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    End point title
    Time to an event of discontinuation of initial therapy occurring in a year
    End point description
    Initial therapy was defined as the treatment that the subject was randomised to at randomisation. Discontinuation of initial therapy was defined as any modification of initial therapy. These included stepping up, stepping down or switching to another class/class combination, or withdrawal from the study. Switching within the same drug class did not count unless participant switched from FF/VI to a different ICS/LABA. The analysis method was a Cox proportional hazards model adjusted for randomized treatment. The probability of discontinuation of initial therapy was measured from the date of randomisation (i.e., exposure start date) to the date of discontinuation of initial therapy to which the participant was randomized, or date of treatment termination (Visit 6 or early withdrawal visit) for participants who completed the study without discontinuing the initial therapy (censored).
    End point type
    Secondary
    End point timeframe
    Up to 364 days
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403 [5]
    1396 [6]
    Units: Participants
        number (not applicable)
    219
    374
    Notes
    [5] - ITT Population
    [6] - ITT Population
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Estimation comments: A hazard ratio <1 indicates a lower risk with FF/VI compared with Usual Care.
    Comparison groups
    Usual Care v Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects included in analysis
    2799
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.6
         upper limit
    2.23

    Secondary: Time to the addition of a further COPD controller medication occurring in a year

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    End point title
    Time to the addition of a further COPD controller medication occurring in a year
    End point description
    The date of an event for addition of a further COPD controller medication was defined as the exposure start date of the first modified treatment medication that included a new COPD maintenance therapy of a new class of drug (to the initial therapy) during the study treatment period, as collected on the investigational product page of the eCRF. Participants who did not add any COPD controller medication during the study were censored at the end of the treatment period (Day 364). This was equivalent to stepping up, defined as the addition of at least one new class of drug. The probability of an event was measured from the date of randomization (i.e., treatment initiation) to the date of a change event. The analysis method was a Cox proportional hazards model adjusted for randomized treatment.
    End point type
    Secondary
    End point timeframe
    Up to 364 days
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403 [7]
    1396 [8]
    Units: Participants
        number (not applicable)
    142
    72
    Notes
    [7] - ITT Population
    [8] - ITT Population
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Estimation comments: A hazard ratio <1 indicates a lower risk with FF/VI compared with Usual Care
    Comparison groups
    Usual Care v Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects included in analysis
    2799
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Cox proprotional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.37
         upper limit
    0.66

    Secondary: Time to first moderate/severe exacerbations occurring in a year

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    End point title
    Time to first moderate/severe exacerbations occurring in a year
    End point description
    The date of an event for moderate / severe COPD exacerbation was defined as the exacerbation onset date. The analysis method was a Cox proportional hazards model adjusted for randomized treatment. The probability of a first moderate / severe exacerbation was measured from the date of randomization (i.e., treatment initiation) to the onset date of first moderate or severe COPD exacerbation, as recorded on eCRF, or date of treatment termination (Visit 6 or early withdrawal visit) for participants who completed the study without any moderate or severe exacerbations (censored). Participants who completed the study without a moderate or severe COPD exacerbation and analyses of time to first moderate/severe exacerbation were censored at Day 364.
    End point type
    Secondary
    End point timeframe
    Up to 364 days
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403 [9]
    1396 [10]
    Units: Participants
        number (not applicable)
    977
    947
    Notes
    [9] - ITT Population
    [10] - ITT Population
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Estimation comments: A hazard ratio <1 indicates a lower risk with FF/VI compared with Usual Care
    Comparison groups
    Usual Care v Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects included in analysis
    2799
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.111
    Method
    Cox porportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    1.02

    Secondary: Time to first moderate/severe exacerbations on initial therapy occurring in a year

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    End point title
    Time to first moderate/severe exacerbations on initial therapy occurring in a year
    End point description
    The date of an event for moderate / severe COPD exacerbation was defined as the exacerbation onset date. The analysis method was a Cox proportional hazards model adjusted for randomized treatment. The probability of first moderate / severe exacerbation on initial therapy was measured from the date of randomization (i.e., exposure start date) to the onset date of first moderate or severe COPD exacerbation, or to the date of discontinuation of initial therapy (analysis was censored at date of discontinuation of initial therapy) for participants who completed the study without any moderate or severe exacerbations on initial therapy.
    End point type
    Secondary
    End point timeframe
    Up to 364 days
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403 [11]
    1396 [12]
    Units: Participants
        number (not applicable)
    943
    852
    Notes
    [11] - ITT Population
    [12] - ITT Population
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Usual Care v Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects included in analysis
    2799
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.081
    Method
    Cox porportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.84
         upper limit
    1.01

    Secondary: Time to first severe exacerbations occurring in a year

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    End point title
    Time to first severe exacerbations occurring in a year
    End point description
    The date of an event for severe exacerbation was defined as the exacerbation onset date. Participants who completed the study without a severe exacerbation were censored. The analysis method was a Cox proportional hazards model adjusted for randomized treatment. The probability of first severe exacerbation was measured from the date of randomization (i.e., treatment initiation) to the onset date of first severe exacerbation, as recorded on eCRF, or date of treatment termination (Visit 6 or early withdrawal visit) for participants who completed the study without any severe exacerbations (censored). At Day 364, all participants who have not experienced a severe exacerbation are considered censored, regardless of whether their on-treatment phase continues beyond day 364, including those who withdrew early.
    End point type
    Secondary
    End point timeframe
    Up to 364 days
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403 [13]
    1396 [14]
    Units: Participants
        number (not applicable)
    97
    122
    Notes
    [13] - ITT Population
    [14] - ITT Population
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Usual Care v Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects included in analysis
    2799
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.075
    Method
    Cox porportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.98
         upper limit
    1.66

    Secondary: Number of participants with Fatal serious adverse events of pneumonia

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    End point title
    Number of participants with Fatal serious adverse events of pneumonia
    End point description
    All SAEs included in the AE subgroup of special interest of “pneumonia” were considered as an SAE of pneumonias. A fatal SAE was defined as a SAE with outcome of fatal for study participant. The number of participants with fatal SAEs of pneumonia was assessed over 14 months.
    End point type
    Secondary
    End point timeframe
    Up to 58 weeks
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403 [15]
    1396 [16]
    Units: Participants
        number (not applicable)
    13
    13
    Notes
    [15] - ITT Population
    [16] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of participants with non-serious adverse drug reactions (ADR)

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    End point title
    Number of participants with non-serious adverse drug reactions (ADR)
    End point description
    The number of participants with non-serious ADRs was assessed for up to 54 weeks. An ADR is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, for which there is a reasonable possibility that the untoward occurrence is causally related to the medicinal product. A non-serious ADR included one of the following: exacerbation of chronic or intermittent pre-existing condition; signs, symptoms, or the clinical sequelae of a suspected interaction; signs, symptoms, or new conditions detected or diagnosed after study treatment administration.
    End point type
    Secondary
    End point timeframe
    Up to 54 weeks
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403 [17]
    1396 [18]
    Units: Participants
        number (not applicable)
    88
    192
    Notes
    [17] - ITT Population
    [18] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of participants with serious adverse events

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    End point title
    Number of participants with serious adverse events
    End point description
    SAEs assessed included medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a significant medical event in the investigator's judgment, or is an event of possible drug-induced liver injury with hyperbilirubinemia. SAEs were includes if the onset date was on or after the treatment start date and on or before the treatment stop date. However, the window for an SAE of pneumonia was longer and included 28 days post study treatment stop date.
    End point type
    Secondary
    End point timeframe
    Up to 56 weeks
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403 [19]
    1396 [20]
    Units: Participants
        number (not applicable)
    383
    404
    Notes
    [19] - ITT Population
    [20] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of participants with serious adverse drug reactions

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    End point title
    Number of participants with serious adverse drug reactions
    End point description
    A serious adverse drug reactions (SADR) is any untoward medical occurrence suspected to be medicinal product-related that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
    End point type
    Secondary
    End point timeframe
    Upto 12 months
    End point values
    Usual Care Fluticasone fuorate (FF)/Vilanterol (VI) 100 mcg/25 mcg
    Number of subjects analysed
    1403 [21]
    1396 [22]
    Units: Participants
        number (not applicable)
    10
    23
    Notes
    [21] - ITT Population
    [22] - ITT Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs; from Visit 1) and non-serious AE and adverse drug reactions (from Visit 2) were collected from study medication start until the end of treatment (up to Visit 6 or withdrawal, i.e, approximately 54 weeks)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Usual Care
    Reporting group description
    Participants continued their existing maintenance therapy that included one of the following: an inhaled corticosteroid (ICS) alone or Long Acting Beta Agonist (LABA) alone or Long Acting Muscarinic Antagonist (LAMA) alone or combination of any two (ICS+LABA/ ICS+LAMA/ LABA+LAMA) or triple therapy (ICS+LABA+LAMA) at the appropriate dosing schedule, for 12 months

    Reporting group title
    FF/VI 100 mcg/25 mcg
    Reporting group description
    Participants were prescribed one inhalation of fluticasone fuorate /vilaneterol (FF/VI) 100 mcg/25 mcg via dry powder inhaler (DPI) once daily in the morning for 12 months in lieu of existing maintenance therapy. Participants on previous triple therapy received LAMA therapy additionally.

    Serious adverse events
    Usual Care FF/VI 100 mcg/25 mcg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    383 / 1403 (27.30%)
    404 / 1396 (28.94%)
         number of deaths (all causes)
    50
    77
         number of deaths resulting from adverse events
    Vascular disorders
    Angiodysplasia
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    3 / 1403 (0.21%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aortic aneurysm rupture
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Aortic dissection
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    2 / 1403 (0.14%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aortic thrombosis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure inadequately controlled
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    3 / 1403 (0.21%)
    9 / 1396 (0.64%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Extremity necrosis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery occlusion
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    3 / 1403 (0.21%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 1403 (0.21%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 1403 (0.00%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         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
    2 / 1403 (0.14%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Carotid endarterectomy
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hospitalisation
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 1403 (0.14%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    1 / 1403 (0.07%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen’s disease
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 1403 (0.07%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoma in situ of skin
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid body tumour
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia recurrent
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colon adenoma
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon neoplasm
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal carcinoma
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioblastoma multiforme
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Glottis carcinoma
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer metastatic
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic neoplasm
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    1 / 1403 (0.07%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung cancer metastatic
         subjects affected / exposed
    1 / 1403 (0.07%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung carcinoma cell type unspecified recurrent
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    7 / 1403 (0.50%)
    10 / 1396 (0.72%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 5
    Lung squamous cell carcinoma recurrent
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung squamous cell carcinoma stage 0
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung squamous cell carcinoma stage IV
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lymphoma
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mantle cell lymphoma
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    3 / 1403 (0.21%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Metastases to lung
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 1403 (0.00%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer recurrent
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    3 / 1403 (0.21%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Refractory anaemia with an excess of blasts
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (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
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of Lung
         subjects affected / exposed
    2 / 1403 (0.14%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ureteral neoplasm
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric cancer
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Allergic granulomatous angiitis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Drug hypersensitivity
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    2 / 1403 (0.14%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    8 / 1403 (0.57%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyst
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         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 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 1403 (0.07%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stent-graft endoleak
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unintentional medical device removal
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular stent occlusion
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    1 / 1403 (0.07%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    2 / 1403 (0.14%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    2 / 1403 (0.14%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium tremens
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    3 / 1403 (0.21%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Self-injurious ideation
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 1403 (0.07%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Postmenopausal haemorrhage
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    4 / 1403 (0.29%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    5 / 1403 (0.36%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brachial plexus injury
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac valve rupture
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chemical injury
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest injury
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contrast media reaction
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    9 / 1403 (0.64%)
    15 / 1396 (1.07%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    3 / 1403 (0.21%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 1403 (0.14%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    2 / 1403 (0.14%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    2 / 1403 (0.14%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign body aspiration
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    4 / 1403 (0.29%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    2 / 1403 (0.14%)
    8 / 1396 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         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
    3 / 1403 (0.21%)
    5 / 1396 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    2 / 1403 (0.14%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    3 / 1403 (0.21%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Open fracture
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    3 / 1403 (0.21%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         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 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation mucositis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (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
    5 / 1403 (0.36%)
    8 / 1396 (0.57%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    9 / 1403 (0.64%)
    5 / 1396 (0.36%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Stress fracture
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    3 / 1403 (0.21%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 1403 (0.00%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral injury
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    2 / 1403 (0.14%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood electrolytes abnormal
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 1403 (0.14%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    2 / 1403 (0.14%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    6 / 1403 (0.43%)
    15 / 1396 (1.07%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic specific antigen increased
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal function test abnormal
         subjects affected / exposed
    9 / 1403 (0.64%)
    12 / 1396 (0.86%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 1403 (0.07%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    12 / 1403 (0.86%)
    5 / 1396 (0.36%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    9 / 1403 (0.64%)
    13 / 1396 (0.93%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 15
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Angina pectoris
         subjects affected / exposed
    9 / 1403 (0.64%)
    5 / 1396 (0.36%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    4 / 1403 (0.29%)
    5 / 1396 (0.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 1403 (0.07%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    29 / 1403 (2.07%)
    27 / 1396 (1.93%)
         occurrences causally related to treatment / all
    1 / 33
    2 / 28
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Atrial flutter
         subjects affected / exposed
    2 / 1403 (0.14%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 1403 (0.14%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure
         subjects affected / exposed
    11 / 1403 (0.78%)
    10 / 1396 (0.72%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    5 / 1403 (0.36%)
    6 / 1396 (0.43%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cor pulmonale
         subjects affected / exposed
    2 / 1403 (0.14%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diastolic dysfunction
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    4 / 1403 (0.29%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    3 / 1403 (0.21%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    3 / 1403 (0.21%)
    6 / 1396 (0.43%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    3 / 1403 (0.21%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Palpitations
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 1403 (0.00%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 1403 (0.00%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trifascicular block
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    3 / 1403 (0.21%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 1403 (0.14%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial secretion retention
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    4 / 1403 (0.29%)
    6 / 1396 (0.43%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    70 / 1403 (4.99%)
    86 / 1396 (6.16%)
         occurrences causally related to treatment / all
    1 / 82
    4 / 94
         deaths causally related to treatment / all
    0 / 4
    0 / 5
    Dyspnoea
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    3 / 1403 (0.21%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 1403 (0.07%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pickwickian syndrome
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural fibrosis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         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 / 1403 (0.07%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonitis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 1403 (0.14%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 1403 (0.14%)
    8 / 1396 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    1 / 3
    Pulmonary hypertension
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    9 / 1403 (0.64%)
    5 / 1396 (0.36%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    24 / 1403 (1.71%)
    15 / 1396 (1.07%)
         occurrences causally related to treatment / all
    0 / 28
    0 / 18
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sputum retention
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    6 / 1403 (0.43%)
    5 / 1396 (0.36%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coagulopathy
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microcytic anaemia
         subjects affected / exposed
    4 / 1403 (0.29%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normochromic normocytic anaemia
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pernicious anaemia
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Basal ganglia infarction
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Brain mass
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery aneurysm
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery disease
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid sinus syndrome
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    1 / 1403 (0.07%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    5 / 1403 (0.36%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cerebrovascular disorder
         subjects affected / exposed
    2 / 1403 (0.14%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cervical myelopathy
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia with Lewy bodies
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug withdrawal convulsions
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    6 / 1403 (0.43%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningism
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peroneal nerve palsy
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (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
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculitis brachial
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sedation
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    4 / 1403 (0.29%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    10 / 1403 (0.71%)
    11 / 1396 (0.79%)
         occurrences causally related to treatment / all
    0 / 10
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    9 / 1403 (0.64%)
    5 / 1396 (0.36%)
         occurrences causally related to treatment / all
    1 / 11
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unresponsive to stimuli
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIth nerve paralysis
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular dementia
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paresis
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness unilateral
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    2 / 1403 (0.14%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 1403 (0.29%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Barrett’s oesophagus
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coeliac disease
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 1403 (0.07%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 1403 (0.07%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    5 / 1403 (0.36%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 1403 (0.14%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyskinesia oesophageal
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric dysplasia
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 1403 (0.14%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 1403 (0.07%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (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
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    2 / 1403 (0.14%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal obstruction
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Large intestine perforation
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal spasm
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic insufficiency
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 1403 (0.14%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 1403 (0.07%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    1 / 1403 (0.07%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 1403 (0.14%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 1403 (0.07%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    16 / 1403 (1.14%)
    23 / 1396 (1.65%)
         occurrences causally related to treatment / all
    0 / 19
    1 / 24
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Acute prerenal failure
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    5 / 1403 (0.36%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    3 / 1403 (0.21%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal artery stenosis
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal disorder
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    7 / 1403 (0.50%)
    10 / 1396 (0.72%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal mass
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sterile pyuria
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    7 / 1403 (0.50%)
    8 / 1396 (0.57%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Alcoholic liver disease
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 1403 (0.00%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    3 / 1403 (0.21%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 1403 (0.07%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 1403 (0.00%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder perforation
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (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 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic function abnormal
         subjects affected / exposed
    3 / 1403 (0.21%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    3 / 1403 (0.21%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Miliaria
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (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
    Arthritis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (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
    3 / 1403 (0.21%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Compartment syndrome
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (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
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle necrosis
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    6 / 1403 (0.43%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    1 / 1403 (0.07%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue swelling
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism primary
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 1403 (0.07%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inappropriate antidiuretic ormone secretion
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 1403 (0.14%)
    6 / 1396 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    6 / 1403 (0.43%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    2 / 1403 (0.14%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemochromatosis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 1403 (0.07%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperosmolar hyperglycaemic state
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 1403 (0.07%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 1403 (0.14%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    2 / 1403 (0.14%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    7 / 1403 (0.50%)
    7 / 1396 (0.50%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    3 / 1403 (0.21%)
    5 / 1396 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Type 2 diabetes mellitus
         subjects affected / exposed
    5 / 1403 (0.36%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    2 / 1403 (0.14%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abscess limb
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess oral
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical mycobacterial infection
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    2 / 1403 (0.14%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 1403 (0.07%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cellulitis
         subjects affected / exposed
    9 / 1403 (0.64%)
    14 / 1396 (1.00%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    2 / 1403 (0.14%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    2 / 1403 (0.14%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    4 / 1403 (0.29%)
    3 / 1396 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 1403 (0.14%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster meningoencephalitis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         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
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    47 / 1403 (3.35%)
    50 / 1396 (3.58%)
         occurrences causally related to treatment / all
    0 / 56
    1 / 57
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Influenza
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         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
    10 / 1403 (0.71%)
    12 / 1396 (0.86%)
         occurrences causally related to treatment / all
    1 / 10
    2 / 12
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycetoma mycotic
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 1403 (0.07%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    3 / 1403 (0.21%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    81 / 1403 (5.77%)
    89 / 1396 (6.38%)
         occurrences causally related to treatment / all
    4 / 94
    3 / 98
         deaths causally related to treatment / all
    1 / 13
    0 / 12
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    10 / 1403 (0.71%)
    9 / 1396 (0.64%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic embolus
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 1403 (0.00%)
    2 / 1396 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    12 / 1403 (0.86%)
    9 / 1396 (0.64%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 1403 (0.07%)
    4 / 1396 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 1403 (0.00%)
    1 / 1396 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral labyrinthitis
         subjects affected / exposed
    1 / 1403 (0.07%)
    0 / 1396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    Usual Care FF/VI 100 mcg/25 mcg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 1403 (2.85%)
    56 / 1396 (4.01%)
    Infections and infestations
    Oral candidiasis
    Additional description: In this study, only information regarding non- serious adverse drug reactions (ADRs) and serious adverse events (SAEs) were detected, documented and reported.
         subjects affected / exposed
    40 / 1403 (2.85%)
    56 / 1396 (4.01%)
         occurrences all number
    42
    57

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jul 2013
    Study design was amended: total # of par. required for study; changes (chg) to the Time Interval (int) for Visit 1; clarified the definition of a moderate exacerbation and NHS contacts in relation to the primary endpoint; clarified the secondary endpoint as COPD related rather than respiratory; added the # of actuations in salbutamol inhalers; added changes in relation to childbearing potential and to exclusion criteria 3 in relation to par. with unstable COPD; added chg in relation to ECG QTc prolongation; included the requirement (req) for signed consent form in definition of screen failure; added short-acting-beta2 agonist as generic class; added a statement (stat) on Adherence as Medication (med.) Possession Ratio; added a stat that all concomitant med. used in the study were to be recorded; removed the list of permitted COPD med. and added stat that all COPD med. were permitted with exceptions listed in Section 4.9.2; added new paragraphs in the section on Prohibited Med. and Non-Drug Therapies; amended the Time &Events Table to include chg in the Visit 1 time interval; genetic sampling and height and weight in the demographic information; added a new section Baseline Cardiovascular Co-Morbid Conditions and Severe Pneumonia History; added definition of History of Pneumonia; state that par. unable to perform spirometry would not be excluded; added the FF/VI in Section 5.3.1 to replace study drug or investigational drug; added a new Section 5.1.4 titled Research data not required for eCRF (crude EHR data); added a new genetics section Amend Section 7.2.1 on Sample Size Assumption to take into account reduced # of par.; added a new reference in relation to GOLD in the Primary Objectives; amended the Study Schematic in relation to the time interval at Visit 1 from Day -30 to Day -60; added a new Appendix 10.4 Genetic section; added a new Appendix 10.5 which identifies all the changes to the protocol; and minor formatting changes.
    21 Aug 2013
    Removed Section 5.1.1; History of serious pneumonia, defined as the total number of episodes with a pneumonia diagnosis for the hospitalization, in the 12 months prior to randomization were identified based on the EHR and recorded in the eCRF; added to Section5.1.4: History of serious pneumonia, defined as the total number of episodes with a pneumonia diagnosis for the hospitalization, in the 3 years prior to randomization were identified based on the EHR. In Section 4.4.1, the following text ‘used due to SAE’ was deleted.
    30 Sep 2013
    All references to ‘this protocol amendment’ changed to ‘protocol amendment 1’; all references to Salford, Greater Manchester expanded to Salford and South Manchester, Greater Manchester, to reflect the increase in regional sites. Reference to eligible population in Salford removed as catchment area is now beyond Salford; NHS contacts text changed to include healthcare professionals; withdrawal of FF/VI reference clarified to show they can continue in the study on a maintenance therapy. Reference to study medication clarified to indicate FF/VI medication; reference to concomitant medications used clarified to reflect concomitant medication prescribed and dispensed; reference to collection of pharmacy data ‘drug trade name’ changed to ‘drug name’. Table 2 corrected to remove incorrectly shaded cells. Crude EHR data amended to add additional secondary care site, University Hospital South Manchester. Genetics research; erroneous references added in error and text modified to reflect current standard text.
    09 Dec 2013
    Updated author list; Secondary objectives and safety endpoints updated to include pneumonia SAEs and analysis. Addition of pharmacy EHR as source of dispensing data and exclusion criteria to exclude 8. Subjects whose current medications include RELVAR™, ELLIPTA™ are not eligible to enter the study. If patients change to RELVAR™, ELLIPTA™ as their maintenance therapy, they should be withdrawn from the study. Data Analysis and Statistical Considerations updated to reflect the additional endpoint for pneumonia SAEs; References added.

    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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