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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 compared with usual maintenance therapy in subjects with Asthma

    Summary
    EudraCT number
    		 2011-005553-31
    Trial protocol
    		 GB  
    Global end of trial date
    16 Dec 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    11 Aug 2018
    First version publication date
    22 Dec 2017
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    115150
    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
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    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
    03 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Dec 2016
    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 of fluticasone furoate(FF)/vilanterol (VI) Inhalation Powder (FF 100 micrograms [mcg]/VI 25mcg or FF 200mcg/VI 25mcg) with usual asthma maintenance therapy over twelve months in a large United Kingdom primary care population of subjects with Asthma. FF/VI will be administered once-daily (QD) via the Novel Dry Powder Inhaler (NDPI).
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Nov 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: 4233
    Worldwide total number of subjects
    4233
    EEA total number of subjects
    4233
    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)
    3352
    From 65 to 84 years
    844
    85 years and over
    37

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a multi-center, randomized, open label study to evaluate the effectiveness of fluticasone furoate (FF)/vilanterol (VI) Inhalation Powder (FF 100 micrograms [mcg]/VI 25 mcg or FF 200 mcg/VI 25 mcg) compared with usual asthma maintenance therapy in participants with asthma in a localized geographical region of United Kingdom.

    Pre-assignment
    Screening details
    		 A total of 4725 participants were screened of which 4233 participants were randomized to either initiate with FF/VI or continue their usual asthma maintenance therapy in a ratio of 1:1. The total duration of study was approximately 12 months (52 weeks).

    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 usual asthma maintenance therapy that is, inhaled corticosteroid without a long acting beta2-agonist or inhaled corticosteroid with long acting beta2-agonist combination (either as a fixed dose combination or an inhaled corticosteroid/long acting beta2-agonist provided in two separate inhalers).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Inhaled corticosteroid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants continued their usual asthma maintenance therapy with inhaled corticosteroid.

    Investigational medicinal product name
    Inhaled corticosteroid/long acting beta2-agonist
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants continued their usual asthma maintenance with inhaled corticosteroid/long acting beta2-agonist as a fixed drug combination or via two separate inhalers.

    Arm title
    		 FF/VI
    Arm description
    		 Participants initiated with an appropriate dose of inhaled FF/VI (100 mcg/25 mcg or 200 mcg/25 mcg per actuation) once daily via Novel Dry Powder Inhaler.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FF/VI (200/25 mcg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    200 mcg of FF blended with lactose in the first strip and 25 mcg of VI blended with lactose and magnesium stearate in the second strip was administered via a novel dry powder inhaler.

    Investigational medicinal product name
    FF/VI (100/25 mcg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    100 mcg of FF blended with lactose in the first strip and 25 mcg of VI blended with lactose and magnesium stearate in the second strip was administered via a novel dry powder inhaler.

    Number of subjects in period 1
    		Usual Care FF/VI
    Started
    2119
    2114
    Completed
    1946
    1920
    Not completed
    173
    194
         Physician decision
    23
    37
         Consent withdrawn by subject
    23
    31
         Adverse event, non-fatal
    12
    15
         Lost to follow-up
    97
    93
         Other: Subject reached stopping criteria
    11
    13
         Protocol deviation
    7
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Usual Care
    Reporting group description
    		 Participants continued their usual asthma maintenance therapy that is, inhaled corticosteroid without a long acting beta2-agonist or inhaled corticosteroid with long acting beta2-agonist combination (either as a fixed dose combination or an inhaled corticosteroid/long acting beta2-agonist provided in two separate inhalers).

    Reporting group title
    FF/VI
    Reporting group description
    		 Participants initiated with an appropriate dose of inhaled FF/VI (100 mcg/25 mcg or 200 mcg/25 mcg per actuation) once daily via Novel Dry Powder Inhaler.

    Reporting group values
    		 Usual Care FF/VI Total
    Number of subjects
    		 2119 2114
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.7 ± 16.69 49.9 ± 16.05 -
    Gender categorical
    Units: Subjects
        Female
    		 1241 1257 2498
        Male
    		 878 857 1735
    Race, Customized
    Units: Subjects
        African American/African Heritage
    		 25 40 65
        Asian - Central/South Asian Heritage
    		 35 46 81
        Asian - East Asian Heritage
    		 4 9 13
        Asian - Japanese Heritage
    		 2 0 2
        Asian - South East Asian Heritage
    		 9 18 27
        Native Hawaiian or Other Pacific Islander
    		 1 1 2
        White - Arabic/North African Heritage
    		 6 5 11
        White - White/Caucasian/European Heritage
    		 2002 1971 3973
        Mixed race
    		 33 23 56
        Unknown
    		 2 1 3

    End points

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    End points reporting groups
    Reporting group title
    Usual Care
    Reporting group description
    		 Participants continued their usual asthma maintenance therapy that is, inhaled corticosteroid without a long acting beta2-agonist or inhaled corticosteroid with long acting beta2-agonist combination (either as a fixed dose combination or an inhaled corticosteroid/long acting beta2-agonist provided in two separate inhalers).

    Reporting group title
    FF/VI
    Reporting group description
    		 Participants initiated with an appropriate dose of inhaled FF/VI (100 mcg/25 mcg or 200 mcg/25 mcg per actuation) once daily via Novel Dry Powder Inhaler.

    Primary: Percentage of participants who have either an Asthma Control Test (ACT) total score of >=20 or an increase from Baseline of >=3 in ACT total score at Week 24.

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    End point title
    		 Percentage of participants who have either an Asthma Control Test (ACT) total score of >=20 or an increase from Baseline of >=3 in ACT total score at Week 24.
    End point description
    The ACT is a validated self-administered questionnaire utilizing 5 questions to assess asthma control during the past 4 weeks on a 5-point categorical scale (1 to 5). By answering all 5 questions, participants with asthma obtained an ACT score ranging between 5 and 25. Higher scores indicated better control of asthma. An ACT score of <=15 showed poorly controlled asthma; 16 to 19 showed partly controlled asthma and >=20 showed well controlled asthma. The total score was calculated as the sum of the scores from all 5 questions. The primary efficacy analysis (PEA) Population is defined as all Intent-to-Treat (ITT) participants (that is, all participants who were randomized and received at least one prescription of study medication) who have an ACT total score of <20 at Baseline (Day 0). The percentage of responders that is participants with an ACT total score >=20 or an increase from Baseline of >=3 has been presented
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) and Week 24
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    1399 [1]
    1373 [2]
    Units: Percentage of participants
        Percentage of participants
    56
    71
    Notes
    [1] - PEA Population. Only participants with non-missing ACT score were analyzed.
    [2] - PEA Population. Only participants with non-missing ACT score were analyzed.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Adjusted odds ratio comparing FF/VI with Usual Care has been presented.
    Comparison groups
    Usual Care v FF/VI
    Number of subjects included in analysis
    2772
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [3]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.7
         upper limit
    		 2.34
    Notes
    [3] - The analysis method was logistic regression adjusted for randomized treatment, asthma maintenance therapy (AMT) at Baseline per randomization stratification, Baseline ACT total score, Baseline ACT total score squared, gender and age.

    Secondary: Percentage of participants who have either an ACT total score of >=20 or an increase from Baseline of >=3 in ACT total score at Week 12, 40 and 52.

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    End point title
    		 Percentage of participants who have either an ACT total score of >=20 or an increase from Baseline of >=3 in ACT total score at Week 12, 40 and 52.
    End point description
    The ACT is a validated self-administered questionnaire utilizing 5 questions to assess asthma control during the past 4 weeks on a 5-point categorical scale (1 to 5). By answering all 5 questions, participants with asthma obtained an ACT score ranging between 5 and 25. Higher scores indicated better control of asthma. An ACT score of <=15 showed poorly controlled asthma; 16 to 19 showed partly controlled asthma and >=20 showed well controlled asthma. The total score was calculated as the sum of the scores from all 5 questions. ITT Population comprised of all participants who were randomized and received at least one prescription of study medication. The percentage of responders that is participants with an ACT total score >=20 or an increase from Baseline of >=3 has been presented. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Weeks 12, 40 and 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [4]
    2114 [5]
    Units: Percentage of participants
        Week 12, n=2032, 2009
    62
    75
        Week 40, n=1938, 1904
    60
    71
        Week 52, n=1922, 1896
    58
    70
    Notes
    [4] - ITT Population
    [5] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Adjusted odds ratio comparing FF/VI with Usual Care for Week 12 has been presented. The correct Number of Subjects Included in Analysis is 4041. Due to a system limitation, the value 4233 is incorrectly auto-populated.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [6]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    1.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.67
         upper limit
    		 2.2
    Notes
    [6] - Logistic regression adjusted for randomized treatment, AMT at Baseline per randomization stratification, Baseline ACT total score, Baseline ACT total score squared, gender and age.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Adjusted odds ratio comparing FF/VI with Usual Care for Week 40 has been presented. The correct Number of Subjects Included in Analysis is 3842. Due to a system limitation, the value 4233 is incorrectly auto-populated.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [7]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    1.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.45
         upper limit
    		 1.91
    Notes
    [7] - Logistic regression adjusted for randomized treatment, AMT at Baseline per randomization stratification, Baseline ACT total score, Baseline ACT total score squared, gender and age.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Adjusted odds ratio comparing FF/VI with Usual Care for Week 52 has been presented. The correct Number of Subjects Included in Analysis is 3818. Due to a system limitation, the value 4233 is incorrectly auto-populated.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [8]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    1.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.54
         upper limit
    		 2.02
    Notes
    [8] - Logistic regression adjusted for randomized treatment, AMT at Baseline per randomization stratification, Baseline ACT total score, Baseline ACT total score squared, gender and age.

    Secondary: Percentage of participants with asthma control (ACT total score >=20) at Weeks 12, 24, 40 and 52.

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    End point title
    		 Percentage of participants with asthma control (ACT total score >=20) at Weeks 12, 24, 40 and 52.
    End point description
    The ACT is a validated self-administered questionnaire utilizing 5 questions to assess asthma control during the past 4 weeks on a 5-point categorical scale (1 to 5). By answering all 5 questions, participants with asthma obtained an ACT score ranging between 5 and 25. Higher scores indicated better control of asthma. An ACT score of <=15 showed poorly controlled asthma; 16 to 19 showed partly controlled asthma and >=20 showed well controlled asthma. The total score was calculated as the sum of the scores from all 5 questions. The percentage of participants with an ACT total score >=20 has been presented. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
    End point type
    Secondary
    End point timeframe
    Weeks 12, 24, 40 and 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [9]
    2114 [10]
    Units: Percentage of participants
        Week 12, n=2032, 2009
    46
    61
        Week 24, n=1957, 1936
    46
    60
        Week 40, n=1938, 1904
    45
    58
        Week 52, n=1922, 1896
    44
    58
    Notes
    [9] - ITT Population
    [10] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Adjusted odds ratio comparing FF/VI with Usual Care at Week 12 has been presented. The correct Number of Subjects Included in Analysis is 4041. Due to a system limitation, the value 4233 is incorrectly auto-populated.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [11]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    2.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.82
         upper limit
    		 2.4
    Notes
    [11] - The analysis method was logistic regression adjusted for randomized treatment, AMT at Baseline per randomization stratification, Baseline ACT total score, gender and age.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Adjusted odds ratio comparing FF/VI with Usual Care at Week 24 has been presented. The correct Number of Subjects Included in Analysis is 3893. Due to a system limitation, the value 4233 is incorrectly auto-populated.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [12]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.7
         upper limit
    		 2.25
    Notes
    [12] - The analysis method was logistic regression adjusted for randomized treatment, AMT at Baseline per randomization stratification, Baseline ACT total score, gender and age.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Adjusted odds ratio comparing FF/VI with Usual Care at Week 40 has been presented. The correct Number of Subjects Included in Analysis is 3842. Due to a system limitation, the value 4233 is incorrectly auto-populated.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [13]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    1.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.56
         upper limit
    		 2.06
    Notes
    [13] - The analysis method was logistic regression adjusted for randomized treatment, AMT at Baseline per randomization stratification, Baseline ACT total score, gender and age.
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Adjusted odds ratio comparing FF/VI with Usual Care at Week 52 has been presented. The correct Number of Subjects Included in Analysis is 3818. Due to a system limitation, the value 4233 is incorrectly auto-populated.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [14]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    1.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.69
         upper limit
    		 2.24
    Notes
    [14] - The analysis method was logistic regression adjusted for randomized treatment, AMT at Baseline per randomization stratification, Baseline ACT total score, gender and age.

    Secondary: Percentage of participants who have an increase from Baseline of >=3 in ACT total score at Weeks 12, 24, 40 and 52.

    		 Close Top of page
    End point title
    		 Percentage of participants who have an increase from Baseline of >=3 in ACT total score at Weeks 12, 24, 40 and 52.
    End point description
    The ACT is a validated self-administered questionnaire utilizing 5 questions to assess asthma control during the past 4 weeks on a 5-point categorical scale (1 to 5). By answering all 5 questions, participants with asthma obtained an ACT score ranging between 5 and 25. Higher scores indicated better control of asthma. An ACT score of <=15 showed poorly controlled asthma; 16 to 19 showed partly controlled asthma and >=20 showed well controlled asthma. The total score was calculated as the sum of the scores from all 5 questions. The percentage of participants with an increase in ACT total score >=3 from Baseline has been presented. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Weeks 12, 24, 40 and 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [15]
    2114 [16]
    Units: Percentage of participants
        Week 12, n=2032, 2009
    39
    55
        Week 24, n=1957, 1936
    40
    54
        Week 40, n=1938, 1904
    42
    53
        Week 52, n=1922, 1896
    37
    50
    Notes
    [15] - ITT Population
    [16] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Adjusted odds ratio comparing FF/VI with Usual Care at Week 12 has been presented. The correct Number of Subjects Included in Analysis is 4041. Due to a system limitation, the value 4233 is incorrectly auto-populated
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [17]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    2.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.98
         upper limit
    		 2.62
    Notes
    [17] - The analysis method was logistic regression adjusted for randomized treatment, AMT at Baseline per randomization stratification, Baseline ACT total score, gender and age.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Adjusted odds ratio comparing FF/VI with Usual Care at Week 24 has been presented. The correct Number of Subjects Included in Analysis is 3893. Due to a system limitation, the value 4233 is incorrectly auto-populated
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [18]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    2.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.81
         upper limit
    		 2.41
    Notes
    [18] - The analysis method was logistic regression adjusted for randomized treatment, AMT at Baseline per randomization stratification, Baseline ACT total score, gender and age.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Adjusted odds ratio comparing FF/VI with Usual Care at Week 40 has been presented. The correct Number of Subjects Included in Analysis is 3842. Due to a system limitation, the value 4233 is incorrectly auto-populated
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [19]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    1.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.53
         upper limit
    		 2.02
    Notes
    [19] - The analysis method was logistic regression adjusted for randomized treatment, AMT at Baseline per randomization stratification, Baseline ACT total score, gender and age.
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Adjusted odds ratio comparing FF/VI with Usual Care at Week 52 has been presented. The correct Number of Subjects Included in Analysis is 3818. Due to a system limitation, the value 4233 is incorrectly auto-populated.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [20]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    1.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.66
         upper limit
    		 2.21
    Notes
    [20] - The analysis method was logistic regression adjusted for randomized treatment, AMT at Baseline per randomization stratification, Baseline ACT total score, gender and age.

    Secondary: Mean change from Baseline in ACT total score at Weeks 12, 24, 40 and 52.

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    End point title
    		 Mean change from Baseline in ACT total score at Weeks 12, 24, 40 and 52.
    End point description
    The ACT is a validated self-administered questionnaire utilizing 5 questions to assess asthma control during the past 4 weeks on a 5-point categorical scale (1 to 5). By answering all 5 questions, participants with asthma obtained an ACT score ranging between 5 and 25. Higher scores indicated better control of asthma. An ACT score of <=15 showed poorly controlled asthma; 16 to 19 showed partly controlled asthma and >=20 showed well controlled asthma. The total score was calculated as the sum of the scores from all 5 questions. Baseline value is the value at Visit 2 (Day 0) assessment. Change from Baseline is the value at post-dose visit minus Baseline. The least square mean change in ACT scores has been presented. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Weeks 12, 24, 40 and 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [21]
    2114 [22]
    Units: Scores on ACT scale
    least squares mean (standard error)
        Week 12, n=2032, 2009
    1.77 ± 0.087
    3.31 ± 0.087
        Week 24, n=1957, 1936
    1.70 ± 0.093
    3.20 ± 0.094
        Week 40, n=1938, 1904
    1.63 ± 0.096
    3.00 ± 0.097
        Week 52, n=1922, 1896
    1.49 ± 0.094
    2.99 ± 0.095
    Notes
    [21] - ITT Population
    [22] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Treatment difference of FF/VI versus Usual Care at Week 12 has been presented. The correct Number of Subjects Included in Analysis is 4041. Due to a system limitation, the value 4233 is incorrectly auto-populated.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [23]
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.3
         upper limit
    		 1.77
    Notes
    [23] - MMRM adjusted for randomized treatment, AMT at Baseline per randomization stratification, Baseline ACT total score, randomized treatment-by-Baseline ACT total score interaction, gender, age, visit and randomized treatment by visit interaction.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Treatment difference of FF/VI versus Usual Care at Week 24 has been presented. The correct Number of Subjects Included in Analysis is 3893. Due to a system limitation, the value 4233 is incorrectly auto-populated.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [24]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.25
         upper limit
    		 1.76
    Notes
    [24] - MMRM adjusted for randomized treatment, AMT at Baseline per randomization stratification, Baseline ACT total score, randomized treatment-by-Baseline ACT total score interaction, gender, age, visit and randomized treatment by visit interaction.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Treatment difference of FF/VI versus Usual Care at Week 40 has been presented. The correct Number of Subjects Included in Analysis is 3842. Due to a system limitation, the value 4233 is incorrectly auto-populated.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [25]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.11
         upper limit
    		 1.63
    Notes
    [25] - MMRM adjusted for randomized treatment, AMT at Baseline per randomization stratification, Baseline ACT total score, randomized treatment-by-Baseline ACT total score interaction, gender, age, visit and randomized treatment by visit interaction.
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Treatment difference of FF/VI versus Usual Care at Week 52 has been presented. The correct Number of Subjects Included in Analysis is 3818. Due to a system limitation, the value 4233 is incorrectly auto-populated.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [26]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.24
         upper limit
    		 1.76
    Notes
    [26] - MMRM adjusted for randomized treatment, AMT at Baseline per randomization stratification, Baseline ACT total score, randomized treatment-by-Baseline ACT total score interaction, gender, age, visit and randomized treatment by visit interaction.

    Secondary: Percentage of participants in each ACT total score category (>=20, 16 to 19, <=15) at Weeks 12, 24, 40 and 52.

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    End point title
    		 Percentage of participants in each ACT total score category (>=20, 16 to 19, <=15) at Weeks 12, 24, 40 and 52.
    End point description
    The ACT is a validated self-administered questionnaire utilizing 5 questions to assess asthma control during the past 4 weeks on a 5-point categorical scale (1 to 5). By answering all 5 questions, participants with asthma obtained an ACT score ranging between 5 and 25. Higher scores indicated better control of asthma. An ACT score of <=15 showed poorly controlled asthma; 16 to 19 showed partly controlled asthma; and >=20 showed well controlled asthma. The total score was calculated as the sum of the scores from all 5 questions. The percentage of participants under each ACT total score category that is >=20, 16 to 19 and <=15 has been presented. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
    End point type
    Secondary
    End point timeframe
    Weeks 12, 24, 40 and 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [27]
    2114 [28]
    Units: Percentage of participants
        >=20, Week 12, n=2032, 2009
    46
    61
        16 to 19, Week 12, n=2032, 2009
    26
    20
        <=15, Week 12, n=2032, 2009
    28
    18
        >=20, Week 24, n=1957, 1936
    46
    60
        16 to 19, Week 24, n=1957, 1936
    25
    20
        <=15, Week 24, n=1957, 1936
    29
    20
        >=20, Week 40, n=1938, 1904
    45
    58
        16 to 19, Week 40, n=1938, 1904
    24
    21
        <=15, Week 40, n=1938, 1904
    31
    21
        >=20, Week 52, n=1922, 1896
    44
    58
        16 to 19, Week 52, n=1922, 1896
    26
    20
        <=15, Week 52, n=1922, 1896
    30
    21
    Notes
    [27] - ITT Population
    [28] - ITT Population
    No statistical analyses for this end point

    Secondary: Annual rate of asthma-related secondary care contacts

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    End point title
    		 Annual rate of asthma-related secondary care contacts
    End point description
    All contacts are defined as any encounter the participant may have with a doctor, nurse or other healthcare professionals working as part of the National Health Service (NHS) as identified in the electronic medical records (EMR). Contacts were defined to be asthma-related if the most prominent signs and symptoms that the participant presented were a direct result of the participant’s asthma. An asthma-related secondary care contact is defined as an inpatient admission or a specialist outpatient visit or an accident and emergency (A&E) contact. A participant with an A&E contact and subsequent inpatient admission was considered to have had two healthcare contacts. The least square mean annual rate of all asthma-related secondary care contacts along with 95% confidence interval has been presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [29]
    2114 [30]
    Units: Contacts per participant per year
    least squares mean (confidence interval 95%)
        Contacts per participant per year
    0.30 (0.25 to 0.34)
    0.30 (0.26 to 0.36)
    Notes
    [29] - ITT Population
    [30] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Ratio comparing FF/VI with Usual Care has been presented.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.786 [31]
    Method
    		 Generalized Linear Model (GLM)
    Parameter type
    		 Ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.28
    Notes
    [31] - GLM assuming negative binomial distribution (NBD) adjusted for randomized treatment, asthma maintenance therapy at Baseline per randomization stratification, ACT total score at Baseline per randomization stratification, gender and age

    Secondary: Annual rate of asthma-related primary care contacts

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    End point title
    		 Annual rate of asthma-related primary care contacts
    End point description
    All contacts are defined as any encounter the participant may have with a doctor, nurse or other healthcare professionals working as part of the NHS as identified in the EMR. Contacts were defined to be asthma-related if the most prominent signs and symptoms that the participant presented were a direct result of the participant’s asthma. Asthma-related primary care contacts is defined as the sum of primary care contacts on a given calendar date with either a nurse, General Practitioner or other healthcare professional that can be considered as asthma-related as per Read codes. The least square mean annual rate of all asthma-related primary care contacts along with 95% confidence interval has been presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [32]
    2114 [33]
    Units: Contacts per participant per year
    least squares mean (confidence interval 95%)
        Contacts per participant per year
    1.42 (1.36 to 1.47)
    1.45 (1.39 to 1.51)
    Notes
    [32] - ITT Population
    [33] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Ratio comparing FF/VI with Usual Care has been presented.
    Comparison groups
    Usual Care v FF/VI
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.461 [34]
    Method
    		 Generalized Linear Model (GLM)
    Parameter type
    		 Ratio
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 1.08
    Notes
    [34] - GLM assuming NBD adjusted for randomized treatment, asthma maintenance therapy at Baseline per randomization stratification, ACT total score at Baseline per randomization stratification, gender and age

    Secondary: Number of participants with time to first asthma-related primary care contact

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    End point title
    		 Number of participants with time to first asthma-related primary care contact
    End point description
    Asthma-related primary care contact is defined as the sum of primary care contacts on a given calendar date with either a nurse, General Practitioner or other healthcare professional that can be considered as asthma-related as per Read codes. Time to first asthma-related primary care contact was measured from the date of randomization (that is, study treatment start date) to the date of first asthma-related primary care contact, or study treatment stop date for participants who completed the study without any asthma-related primary care contacts (censored). Analyses of time to first asthma-related primary care contact was censored at Day 364. The number of participants at risk at Weeks 0, 13, 26, 39 and 52 has been presented. Kaplan Meier method of analysis was used. Study related primary care contacts (that is, contacts scheduled solely due to the participant taking part in clinical trial) were excluded from this analysis.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [35]
    2114 [36]
    Units: Participants
        Week 0
    2119
    2114
        Week 13
    1621
    1599
        Week 26
    1208
    1214
        Week 39
    907
    932
        Week 52
    479
    488
    Notes
    [35] - ITT Population
    [36] - ITT Population
    No statistical analyses for this end point

    Secondary: Annual rate of all on-treatment secondary care contacts

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    End point title
    		 Annual rate of all on-treatment secondary care contacts
    End point description
    A secondary care contact is 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. The inpatient admissions recorded at two hospitals on the same day, were counted as a single (inpatient admission) secondary care contact. In the situation where inpatient admission periods overlapped (example, a new inpatient admission was recorded within the dates of an existing inpatient admission period), it was counted as a single (inpatient admission) healthcare contact with start date defined as the earliest inpatient admission date for either of the overlapping admissions and end date defined as the latest discharge date for either of the overlapping admissions. The least square mean annual rate of all on-treatment secondary care contacts along with 95% confidence interval has been summarized.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [37]
    2114 [38]
    Units: Contacts per participant per year
    least squares mean (confidence interval 95%)
        Contacts per participant per year
    5.23 (4.91 to 5.57)
    5.17 (4.86 to 5.51)
    Notes
    [37] - ITT Population
    [38] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Ratio comparing FF/VI with Usual Care has been presented.
    Comparison groups
    Usual Care v FF/VI
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.822 [39]
    Method
    		 Generalized Linear Model (GLM)
    Parameter type
    		 Ratio
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.08
    Notes
    [39] - GLM assuming NBD adjusted for randomized treatment, asthma maintenance therapy at Baseline per randomization stratification, ACT total score at Baseline per randomization stratification, gender and age

    Secondary: Annual rate of all on-treatment primary care contacts

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    End point title
    		 Annual rate of all on-treatment primary care contacts
    End point description
    All contacts are defined as any encounter the participant may have with a doctor, nurse or other healthcare professionals working as part of the NHS as identified in the EMR. Total primary care contacts is defined as the sum of primary care contacts on a given calendar date with either a nurse, General Practitioner or other healthcare professional. The least square mean annual rate of all on-treatment primary care contacts along with 95% confidence interval has been presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [40]
    2114 [41]
    Units: Contacts per participant per year
    least squares mean (confidence interval 95%)
        Contacts per participant per year
    10.61 (10.26 to 10.98)
    11.64 (11.25 to 12.04)
    Notes
    [40] - ITT Population
    [41] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Ratio comparing FF/VI with Usual Care has been presented.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [42]
    Method
    		 Generalized Linear Model (GLM)
    Parameter type
    		 Ratio
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 1.15
    Notes
    [42] - GLM assuming NBD adjusted for randomized treatment, asthma maintenance therapy at Baseline per randomization stratification, ACT total score at Baseline per randomization stratification, gender and age

    Secondary: Number of participants with time to first primary care contact

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    End point title
    		 Number of participants with time to first primary care contact
    End point description
    Time to first primary care contact is measured from the date of randomization (that is, study treatment start date) to the date of first primary care contact, or study treatment stop date for participants who completed the study without any primary care contacts (censored). Analyses of time to first primary care contact will be censored at Day 364. The number of participants at risk at Weeks 0, 13, 26, 39 and 52 has been presented. Kaplan Meier method of analysis was used. Study related primary care contacts (that is, contacts scheduled solely due to the participant taking part in clinical trial) were excluded from this analysis.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [43]
    2114 [44]
    Units: Participants
        Week 0
    2119
    2114
        Week 13
    513
    483
        Week 26
    245
    242
        Week 39
    160
    178
        Week 52
    79
    96
    Notes
    [43] - ITT Population
    [44] - ITT Population
    No statistical analyses for this end point

    Secondary: Mean annual rate of severe asthma exacerbations

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    End point title
    		 Mean annual rate of severe asthma exacerbations
    End point description
    A severe asthma exacerbation is defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) or antibiotics, and inpatient hospitalization, or emergency department visit due to asthma that required systemic corticosteroids or antibiotics. Least square mean for annual rate of severe asthma exacerbation along with 95% confidence interval has been presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [45]
    2114 [46]
    Units: Exacerbations per participant per year
    least squares mean (confidence interval 95%)
        Exacerbations per participant per year
    0.41 (0.38 to 0.44)
    0.40 (0.37 to 0.43)
    Notes
    [45] - ITT Population
    [46] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Ratio comparing FF/VI with Usual Care has been presented.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.697 [47]
    Method
    		 Generalized Linear Model (GLM)
    Parameter type
    		 Ratio
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.09
    Notes
    [47] - GLM assuming NBD adjusted for randomized treatment; asthma maintenance therapy and ACT total score at Baseline per randomization stratification; number of severe asthma exacerbations in previous year prior to randomization categorized; gender & age

    Secondary: Time to first severe asthma exacerbation.

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    End point title
    		 Time to first severe asthma exacerbation.
    End point description
    A severe asthma exacerbation is defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) or antibiotics, and inpatient hospitalization, or emergency department visit due to asthma that required systemic corticosteroids or antibiotics. The date of a severe asthma exacerbation was defined as the exacerbation onset date. Participants who completed the study without a severe asthma exacerbation were censored. Time to first severe asthma exacerbation was measured from the date of randomization (that is, study treatment start date) to the onset date of first severe asthma exacerbation, or study treatment stop date for participants who completed the study without any severe asthma exacerbations (censored). Analyses of time to first severe asthma exacerbation was censored at Day 364. The number of participants with severe asthma exacerbation has been presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [48]
    2114 [49]
    Units: Participants
        Participants
    654
    634
    Notes
    [48] - ITT Population
    [49] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    A hazard ratio <1 indicated a lower risk with FF/VI compared with Usual Care
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.504 [50]
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.07
    Notes
    [50] - Cox proportional hazards model with randomized treatment, asthma maintenance therapy at Baseline per randomization stratification, ACT total score at Baseline per randomization stratification, gender and age as covariates

    Secondary: Mean number of salbutamol inhalers prescribed for each participant over the 12 month treatment period.

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    End point title
    		 Mean number of salbutamol inhalers prescribed for each participant over the 12 month treatment period.
    End point description
    Salbutamol was prescribed as a rescue medication to be used as and when necessary throughout the study. The number of salbutamol inhalers used by each participant during the study was calculated based on the total number of inhalers (adjusted to an equivalence of 200 metered actuations) prescribed. Number of salbutamol inhalers prescribed during the study was derived taking the participants time on study medication into account so it corresponds to 12 months on treatment The least square mean number of salbutamol inhalers prescribed per participant during the study has been presented. Only participants exposed to study drug for at least 30 days were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2116 [51]
    2108 [52]
    Units: Mean number of inhalers per participant
    least squares mean (standard error)
        Mean number of inhalers per participant
    8.0 ± 0.11
    7.2 ± 0.11
    Notes
    [51] - ITT Population
    [52] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Difference of FF/VI versus Usual Care has been presented.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4224
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [53]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 -0.5
    Notes
    [53] - ANCOVA adjusted for randomized treatment, asthma maintenance therapy at Baseline per randomization stratification, ACT total score at Baseline per randomization stratification, gender,age & number of salbutamol inhalers in year prior to randomization

    Secondary: Time to modification of initial therapy

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    End point title
    		 Time to modification of initial therapy
    End point description
    Initial therapy is defined as the treatment that the participant was prescribed at randomization. Modification of initial therapy included any change in brand, dose or frequency of inhaler, that is, stepping up in class, dose or frequency, stepping down in class, dose or frequency, switching to another brand of inhaler, switching treatment arm or withdrawal from the study. Time to modification of initial therapy was measured from the date of randomization (that is, exposure start date) to the date of modification of initial therapy or date of treatment termination for participants who completed the study without modifiying initial therapy (censored). The number of participants with modification of initial therapy has been presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [54]
    2114 [55]
    Units: Participants
        Participants
    488
    563
    Notes
    [54] - ITT Population
    [55] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Hazard ratio for FF/VI versus Usual Care has been presented
    Comparison groups
    Usual Care v FF/VI
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [56]
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.09
         upper limit
    		 1.38
    Notes
    [56] - Cox proportional hazards model with randomized treatment, asthma maintenance therapy at Baseline per randomization stratification, ACT total score at Baseline per randomization stratification, gender and age as covariates

    Secondary: Percentage of participants who have an increase from Baseline of >=0.5 in Standardized Asthma Quality of Life Questionnaire [AQLQ(S)] total score at Week 52.

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    End point title
    		 Percentage of participants who have an increase from Baseline of >=0.5 in Standardized Asthma Quality of Life Questionnaire [AQLQ(S)] total score at Week 52.
    End point description
    The AQLQ(S) contained 32 items under the following four domains: activity limitation (11 items), symptoms (12 items), emotional function (5 items) and environmental stimuli (4 items). The response format consisted of a seven-point scale where a value of 1 indicated “total impairment” and a value of 7 indicated “no impairment”. The total AQLQ(S) score is the mean of all 32 items in the questionnaire and each individual domain score was calculated as the mean of the items within that domain. Hence, the total and domain scores were each defined on a range from 1 to 7 with higher scores indicating a higher quality of life. Baseline value is the value at Day 0 assessment. Change from Baseline is post dose visit value minus Baseline. The percentage of responders that is, participants with an increase from Baseline of >=0.5 in AQLQ(S) total score has been presented.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    1922 [57]
    1896 [58]
    Units: Percentage of participants
        Percentage of participants
    43
    55
    Notes
    [57] - ITT Population
    [58] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Adjusted odds ratio of FF/VI with Usual Care has been presented.
    Comparison groups
    Usual Care v FF/VI
    Number of subjects included in analysis
    3818
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [59]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    1.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.55
         upper limit
    		 2.06
    Notes
    [59] - Logistic regression adjusted for randomized treatment, asthma maintenance therapy at Baseline per randomization stratification, ACT total score at Baseline per randomization stratification, gender, age and Baseline score.

    Secondary: Percentage of participants who have an increase from Baseline of >=0.5 in AQLQ(S) environmental stimuli domain score at Week 52.

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    End point title
    		 Percentage of participants who have an increase from Baseline of >=0.5 in AQLQ(S) environmental stimuli domain score at Week 52.
    End point description
    The AQLQ(S) contained 32 items under the following four domains: activity limitation (11 items), symptoms (12 items), emotional function (5 items) and environmental stimuli (4 items). The response format consisted of a seven-point scale where a value of 1 indicated “total impairment” and a value of 7 indicated “no impairment”. The total environmental stimuli domain score was calculated as the mean of the items within the environmental stimuli domain. Hence, the environmental stimuli domain scores were each defined on a range from 1 to 7 with higher scores indicating a higher quality of life. Baseline value is the value at Day 0 assessment. Change from Baseline is post dose visit value minus Baseline. The percentage of responders that is, participants with an increase from Baseline of >=0.5 in AQLQ(S) environmental stimuli domain score has been presented.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    1922 [60]
    1896 [61]
    Units: Percentage of participants
        Percentage of participants
    50
    59
    Notes
    [60] - ITT Population
    [61] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Adjusted odds ratio of FF/VI versus Usual Care has been presented.
    Comparison groups
    Usual Care v FF/VI
    Number of subjects included in analysis
    3818
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [62]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    1.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.31
         upper limit
    		 1.73
    Notes
    [62] - Logistic regression adjusted for randomized treatment, asthma maintenance therapy at Baseline per randomization stratification, ACT total score at Baseline per randomization stratification, gender, age and Baseline score.

    Secondary: Percentage of participants with serious adverse event (SAE) of pneumonia

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    End point title
    		 Percentage of participants with serious adverse event (SAE) of pneumonia
    End point description
    A serious advent event (SAE) of pneumonia was defined as any SAE in the adverse event special interest (AESI) group of “pneumonia”. The incidence of the SAEs of pneumonia for each treatment group is defined as the percentage of participants in that group who have experienced at least one SAE of pneumonia from start date of study treatment to the stop date of exposure + 28 days or date of study discontinuation, whichever is earliest. The percentage of participants with SAE of pneumonia has been presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [63]
    2114 [64]
    Units: Percentage of participants
        Percentage of participants
    1
    1
    Notes
    [63] - ITT Population
    [64] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Incidence ratio was calculated as percentage of participants who had at least one SAE of pneumonia in the FF/VI group divided by the percentage of participants who had at least one SAE of pneumonia in the Usual Care group.
    Comparison groups
    Usual Care v FF/VI
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [65]
    Method
    Parameter type
    		 Incidence ratio
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 2.7
    Notes
    [65] - Non-inferiority is demonstrated if the upper limit of the two-sided 95% confidence interval for the incidence ratio is less than 2.

    Secondary: Time to first SAE of pneumonia

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    End point title
    		 Time to first SAE of pneumonia
    End point description
    An SAE of pneumonia was defined as any SAE in the AESI group of “pneumonia”. The date of an event for an SAE of pneumonia was the AE onset date. Participants who do not have an SAE of pneumonia during the first 364 days of the treatment period (start date of exposure to min [end date of exposure + 28 days, date of study discontinuation, start date of exposure + 363]) were censored. Time to first SAE of pneumonia was measured from the date of randomization (that is, study treatment start date) to the onset date of first SAE of pneumonia. The number of participants with first on-treatment SAE of pneumonia has been presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [66]
    2114 [67]
    Units: Participants
        Participants
    16
    23
    Notes
    [66] - ITT Population
    [67] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Hazard ratio for FF/VI versus Usual Care has been presented.
    Comparison groups
    FF/VI v Usual Care
    Number of subjects included in analysis
    4233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.255 [68]
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 2.74
    Notes
    [68] - Cox proportional hazards model with randomized treatment, asthma maintenance therapy at Baseline per randomization stratification, ACT total score at Baseline per randomization stratification, gender and age as covariates.

    Secondary: Number of participants with fatal SAEs of pneumonia

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    End point title
    		 Number of participants with fatal SAEs of pneumonia
    End point description
    All SAEs included in the AESI group of “pneumonia” were considered as an SAE of pneumonia. Fatal SAEs of pneumonia are SAEs that led to death of participants. The number of participants with fatal SAEs of pneumonia has been presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [69]
    2114 [70]
    Units: Participants
        Participants
    3
    1
    Notes
    [69] - ITT Population
    [70] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of participants with SAEs

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    End point title
    		 Number of participants with SAEs
    End point description
    An SAE is any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events which may require medical or surgical intervention for example, invasive or malignant cancers; all events of possible drug-induced liver injury with hyperbilirubinemia. The number of participants with on-treatment SAEs has been summarized.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [71]
    2114 [72]
    Units: Participants
        Participants
    284
    284
    Notes
    [71] - ITT Population
    [72] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of participants with adverse drug reactions (ADRs)

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    End point title
    		 Number of participants with adverse drug reactions (ADRs)
    End point description
    An ADR is any untoward medical occurrence in a clinical investigation participant, 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. ADRs are a subset of AEs for a given medicinal product.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Usual Care FF/VI
    Number of subjects analysed
    2119 [73]
    2114 [74]
    Units: Participants
        Participants
    109
    326
    Notes
    [73] - ITT Population
    [74] - ITT Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    On-treatment serious adverse events (SAEs) and non-serious adverse drug reactions (ADRs) were collected from the start of study treatment and until the follow up contact (Up to Week 52).
    Adverse event reporting additional description
    ITT Population comprised of all randomized participants who received at least one prescription of study medication
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    FF/VI
    Reporting group description
    		 Participants initiated with an appropriate dose of inhaled FF/VI (100 mcg/25 mcg or 200 mcg/25 mcg per actuation) once daily via Novel Dry Powder Inhaler.

    Reporting group title
    Usual Care
    Reporting group description
    		 Participants continued their usual asthma maintenance therapy that is, inhaled corticosteroid without a long acting beta2-agonist or inhaled corticosteroid with long acting beta2-agonist combination (either as a fixed dose combination or an inhaled corticosteroid/long acting beta2-agonist provided in two separate inhalers).

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There were no non-serious adverse events above 3% threshold.
    Serious adverse events
    		 FF/VI Usual Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    284 / 2114 (13.43%)
    284 / 2119 (13.40%)
         number of deaths (all causes)
    15
    27
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acinic cell carcinoma of salivary gland
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenoma benign
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma recurrent
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    4 / 2114 (0.19%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain cancer metastatic
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (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
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    2 / 2114 (0.09%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lymphoma
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chondrosarcoma
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer metastatic
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal carcinoma
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lentigo maligna
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    2 / 2114 (0.09%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    2 / 2114 (0.09%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to liver
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic renal cell carcinoma
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Penile squamous cell carcinoma
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phyllodes tumour
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Precursor B-lymphoblastic lymphoma
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    3 / 2114 (0.14%)
    4 / 2119 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    2 / 2114 (0.09%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer recurrent
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    2 / 2114 (0.09%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         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 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Angiodysplasia
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (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
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Circulatory collapse
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    5 / 2114 (0.24%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Essential hypertension
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 2114 (0.00%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypotension
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Raynaud's phenomenon
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava occlusion
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Temporal arteritis
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion missed
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    2 / 2114 (0.09%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unintended pregnancy
         subjects affected / exposed
    3 / 2114 (0.14%)
    3 / 2119 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unwanted pregnancy
         subjects affected / exposed
    2 / 2114 (0.09%)
    2 / 2119 (0.09%)
         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
    1 / 2114 (0.05%)
    4 / 2119 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         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 / 2114 (0.05%)
    3 / 2119 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical failure
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 2114 (0.00%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycotic allergy
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         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
    Menorrhagia
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema genital
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst torsion
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         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
    24 / 2114 (1.14%)
    30 / 2119 (1.42%)
         occurrences causally related to treatment / all
    2 / 30
    0 / 34
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atelectasis
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 2114 (0.05%)
    5 / 2119 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Emphysema
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 2114 (0.05%)
    3 / 2119 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pharyngeal inflammation
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         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 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    2 / 2114 (0.09%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pulmonary eosinophilia
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 2114 (0.00%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reflux laryngitis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 2114 (0.09%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    2 / 2114 (0.09%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcoholism
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Antisocial personality disorder
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delusion
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed mood
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    4 / 2114 (0.19%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eating disorder
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomania
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Persistent depressive disorder
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post-traumatic stress disorder
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    2 / 2114 (0.09%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizoaffective disorder
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (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
    3 / 2114 (0.14%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 2114 (0.05%)
    3 / 2119 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    3 / 2114 (0.14%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 2114 (0.05%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Hepatic failure
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         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
    1 / 2114 (0.05%)
    0 / 2119 (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
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood potassium decreased
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (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
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio abnormal
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    11 / 2114 (0.52%)
    7 / 2119 (0.33%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal function test abnormal
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (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
    2 / 2114 (0.09%)
    3 / 2119 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    8 / 2114 (0.38%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns third degree
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Comminuted fracture
         subjects affected / exposed
    0 / 2114 (0.00%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corneal abrasion
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    6 / 2114 (0.28%)
    5 / 2119 (0.24%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    2 / 2114 (0.09%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 2114 (0.05%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    3 / 2114 (0.14%)
    3 / 2119 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign body
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (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 / 2114 (0.00%)
    1 / 2119 (0.05%)
         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
    1 / 2114 (0.05%)
    4 / 2119 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 2114 (0.05%)
    3 / 2119 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    2 / 2114 (0.09%)
    5 / 2119 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    5 / 2114 (0.24%)
    5 / 2119 (0.24%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intentional product misuse
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 2114 (0.00%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb crushing injury
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    2 / 2114 (0.09%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 2114 (0.05%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    2 / 2114 (0.09%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    4 / 2114 (0.19%)
    9 / 2119 (0.42%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 2114 (0.09%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fractured base
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    2 / 2114 (0.09%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    2 / 2114 (0.09%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    2 / 2114 (0.09%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Ulna fracture
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound secretion
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         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
    5 / 2114 (0.24%)
    3 / 2119 (0.14%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Branchial cyst
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocardial fibroelastosis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    4 / 2114 (0.19%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    5 / 2114 (0.24%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 2114 (0.00%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    2 / 2114 (0.09%)
    3 / 2119 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    7 / 2114 (0.33%)
    14 / 2119 (0.66%)
         occurrences causally related to treatment / all
    0 / 7
    2 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 2114 (0.09%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 2114 (0.05%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery thrombosis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diastolic dysfunction
         subjects affected / exposed
    0 / 2114 (0.00%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    3 / 2114 (0.14%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 2114 (0.09%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    5 / 2114 (0.24%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myocarditis
         subjects affected / exposed
    2 / 2114 (0.09%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (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
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anosmia
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (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 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    5 / 2114 (0.24%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    2 / 2114 (0.09%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 2114 (0.00%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug withdrawal convulsions
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 2114 (0.05%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 2114 (0.09%)
    4 / 2119 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    3 / 2114 (0.14%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    5 / 2114 (0.24%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 2114 (0.00%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    5 / 2114 (0.24%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sensory disturbance
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural hygroma
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    3 / 2114 (0.14%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 2114 (0.09%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIth nerve paralysis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular dementia
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebral artery dissection
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 2114 (0.14%)
    3 / 2119 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia of chronic disease
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy mediastinal
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microcytic anaemia
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         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 / 2114 (0.00%)
    1 / 2119 (0.05%)
         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
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tinnitus
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         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 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Angle closure glaucoma
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    6 / 2114 (0.28%)
    4 / 2119 (0.19%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic retinopathy
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    4 / 2114 (0.19%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (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 hernia
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    5 / 2114 (0.24%)
    4 / 2119 (0.19%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 2114 (0.05%)
    5 / 2119 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 2114 (0.19%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    2 / 2114 (0.09%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (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
    1 / 2114 (0.05%)
    5 / 2119 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 2114 (0.14%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 2114 (0.00%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated umbilical hernia
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    3 / 2114 (0.14%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia, obstructive
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 2114 (0.09%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    1 / 2114 (0.05%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    3 / 2114 (0.14%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin necrosis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (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
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    6 / 2114 (0.28%)
    9 / 2119 (0.42%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    3 / 2114 (0.14%)
    5 / 2119 (0.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 2114 (0.05%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 2114 (0.09%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loin pain haematuria syndrome
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         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 / 2114 (0.09%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    3 / 2114 (0.14%)
    3 / 2119 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 2114 (0.09%)
    4 / 2119 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperparathyroidism
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (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
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Secondary hypogonadism
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 2114 (0.14%)
    8 / 2119 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibromyalgia
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 2114 (0.00%)
    3 / 2119 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metatarsalgia
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         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
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 2114 (0.00%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteopenia
         subjects affected / exposed
    2 / 2114 (0.09%)
    0 / 2119 (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
    5 / 2114 (0.24%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palindromic rheumatism
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 2114 (0.05%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    7 / 2114 (0.33%)
    11 / 2119 (0.52%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic hepatitis C
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    3 / 2114 (0.14%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 2114 (0.09%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital herpes
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital infection
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 2114 (0.00%)
    3 / 2119 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    2 / 2114 (0.09%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    5 / 2114 (0.24%)
    7 / 2119 (0.33%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neutropenic sepsis
         subjects affected / exposed
    2 / 2114 (0.09%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ophthalmic herpes simplex
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    1 / 2114 (0.05%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    23 / 2114 (1.09%)
    13 / 2119 (0.61%)
         occurrences causally related to treatment / all
    6 / 24
    0 / 14
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    2 / 2114 (0.09%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    1 / 2114 (0.05%)
    3 / 2119 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 2114 (0.14%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 2114 (0.14%)
    7 / 2119 (0.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sialoadenitis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    12 / 2114 (0.57%)
    4 / 2119 (0.19%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 2114 (0.05%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 2114 (0.05%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral labyrinthitis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 2114 (0.05%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 2114 (0.05%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    3 / 2114 (0.14%)
    3 / 2119 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 2114 (0.05%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 2114 (0.00%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 2114 (0.00%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    4 / 2114 (0.19%)
    1 / 2119 (0.05%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 2114 (0.00%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 2114 (0.00%)
    2 / 2119 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 2114 (0.05%)
    0 / 2119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    12 / 2114 (0.57%)
    13 / 2119 (0.61%)
         occurrences causally related to treatment / all
    2 / 12
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 FF/VI Usual Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 2114 (0.00%)
    0 / 2119 (0.00%)

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Dec 2013
    Amendment No. 01: Protocol summary; headings formatted; Secondary objective added; The secondary objective is to compare the incidence serious adverse events of pneumonia during the study of FF 100mcg/VI 25mcg or FF 200mcg/VI 25mcg with usual asthma maintenance therapy over twelve months; Throughout; Salford, Greater Manchester changed to Salford and South Manchester; Sample size changed; from 4820 to 4036; Contacts defined to include; other healthcare professionals; New endpoint deleted from other efficacy endpoints; Safety endpoint added; Incidence of serious adverse events of pneumonia during the study; Rationale; text changed to include collection of data from pharmacy EMR; Throughout; with National Health Service (NHS) contact changed to with or without NHS contact; Inclusion criteria 1 amended to include; Subjects must be able to complete the electronic subject questionnaires or allow a proxy to do so on their behalf; Additional exclusion criteria added; 8. Subjects whose current medications include RELVAR® ELLIPTA® are not eligible to enter the study; Withdrawal criteria; updated to reflect ECG no longer performed at visit 2; Treatment assignment: text added; Subjects with hepatic impairment should be given a maximum dose of FF/VI 100mcg/25mcg; Conmeds and other medications amended to include all medications and trade name not collected; Treatment changes; updated to reflect if the patient is changed to RELVAR® ELLIPTA® they should be withdrawn; Table 4 time and events; updated to remove ECG requirement at V2 and add in Smoking status questions at V2, V6 and early withdrawal, and add in genetic sampling at V6; details of crude patient history to be collected added; Liver stopping and follow up criteria clarified; Section about genetics added; Hypotheses updated to reflect change in endpoint; Sample size calculations and justification updated; Details around data collection and analysis of pneumonia SAEs; Additional references added; Genetics added
    11 Mar 2014
    Amendment No. 02: - Updated author list - Secondary Objectives amended to clarify that all hospitals will use 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD 10) codes - Data Analysis and Statistical considerations updated to reflect request from Committee for Medicinal Products for Human Use (CHMP) re Pneumonias - Safety Endpoints updated to reflect request from CHMP re Pneumonia

    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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