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    Clinical Trial Results:
    A Phase III, randomized, double-blind, active controlled, parallel group study, comparing the efficacy, safety and tolerability of the fixed dose combination FF/UMEC/VI with the fixed dose dual combination of FF/VI, administered once-daily via a dry powder inhaler in subjects with inadequately controlled asthma

    Summary
    EudraCT number
    		 2016-001304-37
    Trial protocol
    		 DE   NL   ES   PL   GB   IT  
    Global end of trial date
    22 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Feb 2020
    First version publication date
    20 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    205715
    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 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effects of FF/UMEC/VI on lung function compared with FF/VI after 24 weeks of treatment
    Protection of trial subjects
    The AM3 electronic diary (eDiary) was used to provide alerts to participants and investigators. These alerts highlighted unfavorable changes in one or more measures of asthma control (e.g. nocturnal awakening requiring rescue medication; increase in daytime asthma symptom score; increase in daily rescue medication use; worsening pulmonary function) which may have warranted investigator intervention to address a participant’s worsening condition.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Oct 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 195
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    Canada: 72
    Country: Number of subjects enrolled
    Germany: 127
    Country: Number of subjects enrolled
    Italy: 37
    Country: Number of subjects enrolled
    Japan: 229
    Country: Number of subjects enrolled
    Korea, Republic of: 58
    Country: Number of subjects enrolled
    Netherlands: 26
    Country: Number of subjects enrolled
    Poland: 238
    Country: Number of subjects enrolled
    Romania: 267
    Country: Number of subjects enrolled
    Russian Federation: 640
    Country: Number of subjects enrolled
    South Africa: 60
    Country: Number of subjects enrolled
    Spain: 58
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    United States: 399
    Worldwide total number of subjects
    2436
    EEA total number of subjects
    766
    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)
    1927
    From 65 to 84 years
    507
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled from 322 centers across 15 countries.

    Pre-assignment
    Screening details
    		 Total 5185 participants were screened and 2436 participants were enrolled into the study and received the study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FF/VI 100/25 mcg
    Arm description
    		 Participants received Fluticasone Furoate/ Vilanterol (FF/VI) 100/25 micrograms (mcg) inhalation powder via dry powder inhaler (DPI), once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    FF/VI 100/25 mcg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received Fluticasone Furoate/ Vilanterol (FF/VI) 100/25 micrograms (mcg) inhalation powder via DPI, once daily in the morning for up to 52 weeks.

    Investigational medicinal product name
    Albuterol/ Salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Albuterol/ Salbutamol were provided as a rescue inhaler to be used on an as needed basis.

    Arm title
    		 FF/UMEC/VI 100/ 31.25/25 mcg
    Arm description
    		 Participants received Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) 100/31.25/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FF/UMEC/VI 100/ 31.25/25 mcg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received FF/UMEC/VI 100/ 31.25/25 mcg inhalation powder via dry powder inhaler (DPI), once daily in the morning for up to 52 weeks.

    Investigational medicinal product name
    Albuterol/ Salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Albuterol/ Salbutamol were provided as a rescue inhaler to be used on an as needed basis.

    Arm title
    		 FF/UMEC/VI 100/62.5/25 mcg
    Arm description
    		 Participants received FF/UMEC/VI 100/62.5/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FF/UMEC/VI 100/62.5/25 mcg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received FF/UMEC/VI 100/62.5/25 mcg inhalation powder via DPI, once daily in the morning for up to 52 weeks.

    Investigational medicinal product name
    Albuterol/ Salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Albuterol/ Salbutamol were provided as a rescue inhaler to be used on an as needed basis.

    Arm title
    		 FF/VI 200/25 mcg
    Arm description
    		 Participants received FF/VI 200/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    FF/VI 200/25 mcg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received FF/VI 200/25 mcg inhalation powder via DPI, once daily in the morning for up to 52 weeks.

    Investigational medicinal product name
    Albuterol/ Salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Albuterol/ Salbutamol were provided as a rescue inhaler to be used on an as needed basis.

    Arm title
    		 FF/UMEC/VI 200/ 31.25/25 mcg
    Arm description
    		 Participants received FF/UMEC/VI 200/31.25/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FF/UMEC/VI 200/ 31.25/25 mcg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received FF/UMEC/VI 200/ 31.25/25 mcg inhalation powder via DPI, once daily in the morning for up to 52 weeks.

    Investigational medicinal product name
    Albuterol/ Salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Albuterol/ Salbutamol were provided as a rescue inhaler to be used on an as needed basis.

    Arm title
    		 FF/UMEC/VI 200/62.5/25 mcg
    Arm description
    		 Participants received FF/UMEC/VI 200/62.5/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FF/UMEC/VI 200/62.5/25 mcg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received FF/UMEC/VI 200/62.5/25 mcg inhalation powder via DPI, once daily in the morning for up to 52 weeks.

    Investigational medicinal product name
    Albuterol/ Salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Albuterol/ Salbutamol were provided as a rescue inhaler to be used on an as needed basis.

    Number of subjects in period 1
    		FF/VI 100/25 mcg FF/UMEC/VI 100/ 31.25/25 mcg FF/UMEC/VI 100/62.5/25 mcg FF/VI 200/25 mcg FF/UMEC/VI 200/ 31.25/25 mcg FF/UMEC/VI 200/62.5/25 mcg
    Started
    407
    405
    406
    406
    404
    408
    Completed
    374
    374
    383
    378
    381
    384
    Not completed
    33
    31
    23
    28
    23
    24
         Adverse event, serious fatal
    -
    2
    -
    1
    -
    -
         Physician decision
    2
    1
    -
    1
    1
    1
         Consent withdrawn by subject
    14
    13
    9
    12
    13
    14
         Adverse event, non-fatal
    9
    1
    2
    1
    3
    2
         Protocol defined withdrawal criteria met
    1
    -
    1
    1
    1
    -
         Lost to follow-up
    2
    4
    2
    4
    2
    4
         Lack of efficacy
    2
    3
    4
    2
    1
    1
         Protocol deviation
    3
    7
    5
    6
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FF/VI 100/25 mcg
    Reporting group description
    		 Participants received Fluticasone Furoate/ Vilanterol (FF/VI) 100/25 micrograms (mcg) inhalation powder via dry powder inhaler (DPI), once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/UMEC/VI 100/ 31.25/25 mcg
    Reporting group description
    		 Participants received Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) 100/31.25/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/UMEC/VI 100/62.5/25 mcg
    Reporting group description
    		 Participants received FF/UMEC/VI 100/62.5/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/VI 200/25 mcg
    Reporting group description
    		 Participants received FF/VI 200/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/UMEC/VI 200/ 31.25/25 mcg
    Reporting group description
    		 Participants received FF/UMEC/VI 200/31.25/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/UMEC/VI 200/62.5/25 mcg
    Reporting group description
    		 Participants received FF/UMEC/VI 200/62.5/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group values
    		 FF/VI 100/25 mcg FF/UMEC/VI 100/ 31.25/25 mcg FF/UMEC/VI 100/62.5/25 mcg FF/VI 200/25 mcg FF/UMEC/VI 200/ 31.25/25 mcg FF/UMEC/VI 200/62.5/25 mcg Total
    Number of subjects
    		 407 405 406 406 404 408 2436
    Age categorical
    Units: Subjects
        All Participants
    		 407 405 406 406 404 408 2436
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 53.3 ( 13.03 ) 51.7 ( 13.27 ) 52.9 ( 13.39 ) 53.9 ( 13.30 ) 53.5 ( 13.12 ) 53.7 ( 12.50 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 254 262 248 252 240 258 1514
        Male
    		 153 143 158 154 164 150 922
    Race/Ethnicity, Customized
    Units: Subjects
        Black or African American (AA)
    		 20 21 17 26 11 24 119
        American Indian or Alaska Native
    		 0 0 0 0 2 2 4
        Asian-Central/South Asian Heritage (H.)
    		 5 4 1 5 9 0 24
        Asian-Japanese H./East Asian H./SouthEast Asian H.
    		 54 55 50 53 55 52 319
        Mixed Asian Race
    		 0 0 0 0 1 0 1
        Native Hawaiian or other Pacific Islander
    		 0 1 0 0 1 1 3
        White
    		 326 319 338 316 325 326 1950
        American Indian or Alaska Native and Black or AA
    		 0 1 0 0 0 0 1
        American Indian or Alaska Native and White
    		 1 0 0 0 0 2 3
        Asian and Black or African American and White
    		 0 1 0 2 0 0 3
        Asian and White
    		 0 1 0 0 0 0 1
        Black or African American and White
    		 1 2 0 3 0 1 7
        Missing
    		 0 0 0 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    FF/VI 100/25 mcg
    Reporting group description
    		 Participants received Fluticasone Furoate/ Vilanterol (FF/VI) 100/25 micrograms (mcg) inhalation powder via dry powder inhaler (DPI), once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/UMEC/VI 100/ 31.25/25 mcg
    Reporting group description
    		 Participants received Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) 100/31.25/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/UMEC/VI 100/62.5/25 mcg
    Reporting group description
    		 Participants received FF/UMEC/VI 100/62.5/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/VI 200/25 mcg
    Reporting group description
    		 Participants received FF/VI 200/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/UMEC/VI 200/ 31.25/25 mcg
    Reporting group description
    		 Participants received FF/UMEC/VI 200/31.25/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/UMEC/VI 200/62.5/25 mcg
    Reporting group description
    		 Participants received FF/UMEC/VI 200/62.5/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Subject analysis set title
    FF/VI
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received FF/VI 100/25 mcg or 200/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Subject analysis set title
    FF/UMEC/VI (UMEC 31.25 mcg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received FF/UMEC/VI 100/31.25/25 mcg or 200/31.25/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Subject analysis set title
    FF/UMEC/VI (UMEC 62.5 mcg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received FF/UMEC/VI 100/62.5/25 mcg or 200/62.5/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Subject analysis set title
    FF/VI
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received FF/VI 100/25 mcg or 200/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Subject analysis set title
    FF/UMEC/VI (UMEC 31.25 mcg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received FF/UMEC/VI 100/31.25/25 mcg or 200/31.25/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Subject analysis set title
    FF/UMEC/VI (UMEC 62.5 mcg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received FF/UMEC/VI 100/62.5/25 mcg or 200/62.5/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Subject analysis set title
    FF/UMEC/VI (UMEC 31.25 mcg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received FF/UMEC/VI 100/31.25/25 mcg or 200/31.25/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Subject analysis set title
    FF/UMEC/VI (UMEC 62.5 mcg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received FF/UMEC/VI 100/62.5/25 mcg or 200/62.5/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Subject analysis set title
    FF/VI
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received FF/VI 100/25 mcg or 200/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Subject analysis set title
    FF/UMEC/VI (UMEC 31.25 mcg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received FF/UMEC/VI 100/31.25/25 mcg or 200/31.25/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Subject analysis set title
    FF/UMEC/VI (UMEC 62.5 mcg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received FF/UMEC/VI 100/62.5/25 mcg or 200/62.5/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Primary: Mean change from Baseline in trough Forced Expiratory Volume in 1 second (FEV1) at Week 24

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    End point title
    		 Mean change from Baseline in trough Forced Expiratory Volume in 1 second (FEV1) at Week 24
    End point description
    FEV1 is a measure of lung function and is defined as the maximal volume of air that can be forcefully exhaled in one second. Trough FEV1 on treatment is defined as the highest FEV1 value obtained prior to the morning dose of investigational product. Baseline value is the last acceptable/borderline acceptable pre-dose FEV1 prior to randomized treatment start date (pre-dose at Day 1). Change from Baseline value is the value at Week 24 minus the Baseline value. Intent-to-Treat(ITT) Population comprised of all randomized participants, excluding those who were randomized in error, who did not receive the study drug. Treatment policy estimand was assessed, including all on- and post-treatment data. Different participants may have been analyzed at different time points; thus, overall number of participants analyzed reflects everyone in ITT Population without missing covariate information, with Baseline and at least one post-baseline measurement. Mixed Model Repeated Measures(MMRM) was used.
    End point type
    Primary
    End point timeframe
    Baseline (pre-dose at Day 1) and Week 24
    End point values
    		 FF/VI 100/25 mcg FF/UMEC/VI 100/ 31.25/25 mcg FF/UMEC/VI 100/62.5/25 mcg FF/VI 200/25 mcg FF/UMEC/VI 200/ 31.25/25 mcg FF/UMEC/VI 200/62.5/25 mcg
    Number of subjects analysed
    400 [1]
    399 [2]
    404 [3]
    403
    399
    405
    Units: Liters
        least squares mean (standard error)
    0.024 ( 0.0157 )
    0.120 ( 0.0157 )
    0.134 ( 0.0155 )
    0.076 ( 0.0156 )
    0.157 ( 0.0156 )
    0.168 ( 0.0155 )
    Notes
    [1] - ITT Population
    [2] - Only those participants with data available at the specified data point were analyzed.
    [3] - Participants with Baseline value and at least one post-baseline measurement were analyzed.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FF/VI 100/25 mcg v FF/UMEC/VI 100/ 31.25/25 mcg
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [4]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.096
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.052
         upper limit
    		 0.139
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0222
    Notes
    [4] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study inhaled corticosteroids (ICS) dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    FF/VI 100/25 mcg v FF/UMEC/VI 100/62.5/25 mcg
    Number of subjects included in analysis
    804
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [5]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.066
         upper limit
    		 0.153
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0221
    Notes
    [5] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    FF/VI 200/25 mcg v FF/UMEC/VI 200/ 31.25/25 mcg
    Number of subjects included in analysis
    802
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [6]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.082
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.039
         upper limit
    		 0.125
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0221
    Notes
    [6] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    FF/VI 200/25 mcg v FF/UMEC/VI 200/62.5/25 mcg
    Number of subjects included in analysis
    808
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [7]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.092
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.049
         upper limit
    		 0.135
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.022
    Notes
    [7] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.

    Secondary: Annualized rate of moderate and severe asthma exacerbations

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    End point title
    		 Annualized rate of moderate and severe asthma exacerbations
    End point description
    A moderate asthma exacerbation is considered to be a deterioration in asthma symptoms or in lung function, or increased rescue bronchodilator use lasting for at least 2 days or more, but not be severe enough to warrant systemic corticosteroid use (or a doubling or more of the maintenance systemic corticosteroid dose, if applicable) for 3 days or more and/or hospitalization. It is an event that, when recognized, should result in a temporary change in treatment, to prevent it from becoming severe. A severe asthma exacerbation is defined as the deterioration of asthma requiring the use of systemic corticosteroids (tablets,suspension or injection), or an increase from a stable maintenance dose (For participants receiving maintenance systemic corticosteroids, at least double the maintenance systemic corticosteroid dose for at least 3 days is required), for at least 3 days or an inpatient hospitalization or emergency department visit because of asthma, requiring systemic corticosteroids.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 FF/VI FF/UMEC/VI (UMEC 31.25 mcg) FF/UMEC/VI (UMEC 62.5 mcg)
    Number of subjects analysed
    813 [8]
    809 [9]
    814 [10]
    Units: Exacerbations per year
        arithmetic mean (confidence interval 95%)
    0.70 (0.61 to 0.80)
    0.68 (0.60 to 0.78)
    0.61 (0.53 to 0.70)
    Notes
    [8] - ITT Population. Participants with at least one day on study post-randomization were analyzed.
    [9] - Primary analysis used pooleddata from 2 FF/UMEC/VI arms for fixed UMEC dose compared to 2 FF/VI arms
    [10] - Arms were pooled to provide more precise estimate for treatment effect of addition of UMEC to FF/VI
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Treatment policy estimand was assessed, including all on- and post-treatment data.
    Comparison groups
    FF/VI v FF/UMEC/VI (UMEC 31.25 mcg)
    Number of subjects included in analysis
    1622
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.778 [11]
    Method
    		 Negative Binomial Model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.17
    Notes
    [11] - p-value was calculated using Generalized linear model with covariates for age, sex, region, treatment group, stratification by pre-study ICS dosage at screening, and severe asthma exacerbations in the previous year (0, 1, >=2).
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Treatment policy estimand was assessed, including all on- and post-treatment data.
    Comparison groups
    FF/VI v FF/UMEC/VI (UMEC 62.5 mcg)
    Number of subjects included in analysis
    1627
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.151 [12]
    Method
    		 Negative Binomial Model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.05
    Notes
    [12] - p-value was calculated using Generalized linear model with covariates for age, sex, region, treatment group, stratification by pre-study ICS dosage at screening, and severe asthma exacerbations in the previous year (0, 1, >=2).

    Secondary: Mean change from Baseline in clinic FEV1 at 3 hours post study treatment at Week 24

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    End point title
    		 Mean change from Baseline in clinic FEV1 at 3 hours post study treatment at Week 24
    End point description
    FEV1 is a measure of lung function and is defined as the maximal volume of air that can be forcefully exhaled in one second. Baseline value is the last acceptable/borderline acceptable pre-dose FEV1 prior to randomized treatment start date (pre-dose at Day 1). Change from Baseline value is the value at Week 24 (recorded at 3 hours post dose) minus the Baseline value. Only those participants with available Baseline and on-treatment data at Week 24 were analyzed
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose at Day 1) and 3 hours post dose at Week 24
    End point values
    		 FF/VI 100/25 mcg FF/UMEC/VI 100/ 31.25/25 mcg FF/UMEC/VI 100/62.5/25 mcg FF/VI 200/25 mcg FF/UMEC/VI 200/ 31.25/25 mcg FF/UMEC/VI 200/62.5/25 mcg
    Number of subjects analysed
    369 [13]
    375
    379
    377
    371
    378
    Units: Liters
        least squares mean (standard error)
    0.132 ( 0.0160 )
    0.220 ( 0.0159 )
    0.243 ( 0.0158 )
    0.168 ( 0.0159 )
    0.256 ( 0.0160 )
    0.286 ( 0.0158 )
    Notes
    [13] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FF/VI 100/25 mcg v FF/UMEC/VI 100/ 31.25/25 mcg
    Number of subjects included in analysis
    744
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [14]
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.088
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.044
         upper limit
    		 0.132
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0226
    Notes
    [14] - p-value was calculated using Analysis of Covariance (ANCOVA) with covariates of treatment, age, sex, region, Baseline value, and pre-study ICS dosage at screening.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    FF/VI 100/25 mcg v FF/UMEC/VI 100/62.5/25 mcg
    Number of subjects included in analysis
    748
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [15]
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.111
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.067
         upper limit
    		 0.155
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0225
    Notes
    [15] - p-value was calculated using ANCOVA with covariates of treatment, age, sex, region, Baseline value, and pre-study ICS dosage at screening.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    FF/VI 200/25 mcg v FF/UMEC/VI 200/ 31.25/25 mcg
    Number of subjects included in analysis
    748
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [16]
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.088
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.044
         upper limit
    		 0.132
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0225
    Notes
    [16] - p-value was calculated using ANCOVA with covariates of treatment, age, sex, region, Baseline value, and pre-study ICS dosage at screening.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    FF/VI 200/25 mcg v FF/UMEC/VI 200/62.5/25 mcg
    Number of subjects included in analysis
    755
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [17]
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.118
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.074
         upper limit
    		 0.162
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0224
    Notes
    [17] - p-value was calculated using ANCOVA with covariates of treatment, age, sex, region, Baseline value, and pre-study ICS dosage at screening.

    Secondary: Mean change from Baseline in Asthma Control Questionnaire-7 (ACQ-7) total score at Week 24

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    End point title
    		 Mean change from Baseline in Asthma Control Questionnaire-7 (ACQ-7) total score at Week 24
    End point description
    The ACQ-7 consists of 7 attributes of asthma control, of which 6 to be self-completed by participant in a 6-item questionnaire, enquire about frequency and/or severity of symptoms over the previous week on: nocturnal awakening, symptoms on waking in the morning, activity limitation, shortness of breath, wheeze,and rescue medication use. The seventh attribute measures the lung function, which was included via pre-bronchodilator FEV1 % predicted value. All 7 items of ACQ have response on 0-6 ordinal scale (0=no impairment/limitation, 6=total impairment/limitation). The total score is calculated as the average of all non-missing item responses, ranges from 0 to 6. Higher score indicates worst symptoms. Treatment policy estimand was assessed, including all on- and post-treatment data. Baseline value was at randomization visit (pre-dose,Day 1). Change from Baseline was defined as value at Week 24 minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose at Day 1) and Week 24
    End point values
    		 FF/VI FF/UMEC/VI (UMEC 31.25 mcg) FF/UMEC/VI (UMEC 62.5 mcg)
    Number of subjects analysed
    784 [18]
    784 [19]
    790 [20]
    Units: Scores on a scale
        least squares mean (standard error)
    -0.678 ( 0.0240 )
    -0.734 ( 0.0240 )
    -0.767 ( 0.0238 )
    Notes
    [18] - ITT Population. Participants with Baseline and at least one post-baseline measurement were analyzed.
    [19] - Primary analysis used pooleddata from 2 FF/UMEC/VI arms for fixed UMEC dose compared to 2 FF/VI arms
    [20] - Arms were pooled to provide more precise estimate for treatment effect of addition of UMEC to FF/VI
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FF/VI v FF/UMEC/VI (UMEC 31.25 mcg)
    Number of subjects included in analysis
    1568
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.094 [21]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.057
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.124
         upper limit
    		 0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.034
    Notes
    [21] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    FF/VI v FF/UMEC/VI (UMEC 62.5 mcg)
    Number of subjects included in analysis
    1574
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008 [22]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.089
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.156
         upper limit
    		 -0.023
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0338
    Notes
    [22] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.

    Secondary: Mean change from Baseline in Saint George's Respiratory Questionnaire (SGRQ) total score at Week 24

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    End point title
    		 Mean change from Baseline in Saint George's Respiratory Questionnaire (SGRQ) total score at Week 24
    End point description
    The SGRQ had 50 questions (scored from 0 to 100 where 0 indicates best and 100 indicates worst health) designed to measure quality of life (QoL) of participants with airway obstruction, measuring symptoms, impact, and activity. The questions are designed to be self-completed by the participant with a recall over the past 3 months. SGRQ total score was calculated by summing the pre-assigned weights of answers, dividing by the sum of the maximum weights for items in SGRQ and multiplying by 100. SGRQ total score ranges from 0 to 100 where 0 indicates best and 100 indicates worst health. A change of 4 points is considered a clinically relevant change. Treatment policy estimand was assessed, including all on- and post-treatment data. Baseline value was at randomization visit (pre-dose at Day 1). Change from Baseline value is the value at Week 24 minus the Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose at Day 1) and Week 24
    End point values
    		 FF/VI FF/UMEC/VI (UMEC 31.25 mcg) FF/UMEC/VI (UMEC 62.5 mcg)
    Number of subjects analysed
    784 [23]
    782 [24]
    795 [25]
    Units: Scores on a scale
        least squares mean (standard error)
    -11.39 ( 0.491 )
    -10.29 ( 0.494 )
    -11.69 ( 0.487 )
    Notes
    [23] - ITT Population. Participants with Baseline and at least one post-baseline measurement were analyzed.
    [24] - Primary analysis used pooleddata from 2 FF/UMEC/VI arms for fixed UMEC dose compared to 2 FF/VI arms
    [25] - Arms were pooled to provide more precise estimate for treatment effect of addition of UMEC to FF/VI
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FF/VI v FF/UMEC/VI (UMEC 31.25 mcg)
    Number of subjects included in analysis
    1566
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.115 [26]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 2.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.697
    Notes
    [26] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    FF/VI v FF/UMEC/VI (UMEC 62.5 mcg)
    Number of subjects included in analysis
    1579
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.662 [27]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.66
         upper limit
    		 1.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.692
    Notes
    [27] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.

    Secondary: Mean change from Baseline in Evaluating Respiratory Symptoms (E-RS) total score over Weeks 21 to 24 (inclusive) of the treatment period

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    End point title
    		 Mean change from Baseline in Evaluating Respiratory Symptoms (E-RS) total score over Weeks 21 to 24 (inclusive) of the treatment period
    End point description
    The E-RS in Chronic Obstructive Pulmonary Disease (COPD) consists of 11 items. E-RS captures information related to respiratory symptoms, i.e. breathlessness, cough, sputum production, chest congestion and chest tightness. The E-RS was completed daily and data was derived by 4-weekly intervals, requiring at least 50% of data to be present during a period. 7 items are scored from 0 (not at all) to 4 (extreme) and 4 items are scored from 0 (not at all) to 3 (extreme). The E-RS total score was calculated by taking sum of all the items. The E-RS total score has a scoring range of 0 to 40, with higher scores indicating more severe respiratory symptoms. Treatment policy estimand was assessed, including all on- and post-treatment data. Baseline value was the mean value of 14 days prior to randomization. Change from Baseline was calculated as post-baseline value (mean of daily E-RS total scores during Week 21 to 24) minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (14 days prior to randomization) and Weeks 21 to 24
    End point values
    		 FF/VI FF/UMEC/VI (UMEC 31.25 mcg) FF/UMEC/VI (UMEC 62.5 mcg)
    Number of subjects analysed
    787 [28]
    796 [29]
    802 [30]
    Units: Scores on a scale
        least squares mean (standard error)
    -2.47 ( 0.131 )
    -2.60 ( 0.130 )
    -2.89 ( 0.130 )
    Notes
    [28] - ITT Population. Participants with Baseline and at least one post-baseline measurement were analyzed.
    [29] - Primary analysis used pooleddata from 2 FF/UMEC/VI arms for fixed UMEC dose compared to 2 FF/VI arms
    [30] - Arms were pooled to provide more precise estimate for treatment effect of addition of UMEC to FF/VI
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FF/VI v FF/UMEC/VI (UMEC 31.25 mcg)
    Number of subjects included in analysis
    1583
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.479 [31]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.185
    Notes
    [31] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and 4-weekly period, interaction terms for Baseline value by 4-weekly period and treatment by 4-weekly period.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    FF/VI v FF/UMEC/VI (UMEC 62.5 mcg)
    Number of subjects included in analysis
    1589
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.023 [32]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.78
         upper limit
    		 -0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.184
    Notes
    [32] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and 4-weekly period, interaction terms for Baseline value by 4-weekly period and treatment by 4-weekly period.

    Secondary: Number of participants with any serious adverse event (SAE) and common (>=3%) non-SAE

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    End point title
    		 Number of participants with any serious adverse event (SAE) and common (>=3%) non-SAE
    End point description
    Adverse event (AE) is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, events associated with liver injury and impaired liver function, or any other situation according to medical or scientific judgment were categorized as SAE. Number of participants with any SAE and common (>=3%) non-SAEs are presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 FF/VI 100/25 mcg FF/UMEC/VI 100/ 31.25/25 mcg FF/UMEC/VI 100/62.5/25 mcg FF/VI 200/25 mcg FF/UMEC/VI 200/ 31.25/25 mcg FF/UMEC/VI 200/62.5/25 mcg
    Number of subjects analysed
    407 [33]
    405
    406
    406
    404
    408
    Units: Participants
        Common non-SAE
    136
    150
    135
    122
    127
    122
        SAE
    25
    18
    23
    21
    23
    21
    Notes
    [33] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal Electrocardiogram (ECG) Findings

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    End point title
    		 Number of Participants With Abnormal Electrocardiogram (ECG) Findings
    End point description
    Twelve-lead ECGs were performed during the study using an automated ECG machine. All ECG measurements were made with the participant in a supine position having rested in this position for approximately 5 minutes before each reading. The number of participants with worst case post-Baseline abnormal ECG findings were reported. Only those participants with data available at the specified time point were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 FF/VI 100/25 mcg FF/UMEC/VI 100/ 31.25/25 mcg FF/UMEC/VI 100/62.5/25 mcg FF/VI 200/25 mcg FF/UMEC/VI 200/ 31.25/25 mcg FF/UMEC/VI 200/62.5/25 mcg
    Number of subjects analysed
    401 [34]
    398
    398
    397
    399
    404
    Units: Participants
    115
    118
    109
    109
    106
    108
    Notes
    [34] - ITT Population
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 24

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    End point title
    		 Mean Change from Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 24
    End point description
    Blood pressure (systolic and diastolic) was measured in the sitting position after approximately 5 minutes rest. Baseline value is the last acceptable/borderline acceptable value prior to randomized treatment start date (pre-dose at Day 1). Change from Baseline value is the value at the clinic visit minus the Baseline value. Different participants may have been analyzed at different time points; thus, overall number of participants analyzed reflects everyone in ITT Population without missing covariate information, with Baseline and at least one post-baseline measurement. Only those participants with data available at the specified data point were analyzed. Participants with a Baseline value and at least one post-baseline measurement were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose at Day 1) and Week 24
    End point values
    		 FF/VI 100/25 mcg FF/UMEC/VI 100/ 31.25/25 mcg FF/UMEC/VI 100/62.5/25 mcg FF/VI 200/25 mcg FF/UMEC/VI 200/ 31.25/25 mcg FF/UMEC/VI 200/62.5/25 mcg
    Number of subjects analysed
    401 [35]
    398
    399
    397
    399
    402
    Units: Millimeter of mercury
    least squares mean (standard error)
        SBP
    1.6 ( 0.53 )
    0.6 ( 0.53 )
    1.1 ( 0.52 )
    0.2 ( 0.53 )
    0.8 ( 0.53 )
    0.9 ( 0.52 )
        DBP
    0.4 ( 0.39 )
    0.1 ( 0.39 )
    1.3 ( 0.39 )
    0.4 ( 0.39 )
    0.2 ( 0.40 )
    0.8 ( 0.39 )
    Notes
    [35] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Comparison for SBP
    Comparison groups
    FF/VI 100/25 mcg v FF/UMEC/VI 100/ 31.25/25 mcg
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.172 [36]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.75
    Notes
    [36] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Comparison for SBP
    Comparison groups
    FF/VI 100/25 mcg v FF/UMEC/VI 100/62.5/25 mcg
    Number of subjects included in analysis
    800
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.436 [37]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.74
    Notes
    [37] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Comparison for SBP
    Comparison groups
    FF/VI 200/25 mcg v FF/UMEC/VI 200/ 31.25/25 mcg
    Number of subjects included in analysis
    796
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.426 [38]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 2.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.75
    Notes
    [38] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Comparison for SBP
    Comparison groups
    FF/VI 200/25 mcg v FF/UMEC/VI 200/62.5/25 mcg
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.349 [39]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 2.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.74
    Notes
    [39] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Comparison for DBP
    Comparison groups
    FF/VI 100/25 mcg v FF/UMEC/VI 100/ 31.25/25 mcg
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.482 [40]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.56
    Notes
    [40] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Comparison for DBP
    Comparison groups
    FF/VI 100/25 mcg v FF/UMEC/VI 100/62.5/25 mcg
    Number of subjects included in analysis
    800
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.142 [41]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 1.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.56
    Notes
    [41] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Comparison for DBP
    Comparison groups
    FF/VI 200/25 mcg v FF/UMEC/VI 200/ 31.25/25 mcg
    Number of subjects included in analysis
    796
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.806 [42]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.56
    Notes
    [42] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Comparison for DBP
    Comparison groups
    FF/VI 200/25 mcg v FF/UMEC/VI 200/62.5/25 mcg
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.447 [43]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 1.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.55
    Notes
    [43] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.

    Secondary: Mean Change from Baseline in Pulse Rate at Week 24

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    End point title
    		 Mean Change from Baseline in Pulse Rate at Week 24
    End point description
    Pulse Rate was measured in the sitting position after approximately 5 minutes rest. Baseline value is the last acceptable/borderline acceptable value prior to randomized treatment start date (pre-dose at Day 1). Change from Baseline value is the value at the clinic visit minus the Baseline value. Different participants may have been analyzed at different time points; thus, overall number of participants analyzed reflects everyone in ITT Population without missing covariate information, with Baseline and at least one post-baseline measurement. Only those participants with data available at the specified data point were analyzed. Participants with a Baseline value and at least one post-baseline measurement were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose at Day 1) and Week 24
    End point values
    		 FF/VI 100/25 mcg FF/UMEC/VI 100/ 31.25/25 mcg FF/UMEC/VI 100/62.5/25 mcg FF/VI 200/25 mcg FF/UMEC/VI 200/ 31.25/25 mcg FF/UMEC/VI 200/62.5/25 mcg
    Number of subjects analysed
    401 [44]
    398
    399
    397
    399
    402
    Units: Beats per minute
        least squares mean (standard error)
    -1.1 ( 0.43 )
    0.2 ( 0.43 )
    -1.0 ( 0.43 )
    -0.7 ( 0.43 )
    -1.3 ( 0.44 )
    -0.5 ( 0.43 )
    Notes
    [44] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FF/VI 100/25 mcg v FF/UMEC/VI 100/ 31.25/25 mcg
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.034 [45]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 2.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.61
    Notes
    [45] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    FF/VI 100/25 mcg v FF/UMEC/VI 100/62.5/25 mcg
    Number of subjects included in analysis
    800
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.839 [46]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 1.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.61
    Notes
    [46] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    FF/VI 200/25 mcg v FF/UMEC/VI 200/ 31.25/25 mcg
    Number of subjects included in analysis
    796
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.349 [47]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.61
    Notes
    [47] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    FF/VI 200/25 mcg v FF/UMEC/VI 200/62.5/25 mcg
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.768 [48]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.61
    Notes
    [48] - p-value was calculated using MMRM with covariates of treatment, age, sex, region, Baseline value, pre-study ICS dosage at screening, and visit, interaction terms for Baseline value by visit and treatment by visit.

    Secondary: Number of Participants With Abnormal Clinical Chemistry Values

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    End point title
    		 Number of Participants With Abnormal Clinical Chemistry Values
    End point description
    Blood samples were collected for assessment of clinical chemistry parameters, which included albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin, total bilirubin, calcium, creatinine, glucose, potassium, protein, sodium and urea. Abnormal laboratory results are categorized as high or low with respect to their normal ranges. Participants having High and Low values from normal ranges for any parameter at any time post-baseline visits are presented. Only those participants with data available at the specified time point were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 FF/VI 100/25 mcg FF/UMEC/VI 100/ 31.25/25 mcg FF/UMEC/VI 100/62.5/25 mcg FF/VI 200/25 mcg FF/UMEC/VI 200/ 31.25/25 mcg FF/UMEC/VI 200/62.5/25 mcg
    Number of subjects analysed
    391 [49]
    392
    394
    390
    391
    397
    Units: Participants
        Albumin, low
    2
    0
    0
    1
    0
    0
        Albumin, high
    1
    6
    5
    2
    3
    1
        ALT, low
    0
    0
    0
    0
    0
    0
        ALT, high
    41
    29
    24
    28
    27
    30
        AST, low
    0
    0
    0
    0
    0
    0
        AST, high
    29
    27
    14
    21
    23
    16
        ALP, low
    1
    0
    0
    0
    1
    0
        ALP, high
    21
    15
    10
    12
    16
    12
        Direct bilirubin, low
    0
    0
    0
    0
    0
    0
        Direct bilirubin, high
    1
    1
    0
    2
    2
    1
        Bilirubin, low
    0
    0
    0
    0
    0
    0
        Bilirubin, high
    9
    12
    5
    15
    17
    13
        Calcium, low
    4
    9
    7
    7
    4
    3
        Calcium, high
    4
    12
    10
    11
    8
    7
        Creatinine, low
    54
    62
    49
    63
    60
    64
        Creatinine, high
    7
    7
    8
    6
    9
    8
        Glucose, low
    15
    11
    11
    7
    12
    7
        Glucose, high
    74
    71
    70
    76
    66
    73
        Potassium, low
    2
    3
    1
    7
    7
    6
        Potassium, high
    15
    13
    11
    9
    12
    19
        Protein, low
    3
    0
    5
    3
    1
    2
        Protein, high
    0
    1
    3
    2
    3
    1
        Sodium, low
    5
    7
    3
    5
    7
    3
        Sodium, high
    6
    7
    7
    4
    5
    7
        Urea, low
    3
    4
    5
    3
    3
    1
        Urea, high
    13
    17
    3
    11
    11
    13
    Notes
    [49] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal hematology values

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    End point title
    		 Number of Participants With Abnormal hematology values
    End point description
    Blood samples were collected for assessment of hematology parameters, which included Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Erythrocytes, Hematocrit, Hemoglobin, Leukocytes, Platelets, Mean Corpuscular Hemoglobin (MCH) and Mean Corpuscular Volume (MCV). Abnormal laboratory results are categorized as high or low with respect to their normal ranges. Participants having High and Low values from normal ranges for any parameter at any time post-baseline visits are presented. Only those participants with data available at the specified time point were analyzed (represented by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 FF/VI 100/25 mcg FF/UMEC/VI 100/ 31.25/25 mcg FF/UMEC/VI 100/62.5/25 mcg FF/VI 200/25 mcg FF/UMEC/VI 200/ 31.25/25 mcg FF/UMEC/VI 200/62.5/25 mcg
    Number of subjects analysed
    391 [50]
    390
    392
    391
    391
    397
    Units: Participants
        Basophils, low, n=390,390,391,389,389,396
    0
    0
    0
    0
    0
    0
        Basophils, high, n=390,390,391,389,389,396
    1
    0
    0
    0
    0
    0
        Eosinophils, low, n=390,390,391,389,389,396
    26
    27
    25
    31
    32
    28
        Eosinophils, high, n=390,390,391,389,389,396
    111
    84
    102
    84
    85
    78
        Lymphocytes, low, n=390,390,391,389,389,396
    13
    11
    13
    8
    13
    10
        Lymphocytes, high, n=390,390,391,389,389,396
    2
    5
    1
    7
    6
    6
        Monocytes, low, n=390,390,391,389,389,396
    60
    68
    57
    64
    51
    63
        Monocytes, high, n=390,390,391,389,389,396
    7
    1
    4
    2
    7
    4
        Neutrophils, low, n=390,390,391,389,389,396
    14
    10
    16
    10
    12
    9
        Neutrophils, high, n=390,390,391,389,389,396
    21
    20
    15
    19
    15
    34
        Erythrocytes, low, n=391,390,392,391,391,397
    14
    16
    11
    15
    21
    22
        Erythrocytes, high, n=391,390,392,391,391,397
    24
    21
    13
    12
    17
    17
        Hematocrit, low, n=391,390,392,391,391,397
    21
    28
    16
    20
    20
    26
        Hematocrit, high, n=391,390,392,391,391,397
    60
    52
    50
    47
    49
    49
        Hemoglobin, low, n=391,390,392,391,391,397
    32
    47
    40
    40
    37
    34
        Hemoglobin, high, n=391,390,392,391,391,397
    14
    13
    8
    17
    10
    13
        Leukocytes, low, n=391,390,391,389,391,396
    9
    12
    14
    9
    12
    8
        Leukocytes, high, n=391,390,391,389,391,396
    38
    29
    20
    31
    26
    40
        Platelets, low, n=391,388,389,391,388,396
    4
    2
    3
    4
    5
    4
        Platelets, high, n=391,388,389,391,388,396
    17
    16
    19
    21
    19
    21
        MCH, low, n=391,390,392,391,391,397
    40
    47
    24
    34
    41
    25
        MCH, high, n=391,390,392,391,391,397
    18
    32
    22
    17
    25
    32
        MCV, low, n=391,390,392,391,391,397
    20
    22
    10
    15
    19
    14
        MCV, high, n=391,390,392,391,391,397
    29
    41
    25
    29
    26
    37
    Notes
    [50] - ITT Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Non-serious AEs and serious AEs were collected from start of study treatment (Week 0) up to Week 52
    Adverse event reporting additional description
    Non-serious AEs and serious AEs were collected for ITT Population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    FF/VI 100/25 mcg
    Reporting group description
    		 Participants received Fluticasone Furoate/ Vilanterol (FF/VI) 100/25 micrograms (mcg) inhalation powder via dry powder inhaler (DPI), once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/UMEC/VI 100/ 31.25/25 mcg
    Reporting group description
    		 Participants received Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) 100/31.25/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/UMEC/VI 100/62.5/25 mcg
    Reporting group description
    		 Participants received FF/UMEC/VI 100/62.5/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/VI 200/25 mcg
    Reporting group description
    		 Participants received FF/VI 200/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/UMEC/VI 200/ 31.25/25 mcg
    Reporting group description
    		 Participants received FF/UMEC/VI 200/31.25/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/UMEC/VI 200/62.5/25 mcg
    Reporting group description
    		 Participants received FF/UMEC/VI 200/62.5/25 mcg inhalation powder via DPI, once daily in the morning up to 52 weeks. Participants were allowed to take albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Serious adverse events
    		 FF/VI 100/25 mcg FF/UMEC/VI 100/ 31.25/25 mcg FF/UMEC/VI 100/62.5/25 mcg FF/VI 200/25 mcg FF/UMEC/VI 200/ 31.25/25 mcg FF/UMEC/VI 200/62.5/25 mcg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 407 (6.14%)
    18 / 405 (4.44%)
    23 / 406 (5.67%)
    21 / 406 (5.17%)
    23 / 404 (5.69%)
    21 / 408 (5.15%)
         number of deaths (all causes)
    0
    2
    0
    1
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    1 / 407 (0.25%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    1 / 406 (0.25%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    1 / 406 (0.25%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal adenocarcinoma
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lip and/or oral cavity cancer
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    1 / 406 (0.25%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 407 (0.25%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    1 / 406 (0.25%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 407 (0.00%)
    1 / 405 (0.25%)
    1 / 406 (0.25%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 407 (0.00%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 407 (0.25%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    7 / 407 (1.72%)
    7 / 405 (1.73%)
    7 / 406 (1.72%)
    6 / 406 (1.48%)
    5 / 404 (1.24%)
    4 / 408 (0.98%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 8
    0 / 8
    0 / 7
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    2 / 406 (0.49%)
    1 / 406 (0.25%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 407 (0.00%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    2 / 408 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic rhinosinusitis with nasal polyps
         subjects affected / exposed
    1 / 407 (0.25%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status asthmaticus
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 407 (0.25%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 407 (0.25%)
    0 / 405 (0.00%)
    1 / 406 (0.25%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    1 / 406 (0.25%)
    1 / 406 (0.25%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 407 (0.00%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 407 (0.25%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    1 / 406 (0.25%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 407 (0.00%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal foreign body
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    1 / 406 (0.25%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary contusion
         subjects affected / exposed
    0 / 407 (0.00%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    1 / 406 (0.25%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hypertrophic cardiomyopathy
         subjects affected / exposed
    0 / 407 (0.00%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    2 / 407 (0.49%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    2 / 406 (0.49%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 407 (0.00%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    1 / 406 (0.25%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 407 (0.25%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    1 / 406 (0.25%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 407 (0.00%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 407 (0.00%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    1 / 406 (0.25%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    1 / 406 (0.25%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 407 (0.25%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    1 / 406 (0.25%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 407 (0.25%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal ulcer haemorrhage
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    1 / 406 (0.25%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    1 / 406 (0.25%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 407 (0.25%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 407 (0.25%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 407 (0.25%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    1 / 406 (0.25%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    1 / 407 (0.25%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    1 / 406 (0.25%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    0 / 407 (0.00%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress urinary incontinence
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    1 / 406 (0.25%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Foot deformity
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    1 / 406 (0.25%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 407 (0.00%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    1 / 406 (0.25%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal disorder
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigger finger
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 407 (0.49%)
    0 / 405 (0.00%)
    3 / 406 (0.74%)
    3 / 406 (0.74%)
    4 / 404 (0.99%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
    0 / 3
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 407 (0.00%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 407 (0.00%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 407 (0.25%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    1 / 404 (0.25%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    1 / 408 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    1 / 406 (0.25%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound sepsis
         subjects affected / exposed
    1 / 407 (0.25%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 407 (0.00%)
    1 / 405 (0.25%)
    0 / 406 (0.00%)
    0 / 406 (0.00%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 407 (0.00%)
    0 / 405 (0.00%)
    0 / 406 (0.00%)
    1 / 406 (0.25%)
    0 / 404 (0.00%)
    0 / 408 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 FF/VI 100/25 mcg FF/UMEC/VI 100/ 31.25/25 mcg FF/UMEC/VI 100/62.5/25 mcg FF/VI 200/25 mcg FF/UMEC/VI 200/ 31.25/25 mcg FF/UMEC/VI 200/62.5/25 mcg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    136 / 407 (33.42%)
    150 / 405 (37.04%)
    135 / 406 (33.25%)
    122 / 406 (30.05%)
    127 / 404 (31.44%)
    122 / 408 (29.90%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    30 / 407 (7.37%)
    31 / 405 (7.65%)
    36 / 406 (8.87%)
    23 / 406 (5.67%)
    27 / 404 (6.68%)
    19 / 408 (4.66%)
         occurrences all number
    46
    51
    52
    47
    38
    25
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    16 / 407 (3.93%)
    12 / 405 (2.96%)
    13 / 406 (3.20%)
    6 / 406 (1.48%)
    14 / 404 (3.47%)
    9 / 408 (2.21%)
         occurrences all number
    16
    14
    19
    8
    20
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    63 / 407 (15.48%)
    56 / 405 (13.83%)
    60 / 406 (14.78%)
    53 / 406 (13.05%)
    51 / 404 (12.62%)
    51 / 408 (12.50%)
         occurrences all number
    76
    68
    73
    70
    58
    67
    Upper respiratory tract infection
         subjects affected / exposed
    21 / 407 (5.16%)
    24 / 405 (5.93%)
    15 / 406 (3.69%)
    13 / 406 (3.20%)
    15 / 404 (3.71%)
    19 / 408 (4.66%)
         occurrences all number
    26
    35
    16
    16
    19
    21
    Bronchitis
         subjects affected / exposed
    14 / 407 (3.44%)
    18 / 405 (4.44%)
    15 / 406 (3.69%)
    19 / 406 (4.68%)
    16 / 404 (3.96%)
    22 / 408 (5.39%)
         occurrences all number
    15
    22
    15
    26
    19
    24
    Respiratory tract infection viral
         subjects affected / exposed
    11 / 407 (2.70%)
    17 / 405 (4.20%)
    10 / 406 (2.46%)
    7 / 406 (1.72%)
    12 / 404 (2.97%)
    9 / 408 (2.21%)
         occurrences all number
    14
    20
    10
    13
    17
    9
    Influenza
         subjects affected / exposed
    13 / 407 (3.19%)
    12 / 405 (2.96%)
    15 / 406 (3.69%)
    9 / 406 (2.22%)
    8 / 404 (1.98%)
    6 / 408 (1.47%)
         occurrences all number
    14
    12
    16
    9
    8
    6
    Pharyngitis
         subjects affected / exposed
    8 / 407 (1.97%)
    10 / 405 (2.47%)
    9 / 406 (2.22%)
    14 / 406 (3.45%)
    11 / 404 (2.72%)
    9 / 408 (2.21%)
         occurrences all number
    11
    11
    11
    15
    14
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jun 2016
    Re-Publishing: Following publication of the original protocol but prior to distribution of the document, an exploratory analysis of the psychometric properties of the Evaluating Respiratory Symptoms (E-RS) and Supplemental asthma items was included in the protocol. This necessitated a re-publishing of the protocol.
    13 Dec 2016
    Amendment 01 was approved on 13 December 2016, and involved the following changes: one other secondary endpoint assessment time point; clarification of patient-reported outcome (PRO)other efficacy endpoint definitions and minimum clinically important differences (MCIDs); clarification of inclusion/exclusion criteria; clarification of the QT interval corrected for heart rate (QTc)stopping criterion; clarification of the use of study-provided fluticasone propionate (FP) for treatment of the symptoms of a moderate asthma exacerbation; clarification of concomitant medications and non-drug therapies; amending the order and timing of the assessments; amended power of the secondary endpoint analyses; updating of the multiplicity plan.
    23 Jun 2017
    Amendment 02was approved on 23 June 2017, and involved correction of the other objective; clarification of PRO other efficacy endpoint definitions and MCIDs; broadening of the inclusion criteria; clarification of Baseline definition for the electronic diary (eDiary) alerts (Section 4.6.2.7); updating of the multiplicity plan (re-ordering of the hierarchy and removal of FEV1 3 hour post-study treatment [IP]endpoint from the hierarchy).
    29 Sep 2017
    Amendment 03 was approved on 29 September 2017 and involved updating and defining the variable treatment period and transition date to determine the planned end of study (EOS) Visit for each participant; removal of the country-specific minimum requirements for Japanese participants (Protocol Appendix 7).
    05 Dec 2017
    Amendment 04 was approved on 05 December 2017 and involved clarification of details regarding the dispensing and administering of the study-provided FP at the investigator’s discretion, to a participant for treatment of the symptoms of a moderate asthma exacerbation.

    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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