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    Clinical Trial Results:
    Multi-centre, randomized, double-blind, parallel-group study evaluating the effect of Fluticasone Furoate/ Vilanterol (FF/VI) Inhalation Powder once daily compared with Vilanterol (VI) Inhalation Powder Once Daily on Bone Mineral Density (BMD) in subjects with Chronic Obstructive Pulmonary Disease (COPD)

    Summary
    EudraCT number
    		 2012-004801-28
    Trial protocol
    		 DE   ES   NL  
    Global end of trial date
    26 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Apr 2019
    First version publication date
    06 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    102972
    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
    21 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the effect of the inhaled corticosteroid FF on bone mineral density assessed at the total hip by comparing FF/VI treatment with VI treatment in participants with moderate COPD.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Jan 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 27
    Country: Number of subjects enrolled
    Germany: 34
    Country: Number of subjects enrolled
    Netherlands: 56
    Country: Number of subjects enrolled
    Spain: 59
    Country: Number of subjects enrolled
    United States: 107
    Worldwide total number of subjects
    283
    EEA total number of subjects
    149
    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)
    129
    From 65 to 84 years
    152
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted on participants with chronic obstructive pulmonary disease (COPD) in five countries to assess the long-term safety effects of Fluticasone Furoate (FF) component of the FF/Vilanterol (VI) inhalation powder.

    Pre-assignment
    Screening details
    		 A total of 482 participants were screened of which 199 were screen failures. A total of 283 participants were randomized in a 1:1 ratio to receive either VI or FF/VI.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Participants administered VI
    Arm description
    		 Following run-in period of 14 to 21 days, eligible participants were administered VI 25 microgram (mcg) once daily via ELLIPTA inhaler for 156 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vilanterol (VI)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants were administered VI 25 microgram (mcg) once daily via ELLIPTA for 156 weeks

    Arm title
    		 Participants administered FF/VI
    Arm description
    		 Following run-in period of 14 to 21 days, eligible participants were administered FF 100 mcg along with VI 25 mcg once daily via ELLIPTA inhaler for 156 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vilanterol (VI)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants were administered VI 25 mcg /FF 100 mcg once daily via ELLIPTA inhaler for 156 weeks

    Investigational medicinal product name
    Fluticasone Furoate (FF)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants were administered VI 25 mcg /FF 100 mcg once daily via ELLIPTA inhaler for 156 weeks

    Number of subjects in period 1
    		Participants administered VI Participants administered FF/VI
    Started
    142
    141
    Completed
    87
    83
    Not completed
    55
    58
         Consent withdrawn by subject
    13
    17
         Physician decision
    3
    6
         Adverse event, non-fatal
    23
    20
         Lost to follow-up
    4
    4
         Protocol deviation
    1
    -
         Lack of efficacy
    11
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Participants administered VI
    Reporting group description
    		 Following run-in period of 14 to 21 days, eligible participants were administered VI 25 microgram (mcg) once daily via ELLIPTA inhaler for 156 weeks.

    Reporting group title
    Participants administered FF/VI
    Reporting group description
    		 Following run-in period of 14 to 21 days, eligible participants were administered FF 100 mcg along with VI 25 mcg once daily via ELLIPTA inhaler for 156 weeks.

    Reporting group values
    		 Participants administered VI Participants administered FF/VI Total
    Number of subjects
    		 142 141 283
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 62 67 129
        From 65-84 years
    		 79 73 152
        85 years and over
    		 1 1 2
    Age Continuous
    Safety population
    Units: Years
        arithmetic mean (standard deviation)
    		 66.0 ( 8.19 ) 64.4 ( 9.04 ) -
    Sex: Female, Male
    Safety population
    Units: Subjects
        Female
    		 70 71 141
        Male
    		 72 70 142
    Race/Ethnicity, Customized
    Safety population
    Units: Subjects
        Central/South Asian Heritage
    		 0 1 1
        Black or African American
    		 1 1 2
        White
    		 141 139 280

    End points

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    End points reporting groups
    Reporting group title
    Participants administered VI
    Reporting group description
    		 Following run-in period of 14 to 21 days, eligible participants were administered VI 25 microgram (mcg) once daily via ELLIPTA inhaler for 156 weeks.

    Reporting group title
    Participants administered FF/VI
    Reporting group description
    		 Following run-in period of 14 to 21 days, eligible participants were administered FF 100 mcg along with VI 25 mcg once daily via ELLIPTA inhaler for 156 weeks.

    Primary: Percentage change from Baseline in Bone mineral density (BMD) measured at total hip

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    End point title
    		 Percentage change from Baseline in Bone mineral density (BMD) measured at total hip
    End point description
    BMD analysis performed on log (BMD ratio to Baseline) using a repeated measures model with covariates of treatment group, age,gender,Baseline BMI,visit,log Baseline BMD,log Baseline BMD by visit and treatment group by visit interactions.These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority.The analysis shown is for the “While on Treatment”estimand of the difference in percentage(%) change from Baseline per annum between FF/VI±BMD medication/SCS (systemic corticosteroids) and VI±BMD medication/SCS.Baseline is defined as the measurement performed at Visit 1.% change is calculated as (BMD value post-Baseline/Baseline value)-1*by 100.Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).All randomized participants who received at least 1 dose of study treatment were included in Safety Population
    End point type
    Primary
    End point timeframe
    Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks
    End point values
    		 Participants administered VI Participants administered FF/VI
    Number of subjects analysed
    132 [1]
    130 [2]
    Units: Percentage change
    least squares mean (confidence interval 95%)
        Overall % change per year, n = 132, 130
    0.18 (-0.18 to 0.55)
    -0.27 (-0.63 to 0.09)
        % change by Week 26, n= 130, 130
    0.37 (-0.07 to 0.82)
    0.31 (-0.13 to 0.76)
        % change by Week 52, n = 104, 121
    0.35 (-0.21 to 0.91)
    -0.43 (-0.96 to 0.10)
        % change by Week 78, n = 97, 102
    0.22 (-0.41 to 0.85)
    -0.68 (-1.29 to -0.07)
        % change by Week 104, n = 94, 96
    -0.16 (-0.84 to 0.52)
    -1.02 (-1.68 to -0.36)
        % change by Week 130, n = 88, 84
    0.00 (-0.73 to 0.75)
    -1.02 (-1.75 to -0.29)
        % change by Week 156, n = 76, 75
    -0.16 (-1.02 to 0.71)
    -1.29 (-2.13 to -0.45)
    Notes
    [1] - Safety Population
    [2] - Safety Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Treatment comparison for overall weeks
    Comparison groups
    Participants administered VI v Participants administered FF/VI
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Percentage Change from Baseline
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.97
         upper limit
    		 0.06
    Notes
    [3] - Non-inferiority was demonstrated if the lower limit of 95 % confidence interval (CI) for the overall treatment difference change from Baseline between FF/VI and VI was greater than -1 % year

    Secondary: Percentage change from Baseline in BMD measurements at total hip by gender (male participants)

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    End point title
    		 Percentage change from Baseline in BMD measurements at total hip by gender (male participants)
    End point description
    BMD analysis performed on log (BMD ratio to Baseline) using separate repeated measures models for each gender with covariates of treatment group, age, Baseline BMI, visit, log Baseline BMD, log Baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the “While on Treatment” estimand of the difference in percentage change from Baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100.Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks
    End point values
    		 Participants administered VI Participants administered FF/VI
    Number of subjects analysed
    67 [4]
    63 [5]
    Units: Percent change
    least squares mean (confidence interval 95%)
        Overall Week % change per year, n = 67, 63
    0.27 (-0.23 to 0.77)
    -0.20 (-0.70 to 0.31)
        % change by Week 26, n = 66, 63
    0.45 (-0.06 to 0.97)
    0.44 (-0.09 to 0.97)
        % change by Week 52, n = 52, 56
    0.48 (-0.31 to 1.27)
    -0.43 (-1.19 to 0.33)
        % change by Week 78, n = 51, 46
    0.06 (-0.81 to 0.95)
    -0.68 (-1.56 to 0.21)
        % change by Week 104, n = 50, 43
    0.07 (-0.86 to 1.00)
    -0.68 (-1.62 to 0.27)
        % change by Week 130, n = 44, 39
    0.37 (-0.75 to 1.50)
    -0.89 (-2.02 to 0.26)
        % change by Week 156, n = 40, 35
    0.05 (-1.26 to 1.37)
    -1.39 (-2.71 to -0.05)
    Notes
    [4] - Safety Population
    [5] - Safety Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Overall Weeks for Male
    Comparison groups
    Participants administered VI v Participants administered FF/VI
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Percentage Change from Baseline
    Point estimate
    -0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.17
         upper limit
    		 0.24
    Notes
    [6] - Non-inferiority was demonstrated if the lower limit of 95% CI for the overall treatment difference change from Baseline between FF/VI and VI was greater than -1 % year

    Secondary: Percentage change from Baseline in BMD measurements at total hip by gender (female participants)

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    End point title
    		 Percentage change from Baseline in BMD measurements at total hip by gender (female participants)
    End point description
    BMD analysis performed on log (BMD ratio to Baseline) using separate repeated measures models for each gender with covariates of treatment group, age, Baseline BMI, visit, log Baseline BMD, log Baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the “While on Treatment” estimand of the difference in percentage change from Baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100.Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks
    End point values
    		 Participants administered VI Participants administered FF/VI
    Number of subjects analysed
    65 [7]
    67 [8]
    Units: Percent change
    least squares mean (confidence interval 95%)
        Overall Week % change per year, n = 65, 67
    0.09 (-0.46 to 0.64)
    -0.31 (-0.84 to 0.22)
        % change by Week 26, n = 64, 67
    0.28 (-0.45 to 1.02)
    0.20 (-0.51 to 0.92)
        % change by Week 52, n = 52, 65
    0.13 (-0.67 to 0.94)
    -0.42 (-1.16 to 0.33)
        % change by Week 78, n = 46, 56
    0.37 (-0.54 to 1.28)
    -0.63 (-1.48 to 0.23)
        % change by Week 104, n = 44, 53
    -0.40 (-1.40 to 0.61)
    -1.26 (-2.19 to -0.32)
        % change by Week 130, n = 44, 45
    -0.18 (-1.12 to 0.77)
    -0.99 (-1.90 to -0.08)
        % change by Week 156, n = 36, 40
    -0.42 (-1.56 to 0.73)
    -1.19 (-2.27 to -0.11)
    Notes
    [7] - Safety Population
    [8] - Safety Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Overall Weeks for females
    Comparison groups
    Participants administered VI v Participants administered FF/VI
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    Parameter type
    		 Percentage Change from Baseline
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.16
         upper limit
    		 0.36
    Notes
    [9] - Non-inferiority was demonstrated if the lower limit of 95% CI for the overall treatment difference change from Baseline between FF/VI and VI was greater than -1 % year

    Secondary: Percentage change from Baseline in BMD measurements at lumbar spine (L1 to L4) by gender (male participants)

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    End point title
    		 Percentage change from Baseline in BMD measurements at lumbar spine (L1 to L4) by gender (male participants)
    End point description
    BMD analysis performed on log (BMD ratio to Baseline) using separate repeated measures models for each gender with covariates of treatment group, age, Baseline BMI, visit, log Baseline BMD, log Baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the “While on Treatment” estimand of the difference in percentage change from Baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100.Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks
    End point values
    		 Participants administered VI Participants administered FF/VI
    Number of subjects analysed
    69 [10]
    64 [11]
    Units: Percent change
    least squares mean (confidence interval 95%)
        Overall, male % change per year, n = 69, 64
    1.41 (0.79 to 2.04)
    0.38 (-0.26 to 1.02)
        % change by Week 26, n = 67, 64
    1.03 (0.26 to 1.80)
    0.42 (-0.36 to 1.21)
        % change by Week 52, n = 53, 56
    1.91 (0.89 to 2.94)
    0.11 (-0.88 to 1.11)
        % change by Week 78, n = 52, 45
    2.09 (0.84 to 3.35)
    0.64 (-0.67 to 1.97)
        % change by Week 104, n = 52, 43
    2.72 (1.48 to 3.98)
    0.42 (-0.88 to 1.75)
        % change by Week 130, n = 47, 38
    1.95 (0.76 to 3.16)
    0.47 (-0.82 to 1.78)
        % change by Week 156, n = 43, 35
    2.96 (1.68 to 4.25)
    1.49 (0.13 to 2.86)
    Notes
    [10] - Safety Population
    [11] - Safety Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Overall Weeks for Male
    Comparison groups
    Participants administered VI v Participants administered FF/VI
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage Change from Baseline
    Point estimate
    -1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 -0.13

    Secondary: Percentage change from Baseline in BMD measurements at lumbar spine (L1 to L4) by gender (female participants)

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    End point title
    		 Percentage change from Baseline in BMD measurements at lumbar spine (L1 to L4) by gender (female participants)
    End point description
    BMD analysis performed on log (BMD ratio to Baseline) using separate repeated measures models for each gender with covariates of treatment group, age, Baseline BMI, visit, log Baseline BMD, log Baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the “While on Treatment” estimand of the difference in percentage change from Baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100.Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks
    End point values
    		 Participants administered VI Participants administered FF/VI
    Number of subjects analysed
    66 [12]
    68 [13]
    Units: Percent change
    least squares mean (confidence interval 95%)
        Overall Week % change per year, n = 66, 68
    0.17 (-0.42 to 0.77)
    0.12 (-0.45 to 0.70)
        % change by Week 26, n = 66, 68
    0.10 (-0.67 to 0.88)
    -0.19 (-0.95 to 0.58)
        % change by Week 52, n = 51, 66
    -0.48 (-1.44 to 0.48)
    0.57 (-0.31 to 1.46)
        % change by Week 78, n = 46, 57
    0.33 (-0.60 to 1.26)
    0.25 (-0.61 to 1.11)
        % change by Week 104, n = 43, 54
    0.65 (-0.50 to 1.80)
    0.64 (0.41 to 1.70)
        % change by Week 130, n = 44, 49
    1.33 (0.01 to 2.67)
    0.10 (-1.12 to 1.33)
        % change by Week 156, n = 36, 42
    0.80 (-0.74 to 2.36)
    0.10 (-1.32 to 1.53)
    Notes
    [12] - Safety Population
    [13] - Safety Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Participants administered VI v Participants administered FF/VI
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    Method
    Parameter type
    		 Percentage Change from Baseline
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.87
         upper limit
    		 0.78
    Notes
    [14] - Overall Weeks for females

    Secondary: Percentage change from Baseline in BMD measurements at lumbar spine (L1 to L4)

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    End point title
    		 Percentage change from Baseline in BMD measurements at lumbar spine (L1 to L4)
    End point description
    BMD analysis performed on log (BMD ratio to Baseline) using a repeated measures model with covariates of treatment group, age, gender, Baseline BMI, visit, log Baseline BMD, log Baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the “While on Treatment” estimand of the difference in percentage change from Baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100.Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks
    End point values
    		 Participants administered VI Participants administered FF/VI
    Number of subjects analysed
    135 [15]
    132 [16]
    Units: Percentage Change
    least squares mean (confidence interval 95%)
        Overall week % change per year, n=135, 132
    0.79 (0.36 to 1.22)
    0.28 (-0.15 to 0.71)
        % change by Week 26, n = 133, 132
    0.55 (0.01 to 1.10)
    0.13 (-0.41 to 0.68)
        % change by Week 52, n = 104, 122
    0.71 (0.01 to 1.42)
    0.40 (-0.26 to 1.07)
        % change by Week 78, n= 98, 102
    1.20 (0.43 to 1.99)
    0.45 (-0.31 to 1.21)
        % change by Week 104, n = 95, 97
    1.66 (0.82 to 2.51)
    0.61 (-0.22 to 1.44)
        % change by Week 130, n = 91, 87
    1.70 (0.80 to 2.61)
    0.30 (-0.60 to 1.20)
        % change by Week 156, n = 79, 77
    1.84 (0.86 to 2.84)
    0.83 (-0.14 to 1.81)
    Notes
    [15] - Safety Population
    [16] - Safety Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Overall week
    Comparison groups
    Participants administered VI v Participants administered FF/VI
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage Change from Baseline
    Point estimate
    -0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.11
         upper limit
    		 0.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks.
    Adverse event reporting additional description
    Safety Population. The non-serious AEs are reported using a frequency threshold of >3%.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Participants administered VI
    Reporting group description
    		 Following run-in period of 14 to 21 days, eligible participants were administered VI 25 microgram (mcg) once daily via ELLIPTA inhaler for 156 weeks.

    Reporting group title
    Participants administered FF/VI
    Reporting group description
    		 Following run-in period of 14 to 21 days, eligible participants were administered FF 100 mcg along with VI 25 mcg once daily via ELLIPTA inhaler for 156 weeks.

    Serious adverse events
    		 Participants administered VI Participants administered FF/VI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 142 (29.58%)
    41 / 141 (29.08%)
         number of deaths (all causes)
    6
    4
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer stage 0, with cancer in situ
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Chest pain
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Contrast media reaction
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectocele
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    10 / 142 (7.04%)
    6 / 141 (4.26%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    1 / 142 (0.70%)
    3 / 141 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 142 (1.41%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance abuse
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 142 (0.00%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hip fracture
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 142 (1.41%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac asthma
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Brain injury
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dementia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular disorder
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ischaemic
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis cholestatic
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vesical fistula
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 142 (2.82%)
    11 / 141 (7.80%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 142 (0.00%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Participants administered VI Participants administered FF/VI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    126 / 142 (88.73%)
    130 / 141 (92.20%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    6 / 142 (4.23%)
    2 / 141 (1.42%)
         occurrences all number
    7
    3
    Procedural pain
         subjects affected / exposed
    6 / 142 (4.23%)
    1 / 141 (0.71%)
         occurrences all number
    7
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 142 (7.75%)
    10 / 141 (7.09%)
         occurrences all number
    12
    10
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 142 (11.27%)
    26 / 141 (18.44%)
         occurrences all number
    24
    44
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    5 / 142 (3.52%)
    4 / 141 (2.84%)
         occurrences all number
    6
    4
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    5 / 142 (3.52%)
    2 / 141 (1.42%)
         occurrences all number
    6
    2
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 142 (2.11%)
    6 / 141 (4.26%)
         occurrences all number
    3
    9
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    11 / 142 (7.75%)
    9 / 141 (6.38%)
         occurrences all number
    12
    9
    Abdominal pain upper
         subjects affected / exposed
    4 / 142 (2.82%)
    7 / 141 (4.96%)
         occurrences all number
    5
    10
    Constipation
         subjects affected / exposed
    3 / 142 (2.11%)
    6 / 141 (4.26%)
         occurrences all number
    4
    7
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 142 (3.52%)
    4 / 141 (2.84%)
         occurrences all number
    5
    5
    Toothache
         subjects affected / exposed
    3 / 142 (2.11%)
    5 / 141 (3.55%)
         occurrences all number
    3
    8
    Vomiting
         subjects affected / exposed
    2 / 142 (1.41%)
    5 / 141 (3.55%)
         occurrences all number
    2
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 142 (10.56%)
    13 / 141 (9.22%)
         occurrences all number
    15
    15
    Oropharyngeal pain
         subjects affected / exposed
    8 / 142 (5.63%)
    12 / 141 (8.51%)
         occurrences all number
    8
    17
    Dyspnoea
         subjects affected / exposed
    5 / 142 (3.52%)
    6 / 141 (4.26%)
         occurrences all number
    6
    6
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    5 / 142 (3.52%)
    5 / 141 (3.55%)
         occurrences all number
    6
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 142 (0.70%)
    6 / 141 (4.26%)
         occurrences all number
    1
    10
    Anxiety
         subjects affected / exposed
    5 / 142 (3.52%)
    0 / 141 (0.00%)
         occurrences all number
    5
    0
    Depression
         subjects affected / exposed
    0 / 142 (0.00%)
    5 / 141 (3.55%)
         occurrences all number
    0
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    13 / 142 (9.15%)
    20 / 141 (14.18%)
         occurrences all number
    27
    28
    Pain in extremity
         subjects affected / exposed
    6 / 142 (4.23%)
    10 / 141 (7.09%)
         occurrences all number
    6
    13
    Osteoarthritis
         subjects affected / exposed
    9 / 142 (6.34%)
    6 / 141 (4.26%)
         occurrences all number
    14
    7
    Musculoskeletal pain
         subjects affected / exposed
    6 / 142 (4.23%)
    4 / 141 (2.84%)
         occurrences all number
    6
    6
    Muscle spasms
         subjects affected / exposed
    4 / 142 (2.82%)
    5 / 141 (3.55%)
         occurrences all number
    4
    5
    Osteoporosis
         subjects affected / exposed
    4 / 142 (2.82%)
    5 / 141 (3.55%)
         occurrences all number
    4
    5
    Arthritis
         subjects affected / exposed
    5 / 142 (3.52%)
    2 / 141 (1.42%)
         occurrences all number
    5
    2
    Arthralgia
         subjects affected / exposed
    14 / 142 (9.86%)
    13 / 141 (9.22%)
         occurrences all number
    15
    19
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    31 / 142 (21.83%)
    40 / 141 (28.37%)
         occurrences all number
    57
    75
    Bronchitis
         subjects affected / exposed
    16 / 142 (11.27%)
    11 / 141 (7.80%)
         occurrences all number
    23
    12
    Influenza
         subjects affected / exposed
    5 / 142 (3.52%)
    20 / 141 (14.18%)
         occurrences all number
    5
    30
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 142 (9.15%)
    12 / 141 (8.51%)
         occurrences all number
    18
    20
    Urinary tract infection
         subjects affected / exposed
    12 / 142 (8.45%)
    12 / 141 (8.51%)
         occurrences all number
    18
    24
    Sinusitis
         subjects affected / exposed
    3 / 142 (2.11%)
    13 / 141 (9.22%)
         occurrences all number
    3
    17
    Pneumonia
         subjects affected / exposed
    5 / 142 (3.52%)
    8 / 141 (5.67%)
         occurrences all number
    5
    8
    Oral candidiasis
         subjects affected / exposed
    4 / 142 (2.82%)
    7 / 141 (4.96%)
         occurrences all number
    5
    13
    Cystitis
         subjects affected / exposed
    5 / 142 (3.52%)
    5 / 141 (3.55%)
         occurrences all number
    6
    7
    Pharyngitis
         subjects affected / exposed
    4 / 142 (2.82%)
    5 / 141 (3.55%)
         occurrences all number
    5
    8
    Herpes zoster
         subjects affected / exposed
    0 / 142 (0.00%)
    6 / 141 (4.26%)
         occurrences all number
    0
    7

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Aug 2013
    Amendment No.: 01 This protocol amendment is being implemented to revise and clarify exclusion criteria concerning participation in pulmonary rehabilitation programs; clarify the description of DEXA procedures and clinical labs; correction of typographical errors.

    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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