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    Clinical Trial Results:
    A phase IIIB, 24-week randomised, double-blind study to compare closed triple therapy (FF/UMEC/VI) with open triple therapy (FF/VI + UMEC), in subjects with chronic obstructive pulmonary disease (COPD)

    Summary
    EudraCT number
    		 2015-005212-14
    Trial protocol
    		 ES   FR   RO   IT  
    Global end of trial date
    23 May 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Nov 2018
    First version publication date
    11 May 2018
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    200812
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of FF/UMEC/VI with FF/VI + UMEC on lung function after 24 weeks of treatment
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Jun 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: 131
    Country: Number of subjects enrolled
    Australia: 112
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Germany: 162
    Country: Number of subjects enrolled
    Italy: 75
    Country: Number of subjects enrolled
    Japan: 102
    Country: Number of subjects enrolled
    Korea, Republic of: 69
    Country: Number of subjects enrolled
    Mexico: 112
    Country: Number of subjects enrolled
    Poland: 122
    Country: Number of subjects enrolled
    Romania: 120
    Country: Number of subjects enrolled
    Russian Federation: 215
    Country: Number of subjects enrolled
    Spain: 60
    Worldwide total number of subjects
    1311
    EEA total number of subjects
    570
    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)
    533
    From 65 to 84 years
    766
    85 years and over
    12

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a 24-week, randomized, double-blind, parallel group multicenter study to compare closed triple therapy Fluticasone Furoate/ Umeclidinium/ Vilanterol Trifenatate (FF/UMEC/VI) with open triple therapy (FF/VI + UMEC), in participants with chronic obstructive pulmonary disease (COPD). This study was conducted across 12 countries.

    Pre-assignment
    Screening details
    		 A total of 1311 participants were pre-screened, of which 1278 participants were screened (33 pre-screen failures). There were 175 screen failures and 48 Run-in failures. A total of 1055 participants were randomized 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/UMEC/VI 100/62.5/25
    Arm description
    		 Participants received FF/UMEC/VI, 100 micrograms (mcg)/62.5 mcg/25 mcg via ELLIPTA dry powder inhaler (DPI) once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FF/UMEC/VI
    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 mcg/62.5 mcg/25 mcg inhalation powder via the DPI, once daily in the morning.

    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
    Participants received albuterol/salbutamol as a rescue medication via metered-dose inhaler (MDI) with a spacer which was used when needed during the study

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received placebo inhalation powder via the DPI, once daily in the morning.

    Arm title
    		 FF/VI 100/25 + UMEC 62.5
    Arm description
    		 Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
    Arm type
    		 Active comparator

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

    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
    Participants received albuterol/salbutamol as a rescue medication via metered-dose inhaler (MDI) with a spacer which was used when needed during the study

    Investigational medicinal product name
    UMEC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received UMEC 62.5 mcg inhalation powder via the DPI, once daily in the morning.

    Number of subjects in period 1 [1]
    		FF/UMEC/VI 100/62.5/25 FF/VI 100/25 + UMEC 62.5
    Started
    527
    528
    Completed
    497
    496
    Not completed
    30
    32
         Physician decision
    1
    1
         Consent withdrawn by subject
    6
    17
         Adverse event, non-fatal
    21
    11
         Lost to follow-up
    1
    2
         Lack of efficacy
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 1311 participants were pre-screened, of which 1278 participants were screened (33 pre-screen failures). There were 175 screen failures and 48 Run-in failures. A total of 1055 participants were randomized and received the study treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FF/UMEC/VI 100/62.5/25
    Reporting group description
    		 Participants received FF/UMEC/VI, 100 micrograms (mcg)/62.5 mcg/25 mcg via ELLIPTA dry powder inhaler (DPI) once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/VI 100/25 + UMEC 62.5
    Reporting group description
    		 Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group values
    		 FF/UMEC/VI 100/62.5/25 FF/VI 100/25 + UMEC 62.5 Total
    Number of subjects
    		 527 528
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.7 ± 8.46 65.9 ± 8.77 -
    Gender categorical
    Units: Subjects
        Female
    		 136 134 270
        Male
    		 391 394 785
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 18 14 32
        Asian - East Asian Heritage
    		 29 30 59
        Asian - Japanese Heritage
    		 41 38 79
        Asian - South East Asian Heritage
    		 2 0 2
        White - Arabic/North African Heritage
    		 1 4 5
        White - White/Caucasian/European Heritage
    		 416 416 832
        American Indian/Alaska Native and Asian and White
    		 0 1 1
        American Indian or Alaska Native and White
    		 20 25 45

    End points

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    End points reporting groups
    Reporting group title
    FF/UMEC/VI 100/62.5/25
    Reporting group description
    		 Participants received FF/UMEC/VI, 100 micrograms (mcg)/62.5 mcg/25 mcg via ELLIPTA dry powder inhaler (DPI) once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/VI 100/25 + UMEC 62.5
    Reporting group description
    		 Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Primary: Change from Baseline in trough forced expiratory volume in one second (FEV1) at Week 24

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    End point title
    		 Change from Baseline in trough forced expiratory volume in one second (FEV1) at Week 24
    End point description
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. It was measured using centralized spirometry. FEV1 values at Week 0, pre-dose were considered as Baseline values. Change from Baseline was calculated by substracting Baseline value from the value at indicated time point. Modified Per Protocol (mPP) Population was used which comprised of all participants in the Intent-to-Treat (ITT) Population, who do not have a full protocol deviation considered to impact efficacy. Data following a moderate/severe COPD exacerbation or pneumonia was excluded from analysis due to the potential impact of the exacerbation or the medications used to treat it. Participants with partial protocol deviations considered to impact efficacy were included in the mPP Population but had their data excluded from analysis from the time of deviation onwards. Analysis was performed using a mixed model repeated measures (MMRM) method.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    		 FF/UMEC/VI 100/62.5/25 FF/VI 100/25 + UMEC 62.5
    Number of subjects analysed
    307 [1]
    287 [2]
    Units: Liter
    least squares mean (standard error)
        Liter
    0.113 ± 0.0112
    0.095 ± 0.0116
    Notes
    [1] - mPP Population
    [2] - mPP Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    MMRM method included covariates of Baseline FEV1, stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), visit, geographical region, treatment, visit by treatment and visit by Baseline interaction.
    Comparison groups
    FF/UMEC/VI 100/62.5/25 v FF/VI 100/25 + UMEC 62.5
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.018
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.013
         upper limit
    		 0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0161
    Notes
    [3] - If the lower bound of the two-sided 95% confidence interval around the (FF/UMEC/VI versus FF/VI+UMEC) treatment difference is above -50 milliliter (mL) then FF/UMEC/VI was to be considered non-inferior to FF/VI+UMEC.

    Secondary: Percentage of responders based on the Saint (St) George Respiratory Questionnaire (SGRQ) Total Score at Week 24

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    End point title
    		 Percentage of responders based on the Saint (St) George Respiratory Questionnaire (SGRQ) Total Score at Week 24
    End point description
    SGRQ is a disease-specific questionnaire designed to measure impact of respiratory disease and its treatment on health related quality of life (HRQoL) of participants with COPD. It contains 14 questions with a total of 40 items grouped into domains (Symptoms, Activity and Impacts). SGRQ total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. It ranges from 0 to 100, higher score indicates poor HRQoL. Response was defined as an SGRQ total score of >=4 units below Baseline. Non response was defined as a SGRQ total score <4 units below Baseline or a missing SGRQ total score with no subsequent on treatment scores. ITT Population comprised of randomized participants, excluding those who were randomized in error. A participant screened or run-in failure and also randomized was considered to be randomized in error. Analysis was performed using a generalized linear mixed model with a logit link function.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 FF/UMEC/VI 100/62.5/25 FF/VI 100/25 + UMEC 62.5
    Number of subjects analysed
    489 [4]
    483 [5]
    Units: Percentage of Participants
        Percentage of Participants
    50
    51
    Notes
    [4] - ITT Population. Only participants with data available at the specified time points were analyzed.
    [5] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis included covariates of treatment group, stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), geographical region, visit, Baseline, Baseline by visit and treatment by visit interactions.
    Comparison groups
    FF/VI 100/25 + UMEC 62.5 v FF/UMEC/VI 100/62.5/25
    Number of subjects included in analysis
    972
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.2

    Secondary: Change from Baseline in SGRQ Total Score at Week 24

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    End point title
    		 Change from Baseline in SGRQ Total Score at Week 24
    End point description
    SGRQ is a disease-specific questionnaire designed to measure impact of respiratory disease and its treatment on HRQoL of participants with COPD. It contains 14 questions with a total of 40 items grouped into domains (Symptoms, Activity and Impacts). SGRQ total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. It ranges from 0 to 100, higher score indicates poor HRQoL. Values at Week 0, pre-dose were considered as Baseline values. Change from Baseline was calculated by subtracting Baseline value from the value at indicated time point. Analysis was performed using a MMRM method including covariates of Baseline SGRQ Total score, stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), visit, geographical region, treatment, visit by treatment and visit by Baseline interaction.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 FF/UMEC/VI 100/62.5/25 FF/VI 100/25 + UMEC 62.5
    Number of subjects analysed
    489 [6]
    483 [7]
    Units: Scores on SGRQ scale
    least squares mean (standard error)
        Scores on SGRQ scale
    -5.841 ± 0.5870
    -4.935 ± 0.5904
    Notes
    [6] - ITT Population. Only participants with data available at the specified time points were analyzed.
    [7] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis performed using a repeated measures model with covariates of Baseline SGRQ, stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), visit, geographical region, treatment, visit by treatment and visit by Baseline interaction.
    Comparison groups
    FF/UMEC/VI 100/62.5/25 v FF/VI 100/25 + UMEC 62.5
    Number of subjects included in analysis
    972
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.906
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.54
         upper limit
    		 0.728
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8327

    Secondary: Percentage of responders based on Transitional Dyspnea Index (TDI) focal score at Week 24

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    End point title
    		 Percentage of responders based on Transitional Dyspnea Index (TDI) focal score at Week 24
    End point description
    The TDI measures changes in the participant’s dyspnea. TDI focal score was calculated as the sum of the ratings recorded for each of the 3 individual scales (Functional Impairment, Magnitude of Task, Magnitude of Effort). Each of these scales had a possible score ranging from -6 to +6. lower scores indicating more impairment. TDI focal score was calculated as the sum of the 3 individual scores and then divided by 2 (so the range of the TDI focal score is -9 to +9). The lower the score, the more deterioration in severity of dyspnea. If a score is missing for any of the three scales, then the TDI focal score was set to missing. A participant was considered as a responder if the on-treatment TDI focal score was at least 1 unit at that visit. Non-response was defined as a TDI focal score of less than 1 unit or a missing TDI focal score with no subsequent non-missing on-treatment scores. Analysis was performed using a generalized linear mixed model with a logit link function.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 FF/UMEC/VI 100/62.5/25 FF/VI 100/25 + UMEC 62.5
    Number of subjects analysed
    482 [8]
    481 [9]
    Units: Percentage of Participants
        Percentage of Participants
    56
    56
    Notes
    [8] - ITT Population. Only participants with data available at the specified time points were analyzed.
    [9] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Include covariates of treatment group, stratum (number of long-acting bronchodilators/ day during the run-in: 0/1 or 2), geographical region, visit, Baseline dyspnea index (BDI) focal score, BDI focal score/ visit and treatment/ visit interactions.
    Comparison groups
    FF/VI 100/25 + UMEC 62.5 v FF/UMEC/VI 100/62.5/25
    Number of subjects included in analysis
    963
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.25

    Secondary: TDI focal score at Week 24

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    End point title
    		 TDI focal score at Week 24
    End point description
    The TDI measures changes in the participant’s dyspnoea. TDI focal score was calculated as the sum of the ratings recorded for each of the 3 individual scales (Functional Impairment, Magnitude of Task, Magnitude of Effort). Each of these scales had a possible score ranging from -6 to +6. lower scores indicating more impairment. TDI focal score was calculated as the sum of the 3 individual scores and then divided by 2 (so the range of the TDI focal score is -9 to +9). If a score is missing for any of the three scales, then the TDI focal score was set to missing. Analysis was performed using a repeated measures model.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 FF/UMEC/VI 100/62.5/25 FF/VI 100/25 + UMEC 62.5
    Number of subjects analysed
    482 [10]
    481 [11]
    Units: Scores on TDI scale
    least squares mean (standard error)
        Scores on TDI scale
    2.029 ± 0.1252
    1.892 ± 0.1254
    Notes
    [10] - ITT Population. Only participants with data available at the specified time points were analyzed.
    [11] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis included covariates of BDI focal score, stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), visit, geographical region, treatment, visit by treatment and visit by BDI Focal score interactions.
    Comparison groups
    FF/UMEC/VI 100/62.5/25 v FF/VI 100/25 + UMEC 62.5
    Number of subjects included in analysis
    963
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.137
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.211
         upper limit
    		 0.485
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1773

    Secondary: Time to first moderate or severe exacerbation

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    End point title
    		 Time to first moderate or severe exacerbation
    End point description
    COPD exacerbations were identified based on the investigator’s clinical judgment. Worsening symptoms of COPD that required treatment with oral/systemic corticosteroids and/or antibiotics were considered as moderate exacerbation. Worsening symptoms of COPD that required treatment with in-subject hospitalization was considered as severe exacerbation. Hazard ratio and 95% confidence interval (CI) is from a Cox proportional hazards model with covariates of treatment group, sex, exacerbation history (0, 1, >=2 moderate/severe exacerbations, prior year), smoking status (screening), stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), geographical region and percent predicted FEV1 at Baseline.
    End point type
    Secondary
    End point timeframe
    Up to 25 weeks
    End point values
    		 FF/UMEC/VI 100/62.5/25 FF/VI 100/25 + UMEC 62.5
    Number of subjects analysed
    527 [12]
    528 [13]
    Units: Days
        Days
    166
    150
    Notes
    [12] - ITT Population
    [13] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis was performed using a Cox proportional hazards model.
    Comparison groups
    FF/VI 100/25 + UMEC 62.5 v FF/UMEC/VI 100/62.5/25
    Number of subjects included in analysis
    1055
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.12

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment serious adverse events (SAEs) and non-serious AEs (nSAEs) were collected from start of study treatment (Week 0) until Week 25 including 1 Week of follow-up.
    Adverse event reporting additional description
    On-treatment SAEs and nSAEs were reported for ITT Population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    FF/UMEC/VI 100/62.5/25
    Reporting group description
    		 Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Reporting group title
    FF/VI 100/25 + UMEC 62.5
    Reporting group description
    		 Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.

    Serious adverse events
    		 FF/UMEC/VI 100/62.5/25 FF/VI 100/25 + UMEC 62.5
    Total subjects affected by serious adverse events
         subjects affected / exposed
    55 / 527 (10.44%)
    60 / 528 (11.36%)
         number of deaths (all causes)
    7
    5
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Angiosarcoma
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign hepatic neoplasm
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (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
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         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
    Chest pain
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    Vaginal prolapse
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    24 / 527 (4.55%)
    32 / 528 (6.06%)
         occurrences causally related to treatment / all
    0 / 28
    0 / 38
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Haemoptysis
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 528 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Organic brain syndrome
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    X-ray abnormal
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 527 (0.38%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Aortic valve incompetence
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 527 (0.38%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiomyopathy
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Degenerative aortic valve disease
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         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 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prinzmetal angina
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain injury
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intensive care unit acquired weakness
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (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 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (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
    Sudden hearing loss
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis hypertrophic
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal polyp haemorrhage
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    2 / 527 (0.38%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudarthrosis
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (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
    Cholecystitis infective
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    3 / 527 (0.57%)
    2 / 528 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 527 (1.71%)
    13 / 528 (2.46%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Pneumonia bacterial
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 528 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Staphylococcal infection
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic shock syndrome
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 528 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 528 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 FF/UMEC/VI 100/62.5/25 FF/VI 100/25 + UMEC 62.5
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    122 / 527 (23.15%)
    125 / 528 (23.67%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    32 / 527 (6.07%)
    33 / 528 (6.25%)
         occurrences all number
    56
    54
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    56 / 527 (10.63%)
    52 / 528 (9.85%)
         occurrences all number
    69
    61
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 527 (3.42%)
    24 / 528 (4.55%)
         occurrences all number
    19
    29
    Influenza
         subjects affected / exposed
    16 / 527 (3.04%)
    17 / 528 (3.22%)
         occurrences all number
    17
    17
    Pharyngitis
         subjects affected / exposed
    12 / 527 (2.28%)
    16 / 528 (3.03%)
         occurrences all number
    12
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jan 2016
    Amendment 1 (Global): 1. Synopsis, Section 1 and Overall Design, Section 4.1: Text updated to include the requirement for an early withdrawal study for participants who stop study treatment early. 2. Time and Events Table, Section 7.1: Scheduling of pulse oximetry corrected and scheduling of genetics sample collection revised. 3. Appendix 3 - Genetics Research: Text corrected to include combinations of study medications used in the protocol and the scheduled visit for sample collection revised. Appendix 8 – Hair Sample, Scalp & Finger Secretion pharmacokinetics (PK) Sub-Study: Discrepancy regarding the timing of sample collection corrected.
    11 Feb 2016
    Amendment 2 (South Korea only): Appendix 6 updated, for South Korea, with study medication labeling and information regarding study equipment.
    29 Jun 2016
    Amendment 3 (Global excluding South Korea): 1. Minor discrepancies corrected and clarifications made to some of the footnotes in the Time and Events Table. 2. The requirement of two views (poster anterior and lateral) for Screening chest x-rays and chest x-rays for suspected pneumonias and moderate/severe exacerbations specified. 3. Reference section updated. 4. A minor update to the wording for when the genetics sample can be collected made in the Time and Events Table and Appendix 3.

    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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