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    Clinical Trial Results:
    A Clinical Study to Evaluate Four Doses of Umeclidinium Bromide in Combination with Fluticasone Furoate in COPD Subjects with an Asthmatic Component

    Summary
    EudraCT number
    		 2014-000883-16
    Trial protocol
    		 DE   RO   PL  
    Global end of trial date
    18 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2016
    First version publication date
    01 Apr 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    200699
    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
    Clinical Trials HelpDesk, GlaxoSmithKline Research & Development Ltd, +44 208990 4466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials HelpDesk, GlaxoSmithKline Research & Development Ltd, +44 208990 4466, 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
    02 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the dose-response of once-daily UMEC in combination with FF (100/15.6, 100/62.5, 100/125, and 100/250 mcg) compared to FF 100 mcg monotherapy over a 4-week treatment period in COPD subjects with an asthmatic component.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jul 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
    Argentina: 13
    Country: Number of subjects enrolled
    Russian Federation: 60
    Country: Number of subjects enrolled
    Ukraine: 96
    Country: Number of subjects enrolled
    United States: 37
    Country: Number of subjects enrolled
    Poland: 42
    Country: Number of subjects enrolled
    Romania: 61
    Country: Number of subjects enrolled
    Germany: 29
    Worldwide total number of subjects
    338
    EEA total number of subjects
    132
    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)
    251
    From 65 to 84 years
    87
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants (par.) with sufficient signs and symptoms to diagnose as having chronic obstructive pulmonary disease (COPD) and evidence of an asthmatic component as demonstrated by spirometry, reversibility and current therapy at the point of screening were eligible for participation in the study.

    Pre-assignment
    Screening details
    		 Participants on inhaled corticosteroid therapy over the previous 12 weeks, including a stable dose during the 4 weeks prior to Visit 0, entered the 4-week run-in period on open-label fluticasone propionate 250 microgram (µg) and salmeterol 50 µg combination. Eligible par. were stratified by smoking status, age and randomized to Treatment Phase A.

    Period 1
    Period 1 title
    Treatment Phase A (4 Weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FF 100 µg
    Arm description
    		 Participants received fluticasone furoate (FF) 100 µg once daily in the morning by inhalation using a dry powder inhaler (DPI) for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via metered-dose inhaler (MDI) to be used on an as-needed basis (rescue medication) throughout the study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fluticasone Furoate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone furoate is available as fluticasone furoate inhalation powder (100 mcg per blister) once daily in the morning

    Arm title
    		 FF/UMEC 100/15.6 µg
    Arm description
    		 Participants received FF 100 µg in combination with umeclidinium bromide (UMEC) 15.6 µg once daily in the morning by inhalation using a DPI for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone Furoate/Umeclidinium Bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    A combination of fluticasone furoate/umeclidinium bromide inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 15.6, 62.5, 125, or 250 mcg per blister) once daily in the morning

    Arm title
    		 FF/UMEC 100/62.5 µg
    Arm description
    		 Participants received FF 100 µg in combination with UMEC 62.5 µg once daily in the morning by inhalation using a DPI for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone Furoate/Umeclidinium Bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    A combination of fluticasone furoate/umeclidinium bromide inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 15.6, 62.5, 125, or 250 mcg per blister) once daily in the morning

    Arm title
    		 FF/UMEC 100/125 µg
    Arm description
    		 Participants received FF 100 µg in combination with UMEC 125 µg once daily in the morning by inhalation using a DPI for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone Furoate/Umeclidinium Bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    A combination of fluticasone furoate/umeclidinium bromide inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 15.6, 62.5, 125, or 250 mcg per blister) once daily in the morning

    Arm title
    		 FF/UMEC 100/250 µg
    Arm description
    		 Participants received FF 100 µg in combination with UMEC 250 µg once daily in the morning by inhalation using a DPI for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone Furoate/Umeclidinium Bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    A combination of fluticasone furoate/umeclidinium bromide inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 15.6, 62.5, 125, or 250 mcg per blister) once daily in the morning

    Arm title
    		 FF/VI 100/25 µg
    Arm description
    		 Participants received FF 100 µg in combination with vilanterol trifenatate (VI) 25 µg once daily in the morning by inhalation using a DPI for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fluticasone Furoate/Vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Combination of fluticasone furoate/vilanterol inhalation powder (fluticasone furoate: 100 mcg per blister, vilanterol: 25 mcg per blister) once daily in the morning

    Number of subjects in period 1
    		FF 100 µg FF/UMEC 100/15.6 µg FF/UMEC 100/62.5 µg FF/UMEC 100/125 µg FF/UMEC 100/250 µg FF/VI 100/25 µg
    Started
    41
    42
    40
    46
    85
    84
    Completed
    39
    42
    39
    44
    82
    83
    Not completed
    2
    0
    1
    2
    3
    1
         Consent withdrawn by subject
    1
    -
    -
    -
    2
    -
         Adverse event, non-fatal
    -
    -
    1
    1
    -
    -
         Protocol defined stopping criteria
    1
    -
    -
    1
    -
    1
         Lack of efficacy
    -
    -
    -
    -
    1
    -
    Period 2
    Period 2 title
    Treatment Phase B (1 Week)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FF/UMEC 100/250 µg
    Arm description
    		 Participants received FF 100 µg in combination with umeclidinium bromide (UMEC) 250 µg and placebo once daily in the morning by inhalation using two separate DPIs for 1 week. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone Furoate/Umeclidinium Bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    A combination of fluticasone furoate/umeclidinium bromide inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 15.6, 62.5, 125, or 250 mcg per blister) once daily in the morning

    Arm title
    		 FF/UMEC/VI 100/250/25 µg
    Arm description
    		 Participants received FF 100 µg in combination with umeclidinium bromide (UMEC) 250 µg and VI 25 µg once daily in the morning by inhalation using two separate DPIs (FF/UMEC 100/250 & VI 25) for 1 week. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone Furoate/Umeclidinium Bromide/Vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Combination of fluticasone furoate/umeclidinium bromide/vilanterol inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 250 mcg per blister, vilanterol: 25 mcg per blister) once daily in the morning (as two separate inhalers: FF/UMEC 100/250 & VI 25)

    Number of subjects in period 2
    		FF/UMEC 100/250 µg FF/UMEC/VI 100/250/25 µg
    Started
    166
    163
    Completed
    163
    162
    Not completed
    3
    1
         Physician decision
    -
    1
         Adverse event, non-fatal
    2
    -
         Protocol defined stopping criteria
    1
    -
    Period 3
    Period 3 title
    Treatment Phase C (1 Week)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FF 100 µg
    Arm description
    		 Participants on inhaled FF/UMEC 100/250 µg once daily in the morning during Treatment Phase B, received inhaled FF 100 µg and placebo once daily in the morning using two separate DPIs for 1 week. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fluticasone Furoate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone furoate is available as fluticasone furoate inhalation powder (100 mcg per blister) once daily in the morning

    Arm title
    		 FF/UMEC 100/250 µg
    Arm description
    		 Participants on inhaled FF/UMEC 100/250 µg once daily in the morning during Treatment Phase B, received inhaled FF/UMEC 100/250 µg and placebo once daily in the morning using two separate DPIs for 1 week. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone Furoate/Umeclidinium Bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    A combination of fluticasone furoate/umeclidinium bromide inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 15.6, 62.5, 125, or 250 mcg per blister) once daily in the morning

    Arm title
    		 FF/VI 100/25 µg
    Arm description
    		 Participants on inhaled FF/UMEC/VI 100/250/25 µg once daily in the morning during Treatment Phase B, received inhaled FF/VI 100/25 µg and placebo once daily in the morning using two separate DPIs for 1 week. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fluticasone Furoate/Vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Combination of fluticasone furoate/vilanterol inhalation powder (fluticasone furoate: 100 mcg per blister, vilanterol: 25 mcg per blister) once daily in the morning

    Arm title
    		 FF/UMEC/VI 100/250/25 µg
    Arm description
    		 Participants on inhaled FF/UMEC/VI 100/250/25 µg once daily in the morning during Treatment Phase B, received inhaled FF/UMEC/VI 100 /250 /25 µg (as two separate inhalers: FF/UMEC 100/250 and VI 25) once daily in the morning using two separate DPIs for 1 week. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone Furoate/Umeclidinium Bromide/Vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Combination of fluticasone furoate/umeclidinium bromide/vilanterol inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 250 mcg per blister, vilanterol: 25 mcg per blister) once daily in the morning (as two separate inhalers: FF/UMEC 100/250 & VI 25)

    Number of subjects in period 3
    		FF 100 µg FF/UMEC 100/250 µg FF/VI 100/25 µg FF/UMEC/VI 100/250/25 µg
    Started
    79
    84
    82
    80
    Completed
    78
    84
    82
    78
    Not completed
    1
    0
    0
    2
         Consent withdrawn by subject
    1
    -
    -
    -
         Physician decision
    -
    -
    -
    1
         Adverse event, non-fatal
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FF 100 µg
    Reporting group description
    		 Participants received fluticasone furoate (FF) 100 µg once daily in the morning by inhalation using a dry powder inhaler (DPI) for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via metered-dose inhaler (MDI) to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC 100/15.6 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with umeclidinium bromide (UMEC) 15.6 µg once daily in the morning by inhalation using a DPI for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC 100/62.5 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with UMEC 62.5 µg once daily in the morning by inhalation using a DPI for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC 100/125 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with UMEC 125 µg once daily in the morning by inhalation using a DPI for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC 100/250 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with UMEC 250 µg once daily in the morning by inhalation using a DPI for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/VI 100/25 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with vilanterol trifenatate (VI) 25 µg once daily in the morning by inhalation using a DPI for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group values
    		 FF 100 µg FF/UMEC 100/15.6 µg FF/UMEC 100/62.5 µg FF/UMEC 100/125 µg FF/UMEC 100/250 µg FF/VI 100/25 µg Total
    Number of subjects
    		 41 42 40 46 85 84 338
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.4 ( 8.59 ) 55.5 ( 11.33 ) 56.7 ( 10.14 ) 58.2 ( 10.47 ) 57.8 ( 11.03 ) 57.6 ( 10.95 ) -
    Gender categorical
    Units: Subjects
        Female
    		 21 23 19 18 38 41 160
        Male
    		 20 19 21 28 47 43 178
    Race, Customized
    Units: Subjects
        African American/African Heritage
    		 1 0 1 1 3 1 7
        White- Arabic/ North African Heritage
    		 0 0 0 1 0 0 1
        White- White/Caucasian/European Heritage
    		 40 42 39 44 81 83 329
        Mixed Race
    		 0 0 0 0 1 0 1

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    FF 100 µg
    Reporting group description
    		 Participants received fluticasone furoate (FF) 100 µg once daily in the morning by inhalation using a dry powder inhaler (DPI) for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via metered-dose inhaler (MDI) to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC 100/15.6 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with umeclidinium bromide (UMEC) 15.6 µg once daily in the morning by inhalation using a DPI for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC 100/62.5 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with UMEC 62.5 µg once daily in the morning by inhalation using a DPI for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC 100/125 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with UMEC 125 µg once daily in the morning by inhalation using a DPI for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC 100/250 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with UMEC 250 µg once daily in the morning by inhalation using a DPI for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/VI 100/25 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with vilanterol trifenatate (VI) 25 µg once daily in the morning by inhalation using a DPI for 4 weeks. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.
    Reporting group title
    FF/UMEC 100/250 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with umeclidinium bromide (UMEC) 250 µg and placebo once daily in the morning by inhalation using two separate DPIs for 1 week. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC/VI 100/250/25 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with umeclidinium bromide (UMEC) 250 µg and VI 25 µg once daily in the morning by inhalation using two separate DPIs (FF/UMEC 100/250 & VI 25) for 1 week. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.
    Reporting group title
    FF 100 µg
    Reporting group description
    		 Participants on inhaled FF/UMEC 100/250 µg once daily in the morning during Treatment Phase B, received inhaled FF 100 µg and placebo once daily in the morning using two separate DPIs for 1 week. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC 100/250 µg
    Reporting group description
    		 Participants on inhaled FF/UMEC 100/250 µg once daily in the morning during Treatment Phase B, received inhaled FF/UMEC 100/250 µg and placebo once daily in the morning using two separate DPIs for 1 week. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/VI 100/25 µg
    Reporting group description
    		 Participants on inhaled FF/UMEC/VI 100/250/25 µg once daily in the morning during Treatment Phase B, received inhaled FF/VI 100/25 µg and placebo once daily in the morning using two separate DPIs for 1 week. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC/VI 100/250/25 µg
    Reporting group description
    		 Participants on inhaled FF/UMEC/VI 100/250/25 µg once daily in the morning during Treatment Phase B, received inhaled FF/UMEC/VI 100 /250 /25 µg (as two separate inhalers: FF/UMEC 100/250 and VI 25) once daily in the morning using two separate DPIs for 1 week. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Primary: Change from Baseline in clinic trough forced expiratory volume in one second (FEV1) at the end of Treatment Phase A (Visit 6/Day 29)

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    End point title
    		 Change from Baseline in clinic trough forced expiratory volume in one second (FEV1) at the end of Treatment Phase A (Visit 6/Day 29)
    End point description
    FEV1 is defined as forced expiratory volume in one second and measured in the morning at Visits 1 through 8 between 6:00 and 11:00 electronically by spirometry. Change from Baseline in trough FEV1 is defined as the difference in the value obtained at Visit 6 (24 hours post-dose on Visit 5) and the last acceptable/borderline acceptable value obtained prior to randomization (from Visit 2 pre-bronchodilator or Visit 3 pre-dose). Trough FEV1 is defined as the acceptable/borderline acceptable FEV1 value obtained at Visit 6, approximately 24 hours after morning dosing on Visit 5. ITT population is comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period. All comparisons for statistical purposes are with the FF 100 µg arm.
    End point type
    Primary
    End point timeframe
    Baseline and Day 29
    End point values
    		 FF 100 µg FF/UMEC 100/15.6 µg FF/UMEC 100/62.5 µg FF/UMEC 100/125 µg FF/UMEC 100/250 µg FF/VI 100/25 µg
    Number of subjects analysed
    39 [1]
    42 [2]
    39 [3]
    44 [4]
    81 [5]
    83 [6]
    Units: Liters
        arithmetic mean (standard deviation)
    0.047 ( 0.3002 )
    0.146 ( 0.233 )
    0.193 ( 0.2192 )
    0.175 ( 0.2478 )
    0.143 ( 0.315 )
    0.121 ( 0.2779 )
    Notes
    [1] - ITT Population. Only those participants available at the specified time point were analyzed.
    [2] - ITT Population. Only those participants available at the specified time point were analyzed.
    [3] - ITT Population. Only those participants available at the specified time point were analyzed.
    [4] - ITT Population. Only those participants available at the specified time point were analyzed.
    [5] - ITT Population. Only those participants available at the specified time point were analyzed.
    [6] - ITT Population. Only those participants available at the specified time point were analyzed.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FF 100 µg v FF/UMEC 100/15.6 µg
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 Final step dose response model
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.103
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.014
         upper limit
    		 0.193
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    FF 100 µg v FF/UMEC 100/62.5 µg
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 Final step dose response model
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.103
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.014
         upper limit
    		 0.193
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    FF 100 µg v FF/UMEC 100/125 µg
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 Final step dose response model
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.103
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.014
         upper limit
    		 0.193
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    FF 100 µg v FF/UMEC 100/250 µg
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 Final step dose response model
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.103
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.014
         upper limit
    		 0.193
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    FF 100 µg v FF/VI 100/25 µg
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.152
    Method
    		 Final step dose response model
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.073
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.027
         upper limit
    		 0.172

    Secondary: Mean change from Baseline in rescue medication use at the end of Treatment Phase A

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    End point title
    		 Mean change from Baseline in rescue medication use at the end of Treatment Phase A
    End point description
    All participants (par) received the albuterol/salbutamol via MDI as a rescue medication on an as-needed basis. Total daily rescue medication (RM) use for a given day is defined as the sum of daytime albuterol/salbutamol use recorded in PM and nighttime albuterol/salbutamol use recorded in AM the next day.The number of puffs of albuterol (salbutamol) MDI used in the last 12 hours for relief of symptoms were recorded morning and evening in the eDiary by the par. End of Treatment Phase A is defined as the last 7 days of Treatment Phase A.Change from Baseline at the end of Treatment Phase is the difference between the end of Treatment Phase value and the appropriate baseline week.Analysis performed using analysis of covariance with covariates of treatment, age, sex, baseline RM use, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification.Baseline is the last 7 days of run-in period of randomization.
    End point type
    Secondary
    End point timeframe
    Baseline and End of Treatment Phase A (All comparisons for statistical purposes are with the FF 100 µg arm).
    End point values
    		 FF 100 µg FF/UMEC 100/15.6 µg FF/UMEC 100/62.5 µg FF/UMEC 100/125 µg FF/UMEC 100/250 µg FF/VI 100/25 µg
    Number of subjects analysed
    41 [7]
    42 [8]
    40 [9]
    46 [10]
    85 [11]
    84 [12]
    Units: Puffs
    least squares mean (standard error)
        Daily rescue medication, n=39,42,39,43,80,82
    0.6 ( 0.29 )
    -0.4 ( 0.29 )
    -0.5 ( 0.29 )
    0 ( 0.27 )
    -0.2 ( 0.21 )
    -0.1 ( 0.21 )
    Notes
    [7] - ITT Population. Only those participants available at the specified time point were analyzed.
    [8] - ITT Population. Only those participants available at the specified time point were analyzed.
    [9] - ITT Population. Only those participants available at the specified time point were analyzed.
    [10] - ITT Population. Only those participants available at the specified time point were analyzed.
    [11] - ITT Population. Only those participants available at the specified time point were analyzed.
    [12] - ITT Population. Only those participants available at the specified time point were analyzed.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FF 100 µg v FF/UMEC 100/15.6 µg
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 -0.2
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    FF 100 µg v FF/UMEC 100/62.5 µg
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 -0.4
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    FF 100 µg v FF/UMEC 100/125 µg
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.083
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 0.1
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    FF 100 µg v FF/UMEC 100/250 µg
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.014
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 -0.2
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    FF 100 µg v FF/VI 100/25 µg
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.031
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 -0.1

    Secondary: Mean change from Baseline in E-RS total scores at the end of Treatment Phase A

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    End point title
    		 Mean change from Baseline in E-RS total scores at the end of Treatment Phase A
    End point description
    A daily symptoms score for exacerbations of chronic pulmonary disease tool - Respiratory Symptoms (E-RS) is derived by summing the 11 item-level E-RS scores. E-RS is intended to capture information related to the respiratory symptoms of COPD. The Baseline E-RS score is defined as the mean within-subject daily score over 7 days prior to randomization, with data present for a minimum of 4 of the 7 days. End of Treatment Phase A is defined as the last 7 days of Treatment Phase A. Change from Baseline at the end of Treatment Phase is the difference between the end of Treatment Phase value and the appropriate Baseline week. Analysis performed using analysis of covariance with covariates of treatment, age, sex, baseline score, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification. Baseline is the last 7 days of the run-in period prior to randomization. All comparisons for statistical purposes are with the FF 100 µg arm
    End point type
    Secondary
    End point timeframe
    Baseline and End of Treatment Phase A
    End point values
    		 FF 100 µg FF/UMEC 100/15.6 µg FF/UMEC 100/62.5 µg FF/UMEC 100/125 µg FF/UMEC 100/250 µg FF/VI 100/25 µg
    Number of subjects analysed
    39 [13]
    42 [14]
    39 [15]
    43 [16]
    81 [17]
    83 [18]
    Units: Score on scale
        least squares mean (standard error)
    0.5 ( 0.54 )
    -2.6 ( 0.55 )
    -2.5 ( 0.56 )
    -1.5 ( 0.52 )
    -1.5 ( 0.4 )
    -1.1 ( 0.41 )
    Notes
    [13] - ITT Population. Only those participants available at the specified time point were analyzed.
    [14] - ITT Population. Only those participants available at the specified time point were analyzed.
    [15] - ITT Population. Only those participants available at the specified time point were analyzed.
    [16] - ITT Population. Only those participants available at the specified time point were analyzed.
    [17] - ITT Population. Only those participants available at the specified time point were analyzed.
    [18] - ITT Population. Only those participants available at the specified time point were analyzed.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FF 100 µg v FF/UMEC 100/15.6 µg
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.6
         upper limit
    		 -1.7
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    FF 100 µg v FF/UMEC 100/62.5 µg
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 -1.6
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    FF 100 µg v FF/UMEC 100/125 µg
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 -0.6
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    FF 100 µg v FF/UMEC 100/250 µg
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 -0.7
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    FF 100 µg v FF/VI 100/25 µg
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 -0.4

    Secondary: Change from Baseline in daily morning (AM) PEF (pre-dose and pre-rescue bronchodilator) measured at home and averaged over the last 21 days of Treatment Phase A

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    End point title
    		 Change from Baseline in daily morning (AM) PEF (pre-dose and pre-rescue bronchodilator) measured at home and averaged over the last 21 days of Treatment Phase A
    End point description
    Peak expiratory flow (PEF) stability limit was calculated from AM PEF measurements on the 7days preceding Visit 3 as mean AM PEF from the available 7days preceding Visit 3x80%.The PEF stability limit serves as a benchmark of the participants run-in COPD status and used for comparison during the treatment phase to assess subject safety.Change from Baseline over the last 21days of Treatment Phase A is the difference between the last 21days of Treatment Phase Aand the appropriate Baseline week.The last 21days of Treatment Phase A include the AM assessments on the date of Visit 6.For the AM assessments, these include the date of Visit 6 and the 20 consecutive days preceding the date of Visit Analysis performed using analysis of covariance with covariates of treatment, age, sex, Baseline AM PEF, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification.Baseline is the last 7days of the run-in period prior to randomization
    End point type
    Secondary
    End point timeframe
    Baseline and from Day 8 through Day 29 (All comparisons for statistical purposes are with the FF 100 µg arm)
    End point values
    		 FF 100 µg FF/UMEC 100/15.6 µg FF/UMEC 100/62.5 µg FF/UMEC 100/125 µg FF/UMEC 100/250 µg FF/VI 100/25 µg
    Number of subjects analysed
    39 [19]
    42 [20]
    39 [21]
    43 [22]
    81 [23]
    83 [24]
    Units: Liters per minute (L/min)
        least squares mean (standard error)
    -14.2 ( 4.62 )
    3.9 ( 4.7 )
    7.6 ( 4.76 )
    5.5 ( 4.4 )
    10.5 ( 3.37 )
    4.3 ( 3.47 )
    Notes
    [19] - ITT Population. Only those participants available at the specified time point were analyzed.
    [20] - ITT Population. Only those participants available at the specified time point were analyzed.
    [21] - ITT Population. Only those participants available at the specified time point were analyzed.
    [22] - ITT Population. Only those participants available at the specified time point were analyzed.
    [23] - ITT Population. Only those participants available at the specified time point were analyzed.
    [24] - ITT Population. Only those participants available at the specified time point were analyzed.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FF 100 µg v FF/UMEC 100/15.6 µg
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    18.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.9
         upper limit
    		 30.3
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    FF 100 µg v FF/UMEC 100/62.5 µg
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    21.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.4
         upper limit
    		 34.1
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    FF 100 µg v FF/UMEC 100/125 µg
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    19.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.7
         upper limit
    		 31.7
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    FF 100 µg v FF/UMEC 100/250 µg
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    24.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.1
         upper limit
    		 35.4
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    FF 100 µg v FF/VI 100/25 µg
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    18.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8
         upper limit
    		 29.1

    Secondary: Change from trough in clinic FEV1 at 3 hours post-study Treatment at Visit 5/Day 28

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    End point title
    		 Change from trough in clinic FEV1 at 3 hours post-study Treatment at Visit 5/Day 28
    End point description
    FEV1 is defined as forced expiratory volume in one second and measured in the morning between 6:00 and 11:00 electronically by spirometry.At Visit 5, after trough FEV1 is measured the subject received investigational product.3 hours post-dose, spirometry was repeated and subject then receiving 2 puffs of albuterol/salbutamol.After 30 minutes elapsed, the subject repeated the spirometry assessment again.Change from Baseline in clinic trough (pre-dose) FEV1 is defined as the difference in the trough value at 3 hours post-dose peak FEV1 and the Baseline value.If either the trough value or the Baseline was missing, then change from Baseline was considered as missing.Baseline value of clinic FEV1 is the last acceptable/borderline acceptable (pre-dose) FEV1 value obtained prior to randomization (either from Visit 3 pre-dose or from Visit 2 pre-bronchodilator).
    End point type
    Secondary
    End point timeframe
    Baseline and Day 28
    End point values
    		 FF 100 µg FF/UMEC 100/15.6 µg FF/UMEC 100/62.5 µg FF/UMEC 100/125 µg FF/UMEC 100/250 µg FF/VI 100/25 µg
    Number of subjects analysed
    38 [25]
    42 [26]
    39 [27]
    45 [28]
    81 [29]
    82 [30]
    Units: Liters (L)
        least squares mean (standard error)
    0.048 ( 0.0307 )
    0.093 ( 0.0305 )
    0.088 ( 0.0309 )
    0.072 ( 0.0279 )
    0.052 ( 0.022 )
    0.124 ( 0.0227 )
    Notes
    [25] - ITT Population. Only those participants available at the specified time point were analyzed.
    [26] - ITT Population. Only those participants available at the specified time point were analyzed.
    [27] - ITT Population. Only those participants available at the specified time point were analyzed.
    [28] - ITT Population. Only those participants available at the specified time point were analyzed.
    [29] - ITT Population. Only those participants available at the specified time point were analyzed.
    [30] - ITT Population. Only those participants available at the specified time point were analyzed.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FF 100 µg v FF/UMEC 100/15.6 µg
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.264
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.045
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.034
         upper limit
    		 0.125
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    FF 100 µg v FF/UMEC 100/62.5 µg
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.328
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.041
         upper limit
    		 0.121
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    FF 100 µg v FF/UMEC 100/125 µg
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.534
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.025
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.054
         upper limit
    		 0.103
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    FF 100 µg v FF/UMEC 100/250 µg
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.895
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.005
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.065
         upper limit
    		 0.075
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    FF 100 µg v FF/VI 100/25 µg
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.031
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.076
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.007
         upper limit
    		 0.146

    Secondary: Change in clinic FEV1 following 2 puffs of albuterol/salbutamol given 3 hours post-study treatment dose at Visit 5/Day 28

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    End point title
    		 Change in clinic FEV1 following 2 puffs of albuterol/salbutamol given 3 hours post-study treatment dose at Visit 5/Day 28
    End point description
    FEV1 is defined as forced expiratory volume in one second and measured in the morning electronically by spirometry. At Visit 5 trough FEV1 is measured and subject received investigational product. 3 hours post-dose, spirometry was repeated and subject then received 2 puffs of albuterol/salbutamol. After 30 minutes elapsed, subject repeated spirometry assessment. Change from Baseline in clinic trough (pre-dose) FEV1 is defined as the difference in trough value at 3 hours post-dose peak FEV1 and Baseline. If either trough or Baseline value was missing, change from Baseline was considered missing. Baseline clinic FEV1 is the last acceptable/borderline acceptable (pre-dose) FEV1 prior to randomization. Analysis performed using analysis of covariance with covariates of treatment, age, sex, baseline clinic trough FEV1, pre-dose trough FEV1 at Visit 5, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 28
    End point values
    		 FF 100 µg FF/UMEC 100/15.6 µg FF/UMEC 100/62.5 µg FF/UMEC 100/125 µg FF/UMEC 100/250 µg FF/VI 100/25 µg
    Number of subjects analysed
    37 [31]
    40 [32]
    38 [33]
    42 [34]
    80 [35]
    80 [36]
    Units: Liters
        least squares mean (standard error)
    0.249 ( 0.0287 )
    0.161 ( 0.0284 )
    0.159 ( 0.0284 )
    0.16 ( 0.0262 )
    0.189 ( 0.0202 )
    0.087 ( 0.0209 )
    Notes
    [31] - ITT Population. Only those participants available at the specified time point were analyzed.
    [32] - ITT Population. Only those participants available at the specified time point were analyzed.
    [33] - ITT Population. Only those participants available at the specified time point were analyzed.
    [34] - ITT Population. Only those participants available at the specified time point were analyzed.
    [35] - ITT Population. Only those participants available at the specified time point were analyzed.
    [36] - ITT Population. Only those participants available at the specified time point were analyzed.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FF 100 µg v FF/UMEC 100/15.6 µg
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.019
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.088
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.162
         upper limit
    		 -0.014
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    FF 100 µg v FF/UMEC 100/62.5 µg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.091
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.165
         upper limit
    		 -0.016
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    FF 100 µg v FF/UMEC 100/125 µg
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.089
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.162
         upper limit
    		 -0.016
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    FF 100 µg v FF/UMEC 100/250 µg
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.066
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.124
         upper limit
    		 0.004
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    FF 100 µg v FF/VI 100/25 µg
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.163
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.227
         upper limit
    		 -0.099

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AE) and serious adverse events (SAE) were collected from start of the run-in period until follow-up. SAEs related to participation or GSK concomitant medication were recorded from time of consent up to and including any follow up contact.
    Adverse event reporting additional description
    AEs and SAEs were collected for the ITT population, comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period. Assessed as related to participation might include; study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    FF 100 µg
    Reporting group description
    		 Participants received fluticasone furoate (FF) 100 µg once daily in the morning by inhalation using a dry powder inhaler (DPI) for 4 weeks during Treatment Phase A and 1 week during Treatment Phase C. In addition, all participants received supplemental albuterol/salbutamol via metered-dose inhaler (MDI) to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC 100/15.6 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with umeclidinium bromide (UMEC) 15.6 µg once daily in the morning by inhalation using a DPI for 4 weeks during Treatment Phase A. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC 100/62.5 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with UMEC 62.5 µg once daily in the morning by inhalation using a DPI for 4 weeks during Treatment Phase A. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC 100/125 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with UMEC 125 µg once daily in the morning by inhalation using a DPI for 4 weeks during Treatment Phase A. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC 100/250 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with UMEC 250 µg once daily in the morning by inhalation using a DPI for 4 weeks during Treatment Phase A and 1 week during Treatment Phase B and C. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/VI 100/25 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with vilanterol trifenatate (VI) 25 µg once daily in the morning by inhalation using a DPI for 4 weeks during Treatment Phase A and 1 week during Treatment Phase C. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Reporting group title
    FF/UMEC/VI 100/250/25 µg
    Reporting group description
    		 Participants received FF 100 µg in combination with umeclidinium bromide (UMEC) 250 µg and VI 25 µg once daily in the morning by inhalation using two separate DPIs (FF/UMEC 100/250 &amp;amp; VI 25) for 1 week during Treatment Phase B and C. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study.

    Serious adverse events
    		 FF 100 µg FF/UMEC 100/15.6 µg FF/UMEC 100/62.5 µg FF/UMEC 100/125 µg FF/UMEC 100/250 µg FF/VI 100/25 µg FF/UMEC/VI 100/250/25 µg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    1 / 210 (0.48%)
    0 / 146 (0.00%)
    0 / 163 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Hypertensive crisis
    Additional description: One subject had a non-fatal SAE of pneumonia 2 days after withdrawal, which resolved. This subject also had 2 fatal SAEs; TIA and PE, onset 14 and 17 days after last dose, respectively. The investigator considered pneumonia and PE treatment-related.
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    1 / 210 (0.48%)
    0 / 146 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 FF 100 µg FF/UMEC 100/15.6 µg FF/UMEC 100/62.5 µg FF/UMEC 100/125 µg FF/UMEC 100/250 µg FF/VI 100/25 µg FF/UMEC/VI 100/250/25 µg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 111 (5.41%)
    5 / 42 (11.90%)
    4 / 40 (10.00%)
    4 / 46 (8.70%)
    5 / 210 (2.38%)
    4 / 146 (2.74%)
    0 / 163 (0.00%)
    Gastrointestinal disorders
    Toothache
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 42 (7.14%)
    1 / 40 (2.50%)
    0 / 46 (0.00%)
    1 / 210 (0.48%)
    0 / 146 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    3
    1
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    3 / 46 (6.52%)
    0 / 210 (0.00%)
    0 / 146 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    1
    3
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 111 (5.41%)
    3 / 42 (7.14%)
    2 / 40 (5.00%)
    2 / 46 (4.35%)
    4 / 210 (1.90%)
    4 / 146 (2.74%)
    0 / 163 (0.00%)
         occurrences all number
    6
    3
    3
    2
    4
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Aug 2014
    This amendment was implemented in order to modify the treatment duration of Phase B and visit windows of Phase B and Phase C. Updates were also made to clarify procedures, update inclusion/exclusion criteria, ensure consistency in the definition of severe exacerbation, and ensure the EXACT endpoint definition was consistent with the EXACT manual. Minor adjustments in wording were made to exploratory endpoints and statistical testing methods.

    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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