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    Clinical Trial Results:
    A Phase IV, 12-week, randomised, double-blind, triple dummy study to compare single inhaler triple therapy, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) with multiple inhaler therapy (budesonide/formoterol plus tiotropium) based on lung function and symptoms in participants with chronic obstructive pulmonary disease

    Summary
    EudraCT number
    		 2017-001149-28
    Trial protocol
    		 DE   CZ   NL  
    Global end of trial date
    14 Mar 2019

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

    Trial information

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    Trial identification
    Sponsor protocol code
    207608
    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, TW8 9GS
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effects of single inhaler triple therapy (FF/UMEC/VI) compared to multiple inhaler triple combination therapy with budesonide/formoterol plus tiotropium after 12 weeks of treatment on lung function
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jun 2018
    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
    Germany: 71
    Country: Number of subjects enrolled
    Czech Republic: 85
    Country: Number of subjects enrolled
    Netherlands: 24
    Country: Number of subjects enrolled
    United States: 548
    Worldwide total number of subjects
    728
    EEA total number of subjects
    180
    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)
    330
    From 65 to 84 years
    397
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a randomized, multicenter, parallel group study where participants with chronic obstructive pulmonary disease (COPD) were randomized to receive either fluticasone furoate/umeclidinium/vilanterol or budesonide/formoterol plus tiotropium in a 1:1 ratio. The study was conducted across 65 centers in 4 countries.

    Pre-assignment
    Screening details
    		 A total of 1036 participants were screened in the study, of which 215 failed during screening. Of the 821 participants who entered the run-in period, 92 were run-in failures. A total of 729 participants were randomized in the study, of which one participant was randomized in error. A total of 728 participants received randomized 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
    		 Investigator, Monitor, Carer, Data analyst, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg
    Arm description
    		 Participants received fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 microgram (mcg) via the ELLIPTA (once daily in the morning) plus placebo to match budesonide/formoterol (BUD/FOR) via metered dose inhaler (MDI) (two inhalations twice daily) plus placebo to match tiotropium (TIO) via HandiHaler (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone furoate/Umeclidinium/Vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone furoate/Umeclidinium/Vilanterol (100/62.5/25 mcg) was available as dry white powder to be administered via ELLIPTA once daily in the morning.

    Investigational medicinal product name
    Placebo matching Budesonide/Formoterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation, suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received two inhalations of placebo matching Budesonide/Formoterol via MDI twice daily.

    Investigational medicinal product name
    Placebo matching Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo matching tiotropium was available as hard gelatin capsule containing lactose. Participants received placebo matching tiotropium once daily in the morning via HandiHaler device.

    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 short-acting Albuterol/Salbutamol as-rescue medication during the study period, if required.

    Arm title
    		 Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Arm description
    		 Participants received two inhalations of budesonide/formoterol 160/4.5 mcg via MDI in the morning and two inhalations in the evening (total dose of 320/9 mcg twice daily) plus tiotropium 18 mcg via HandiHaler (once daily in the morning) plus placebo to match fluticasone furoate/umeclidinium/vilanterol via the ELLIPTA (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Budesonide/Formoterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation, suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Budesonide/Formoterol was available as suspension for inhalation. Participants received two inhalations of Budesonide/Formoterol (320/9 mcg) via MDI twice daily.

    Investigational medicinal product name
    Placebo matching Fluticasone furoate/Umeclidinium/Vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo matching Fluticasone furoate/Umeclidinium/Vilanterol was available as dry white powder to be administered via ELLIPTA once daily in the morning.

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium was available as a hard gelatin capsule containing 18 mcg of tiotropium bromide blended with lactose. Participants received tiotropium (18 mcg) once daily in the morning via HandiHaler device.

    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 short-acting Albuterol/Salbutamol as-rescue medication during the study period, if required.

    Number of subjects in period 1
    		Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Started
    363
    365
    Completed
    350
    347
    Not completed
    13
    18
         Physician decision
    1
    3
         Consent withdrawn by subject
    7
    7
         Adverse event, non-fatal
    5
    3
         Lost to follow-up
    -
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg
    Reporting group description
    		 Participants received fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 microgram (mcg) via the ELLIPTA (once daily in the morning) plus placebo to match budesonide/formoterol (BUD/FOR) via metered dose inhaler (MDI) (two inhalations twice daily) plus placebo to match tiotropium (TIO) via HandiHaler (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.

    Reporting group title
    Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Reporting group description
    		 Participants received two inhalations of budesonide/formoterol 160/4.5 mcg via MDI in the morning and two inhalations in the evening (total dose of 320/9 mcg twice daily) plus tiotropium 18 mcg via HandiHaler (once daily in the morning) plus placebo to match fluticasone furoate/umeclidinium/vilanterol via the ELLIPTA (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.

    Reporting group values
    		 Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg Total
    Number of subjects
    		 363 365 728
    Age categorical
    Units: Subjects
        Total participants
    		 363 365 728
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 65.4 ( 7.90 ) 64.9 ( 8.06 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 180 164 344
        Male
    		 183 201 384
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    		 34 33 67
        American Indian Or Alaska Native
    		 0 1 1
        Asian - Central/South Asian Heritage
    		 1 0 1
        Asian - South East Asian Heritage
    		 0 1 1
        White - Arabic/North African Heritage
    		 0 2 2
        White - White/Caucasian/European
    		 327 328 655
        Multiple
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg
    Reporting group description
    		 Participants received fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 microgram (mcg) via the ELLIPTA (once daily in the morning) plus placebo to match budesonide/formoterol (BUD/FOR) via metered dose inhaler (MDI) (two inhalations twice daily) plus placebo to match tiotropium (TIO) via HandiHaler (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.

    Reporting group title
    Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Reporting group description
    		 Participants received two inhalations of budesonide/formoterol 160/4.5 mcg via MDI in the morning and two inhalations in the evening (total dose of 320/9 mcg twice daily) plus tiotropium 18 mcg via HandiHaler (once daily in the morning) plus placebo to match fluticasone furoate/umeclidinium/vilanterol via the ELLIPTA (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.

    Primary: Weighted mean change from Baseline in forced expiratory volume in 1 second (FEV1) over 0-24 hours at Week 12 for modified per protocol (mPP) population

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    End point title
    		 Weighted mean change from Baseline in forced expiratory volume in 1 second (FEV1) over 0-24 hours at Week 12 for modified per protocol (mPP) population
    End point description
    FEV1 is the maximum amount of air that can be forced out in 1 second after taking a deep breath. Serial FEV1 assessments were performed at multiple time points (-30, -5 minutes[m] pre-dose and 5m, 15m, 30m, 1 hour[h], 3h, 6h, 12h, 15h, 21h, 23h and 24h post-dose) at Week 12. The weighted mean was derived by calculating the area under the FEV1 time curve (AUC) over the actual time of assessment relative to the time of dosing using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. Baseline FEV1 is average of the two FEV1 measurements made at 30m and 5m pre-dose on Day 1. Weighted mean change from Baseline was calculated by subtracting post-dose weighted mean FEV1 from Baseline FEV1. mPP Population included participants in Intent-to-Treat (ITT) population who do not have protocol deviation of not meeting eligibility or randomization criteria. Only those participants with data available at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Number of subjects analysed
    282 [1]
    272 [2]
    Units: Liters
        least squares mean (standard error)
    0.045 ( 0.0101 )
    0.030 ( 0.0101 )
    Notes
    [1] - mPP Population
    [2] - mPP Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The primary treatment effect estimated (hypothetical effect) excluded data following intercurrent events: discontinuation of treatment, taking wrong treatment, taking prohibited medication, unblinding, noncompliance, COPD exacerbation or pneumonia.
    Comparison groups
    Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg v Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.015
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.013
         upper limit
    		 0.043
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0143
    Notes
    [3] - Non-inferiority was to be demonstrated, if the lower bound of the two-sided 95 percentage (%) confidence interval around the (FF/UMEC/VI versus BUD/FOR+TIO) treatment difference was above -50 milliliter.

    Primary: Weighted mean change from Baseline in FEV1 over 0-24 hours at Week 12 for ITT population

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    End point title
    		 Weighted mean change from Baseline in FEV1 over 0-24 hours at Week 12 for ITT population
    End point description
    FEV1 is the maximum amount of air that can be forced out in 1 second after taking a deep breath. Serial FEV1 assessments were performed at multiple time points (-30 and -5m pre-dose, and 5m, 15m, 30m, 1h, 3h, 6h, 12h, 15h, 21h, 23h and 24h post dose) over 24h period at Week 12. The weighted mean was derived by calculating the area under the FEV1 time curve (AUC) over the actual time of assessment relative to the time of dosing using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. Baseline FEV1 is the average of the two FEV1 measurements made at 30m and 5m pre-dose on Day 1. Weighted mean change from Baseline at week 12 was calculated by subtracting weighted mean FEV1 at week 12 from Baseline FEV1. ITT Population included all randomized participants, excluding those who were randomized in error. Only those participants with data available at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Number of subjects analysed
    336 [4]
    332 [5]
    Units: Liters
        least squares mean (standard error)
    0.046 ( 0.0097 )
    0.032 ( 0.0098 )
    Notes
    [4] - ITT Population
    [5] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The treatment effect to be estimated was hypothetical effect if all participants stayed on their randomized study treatment. Only on treatment data was included in analysis.
    Comparison groups
    Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg v Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Number of subjects included in analysis
    668
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.335 [6]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.013
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.014
         upper limit
    		 0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0138
    Notes
    [6] - The analysis was performed using mixed model repeated measures analysis, which included covariates of Baseline FEV1, geographical region, treatment, visit, visit by treatment and visit by Baseline interaction.

    Secondary: Change from Baseline in trough FEV1 on Day 2, Day 28, Day 84 and Day 85

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    End point title
    		 Change from Baseline in trough FEV1 on Day 2, Day 28, Day 84 and Day 85
    End point description
    FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. For Day 2 and Day 85, trough FEV1 was defined as the mean of the 23-hour and 24-hour serial spirometry FEV1 measurements. For Day 28 and Day 84, trough FEV1 was defined as the average of the pre-dose FEV1 measurements recorded before the morning dose of randomized study treatment. Change from Baseline in trough FEV1 was calculated by subtracting post-dose trough FEV1 value from Baseline FEV1, where Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. The treatment effect to be estimated for trough FEV1 was hypothetical effect if all participants stayed on their randomized study treatment. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline, Days 2, 28, 84 and 85
    End point values
    		 Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Number of subjects analysed
    358 [7]
    359 [8]
    Units: Liters
    least squares mean (standard error)
        Day 2, n=358,359
    0.008 ( 0.0098 )
    0.018 ( 0.0098 )
        Day 28, n=355,353
    0.046 ( 0.0088 )
    -0.015 ( 0.0088 )
        Day 84, n=344,340
    0.040 ( 0.0094 )
    -0.018 ( 0.0094 )
        Day 85, n=341,337
    0.026 ( 0.0099 )
    -0.012 ( 0.0099 )
    Notes
    [7] - ITT Population
    [8] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Day 2
    Comparison groups
    Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg v Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Number of subjects included in analysis
    717
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.481 [9]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.037
         upper limit
    		 0.018
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0139
    Notes
    [9] - Only if superiority is achieved on the primary study endpoint, then inferences can be made on change from Baseline in trough FEV1 on Day 2 using p-values.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Day 28
    Comparison groups
    Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg v Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Number of subjects included in analysis
    717
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [10]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.061
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.037
         upper limit
    		 0.086
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0124
    Notes
    [10] - Only if superiority is achieved on the primary study endpoint, then inferences can be made on change from Baseline in trough FEV1 on Day 28 using p-values.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Day 84
    Comparison groups
    Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg v Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Number of subjects included in analysis
    717
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [11]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.058
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.032
         upper limit
    		 0.084
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0133
    Notes
    [11] - Only if superiority is achieved on the primary study endpoint, then inferences can be made on change from Baseline in trough FEV1 on Day 84 using p-values.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Day 85
    Comparison groups
    Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg v Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Number of subjects included in analysis
    717
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007 [12]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.038
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.066
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Notes
    [12] - Only if superiority is achieved on the primary study endpoint, then inferences can be made on change from Baseline in trough FEV1 on Day 85 using p-values.

    Secondary: Weighted mean change from Baseline in FEV1 over 0-24 hours on Day 1

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    End point title
    		 Weighted mean change from Baseline in FEV1 over 0-24 hours on Day 1
    End point description
    FEV1 is the maximum amount of air that can be forced out in 1 second after taking a deep breath. FEV1 was measured using spirometry. Serial FEV1 assessments were performed at multiple time points (-30 and -5 minutes pre-dose, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 15 hours, 21 hours, 23 hours and 24 hours post dose) over 24-hour period on Day 1. The weighted mean was derived by calculating the area under the FEV1 time curve (AUC) over the actual time of assessment relative to the time of dosing using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. Weighted mean change from Baseline on Day 1 was calculated by subtracting weighted mean FEV1 on Day 1 from Baseline FEV1. Only those participants with data available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 1
    End point values
    		 Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Number of subjects analysed
    354 [13]
    355 [14]
    Units: Liters
        least squares mean (standard error)
    0.054 ( 0.0078 )
    0.063 ( 0.0077 )
    Notes
    [13] - ITT Population
    [14] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The treatment effect to be estimated was hypothetical effect if all participants stayed on their randomized study treatment. Only on treatment data was included in analysis.
    Comparison groups
    Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg v Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Number of subjects included in analysis
    709
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.415 [15]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.009
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.013
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.011
    Notes
    [15] - Only if superiority is achieved on the primary study endpoint, then inferences can be made on weighted mean change from Baseline in FEV1 over 0-24 hours on Day 1 using p-values.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) and non-SAEs were reported from start of study treatment and up to Week 13
    Adverse event reporting additional description
    Non-SAEs and SAEs were reported for ITT Population. Adverse events were presented treatment-wise.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg
    Reporting group description
    		 Participants received fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 microgram (mcg) via the ELLIPTA (once daily in the morning) plus placebo to match budesonide/formoterol (BUD/FOR) via metered dose inhaler (MDI) (two inhalations twice daily) plus placebo to match tiotropium (TIO) via HandiHaler (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.

    Reporting group title
    Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Reporting group description
    		 Participants received two inhalations of budesonide/formoterol 160/4.5 mcg via MDI in the morning and two inhalations in the evening (total dose of 320/9 mcg twice daily) plus tiotropium 18 mcg via HandiHaler (once daily in the morning) plus placebo to match fluticasone furoate/umeclidinium/vilanterol via the ELLIPTA (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.

    Serious adverse events
    		 Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 363 (7.99%)
    16 / 365 (4.38%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 365 (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
    Femur fracture
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 365 (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
    0 / 363 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 363 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    2 / 363 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 365 (0.27%)
         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
    0 / 363 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 365 (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 respiratory failure
         subjects affected / exposed
    2 / 363 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    15 / 363 (4.13%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    4 / 19
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 365 (0.27%)
         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
    2 / 363 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    2 / 363 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 363 (1.10%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoas abscess
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 363 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Fluticasone furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg Budesonide/Formoterol 320/9 mcg plus Tiotropium 18 mcg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 363 (4.96%)
    12 / 365 (3.29%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    18 / 363 (4.96%)
    12 / 365 (3.29%)
         occurrences all number
    20
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jul 2018
    This amendment was required to update the QT interval corrected for heart rate (QTc) stopping criteria to that which was used in the Phase III Trelegy registration studies. In addition, a section describing Smoking Cessation Counselling has been added as does a corresponding assessment at the end of study (Visit 4). Clarified that it is preferable to have the participants stay at the clinic or approved facility during the serial spirometry assessments. The physical form of Symbicort and matching placebo was reported as a solution for inhalation, which is incorrect, and should be corrected to a suspension for inhalation. An additional footnote has been added to the Schedule of Activities (SoA), to provide clarity on the collection of trough forced expiratory volume in 1 second (FEV1) spirometry on Day 28. Clarified that run-in treatment will be collected at Visit 2. Correction made (reference section) regarding prohibited medications within a specified time interval during pre-screening and prior to Visit 1. Also, wording regarding suggested order for assessments and procedures had been added to the end of the Schedule of Activities section. Removed reference to Fridericia formula in calculation of QTc. Clarification regarding collecting the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) assessment questionnaire prior to the Saint George’s Respiratory Questionnaire for COPD participants (SGRQ-C) had also been provided along with clarification that vital signs should be collected before the electrocardiogram (ECG) and prior to spirometry. Corrected reporting time regarding pregnancy. Routine urinalysis assessment has been deleted as this will not be collected during the study. Finally, added wording to Genetics Appendix regarding withdraw process and sample destruction process.

    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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