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

    Summary
    EudraCT number
    		 2017-001190-16
    Trial protocol
    		 PL  
    Global end of trial date
    17 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Apr 2020
    First version publication date
    22 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    207626
    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
    30 Sep 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of single inhaler triple therapy (FF/UMEC/VI) compared to Tiotropium after 12 weeks of treatment on lung function
    Protection of trial subjects
    NA
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Mar 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
    Poland: 400
    Country: Number of subjects enrolled
    Russian Federation: 198
    Country: Number of subjects enrolled
    United States: 202
    Worldwide total number of subjects
    800
    EEA total number of subjects
    400
    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)
    321
    From 65 to 84 years
    473
    85 years and over
    6

    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 tiotropium in a 1:1 ratio. The study was conducted across 68 centers in 3 countries.

    Pre-assignment
    Screening details
    		 A total of 1049 participants were screened, of which 179 failed screening. Total of 870 participants entered in run-in period, of which 70 were run-in failures. Total of 800 participants were enrolled and randomized.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 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 tiotropium (TIO) via HandiHaler (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication via metered dose inhaler (MDI) 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 Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    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
    		 Tiotropium 18 mcg
    Arm description
    		 Participants received 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 via MDI during conduct of the study, if required.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    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
    Placebo to match 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
    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 Tiotropium 18 mcg
    Started
    400
    400
    Received study treatment
    400
    399
    Completed
    383
    387
    Not completed
    17
    13
         Adverse event, serious fatal
    1
    1
         Physician decision
    3
    2
         Consent withdrawn by subject
    5
    7
         Investigator site closed
    1
    -
         Adverse event, non-fatal
    5
    2
         Lost to follow-up
    2
    1

    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 tiotropium (TIO) via HandiHaler (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication via metered dose inhaler (MDI) during conduct of the study, if required.

    Reporting group title
    Tiotropium 18 mcg
    Reporting group description
    		 Participants received 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 via MDI during conduct of the study, if required.

    Reporting group values
    		 Fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg Tiotropium 18 mcg Total
    Number of subjects
    		 400 400 800
    Age categorical
    Units: Subjects
        Total participants
    		 400 400 800
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 66.2 ± 8.08 66.1 ± 7.78 -
    Sex: Female, Male
    Units: Participants
        Female
    		 126 131 257
        Male
    		 274 269 543
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    		 10 12 22
        White - White/Caucasian/European Heritage
    		 390 388 778

    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 tiotropium (TIO) via HandiHaler (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication via metered dose inhaler (MDI) during conduct of the study, if required.

    Reporting group title
    Tiotropium 18 mcg
    Reporting group description
    		 Participants received 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 via MDI during conduct of the study, if required.

    Primary: Change from Baseline in trough forced expiratory volume in 1 second (FEV1) on Day 85

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    End point title
    		 Change from Baseline in trough forced expiratory volume in 1 second (FEV1) on Day 85
    End point description
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Day 85 was defined as the mean of the two planned spirometry FEV1 measurements. Change from Baseline in trough FEV1 on Day 85 was calculated by subtracting Baseline FEV1 value from the trough FEV1 value on Day 85. Baseline FEV1 was defined as the mean of the two assessments made at 30 and 5 minutes pre-dose on Day 1. Intent-To-Treat (ITT) Population comprised of all randomized participants, excluding those who were randomized in error. Only those participants with data available at the specified time point were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1 [Pre-dose at 30 minutes and 5 minutes]) and Day 85
    End point values
    		 Fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg Tiotropium 18 mcg
    Number of subjects analysed
    362 [1]
    375 [2]
    Units: Liters
        least squares mean (standard error)
    0.115 ± 0.0119
    0.020 ± 0.0117
    Notes
    [1] - ITT Population
    [2] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg v Tiotropium 18 mcg
    Number of subjects included in analysis
    737
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [3]
    Method
    		 Mixed model repeated measures (MMRM)
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.095
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.062
         upper limit
    		 0.128
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0167
    Notes
    [3] - The MMRM model included Baseline FEV1, visit, geographical region, and treatment as covariates and visit-by-Baseline FEV1 and visit-by-treatment interaction terms.

    Secondary: Change from Baseline in trough FEV1 on Day 28

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    End point title
    		 Change from Baseline in trough FEV1 on Day 28
    End point description
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Day 28 was defined as the average of the two pre-dose FEV1 measurements recorded before the morning dose of randomized study medication on Day 28. Change from Baseline in trough FEV1 on Day 28 was calculated by subtracting Baseline FEV1 value from the trough FEV1 value on Day 28. Baseline FEV1 was defined as the mean of the two assessments made at 30 and 5 minutes pre-dose on Day 1. Only those participants with data available at the specified time point were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 [Pre-dose at 30 minutes and 5 minutes]) and Day 28
    End point values
    		 Fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg Tiotropium 18 mcg
    Number of subjects analysed
    385 [4]
    390 [5]
    Units: Liters
        least squares mean (standard error)
    0.115 ± 0.0102
    -0.007 ± 0.0101
    Notes
    [4] - ITT Population
    [5] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg v Tiotropium 18 mcg
    Number of subjects included in analysis
    775
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [6]
    Method
    		 Mixed model repeated measures (MMRM)
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.122
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.094
         upper limit
    		 0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0144
    Notes
    [6] - The MMRM model included Baseline FEV1, visit, geographical region, and treatment as covariates and visit-by-Baseline FEV1 and visit-by-treatment interaction terms.

    Secondary: Change from Baseline in trough FEV1 on Day 84

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    End point title
    		 Change from Baseline in trough FEV1 on Day 84
    End point description
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Day 84 was defined as the average of the two pre-dose FEV1 measurements recorded before the morning dose of randomized study medication on Day 84. Change from Baseline in trough FEV1 on Day 84 was calculated by subtracting Baseline FEV1 value from the trough FEV1 value on Day 84. Baseline FEV1 was defined as the mean of the two assessments made at 30 and 5 minutes pre-dose on Day 1. Only those participants with data available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 [Pre-dose at 30 minutes and 5 minutes]) and Day 84
    End point values
    		 Fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg Tiotropium 18 mcg
    Number of subjects analysed
    376 [7]
    386 [8]
    Units: Liters
        least squares mean (standard error)
    0.105 ± 0.0113
    0.018 ± 0.0111
    Notes
    [7] - ITT Population
    [8] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg v Tiotropium 18 mcg
    Number of subjects included in analysis
    762
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [9]
    Method
    		 Mixed model repeated measures (MMRM)
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.087
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.056
         upper limit
    		 0.118
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0159
    Notes
    [9] - The MMRM model included Baseline FEV1, visit, geographical region, and treatment as covariates and visit-by-Baseline FEV1 and visit-by-treatment interaction terms.

    Secondary: Number of participants with non-serious adverse events (non-SAEs) and serious adverse events (SAEs)

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    End point title
    		 Number of participants with non-serious adverse events (non-SAEs) and serious adverse events (SAEs)
    End point description
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other important medical event according to medical or scientific judgement was categorized as SAE. Non-SAEs and SAEs were presented for all randomized participants excluding one participant in ITT population who was randomized correctly to "Tiotropium 18 mcg" arm but did not take any randomized study treatment due to withdrawal of consent.
    End point type
    Secondary
    End point timeframe
    Up to Day 95
    End point values
    		 Fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg Tiotropium 18 mcg
    Number of subjects analysed
    400 [10]
    399 [11]
    Units: Participants
        Non-SAEs
    31
    29
        SAEs
    13
    11
    Notes
    [10] - ITT Population
    [11] - ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP)

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    End point title
    		 Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP)
    End point description
    SBP and DBP were assessed in the sitting position after approximately 5 minutes rest. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Baseline was defined as the latest pre-first-dose assessment with a non-missing value, including those from unscheduled visits. Only those participants with data available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, Pre-dose) and Day 84
    End point values
    		 Fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg Tiotropium 18 mcg
    Number of subjects analysed
    387 [12]
    392 [13]
    Units: Millimeters of mercury
    arithmetic mean (standard deviation)
        SBP
    -0.3 ± 12.53
    -0.1 ± 11.02
        DBP
    -0.3 ± 8.17
    -0.7 ± 7.88
    Notes
    [12] - ITT Population
    [13] - ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in pulse rate

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    End point title
    		 Change from Baseline in pulse rate
    End point description
    Pulse rate was assessed in the sitting position after approximately 5 minutes rest. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Baseline was defined as the latest pre-first-dose assessment with a non-missing value, including those from unscheduled visits. Only those participants with data available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, Pre-dose) and Day 84
    End point values
    		 Fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg Tiotropium 18 mcg
    Number of subjects analysed
    387 [14]
    392 [15]
    Units: Beats per minute
        arithmetic mean (standard deviation)
    0.2 ± 8.55
    0.8 ± 8.51
    Notes
    [14] - ITT Population
    [15] - ITT Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Non-SAEs and SAEs were reported from start of study treatment and up to 95 days
    Adverse event reporting additional description
    Non-SAEs and SAEs were presented for all randomized participants excluding one randomized participant who withdrew consent and never received study treatment in "Tiotropium 18 mcg" arm. 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 tiotropium (TIO) via HandiHaler (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication via metered dose inhaler (MDI) during conduct of the study, if required.

    Reporting group title
    Tiotropium 18 mcg
    Reporting group description
    		 Participants received 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 via MDI during conduct of the study, if required.

    Serious adverse events
    		 Fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg Tiotropium 18 mcg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 400 (3.25%)
    11 / 399 (2.76%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    1 / 400 (0.25%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 400 (0.25%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 399 (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
    1 / 400 (0.25%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    5 / 400 (1.25%)
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 399 (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
    Osteoarthritis
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 400 (0.25%)
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    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 Tiotropium 18 mcg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 400 (7.75%)
    29 / 399 (7.27%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 400 (4.50%)
    22 / 399 (5.51%)
         occurrences all number
    30
    69
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 400 (4.00%)
    8 / 399 (2.01%)
         occurrences all number
    17
    8

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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 run-in treatment should be collected at Visit 2, study treatment at Visit 3, and albuterol/salbutamol at Visit 5. Also, wording regarding suggested order for assessments and procedures has been added to the end of the Schedule of Activities section. Removed reference to Fridericia formula in calculation of QTc. Clarification regarding collecting the COPD Assessment Test (CAT) assessment questionnaire prior to the St. George’s Respiratory Questionnaire for COPD participants (SGRQ-C) has also been provided along with clarification that vital signs should be collected before the electrocardiogram (ECG) and prior to spirometry. Also added clarification that CAT and SGRQ-C should be collected at Visit 3 to mirror the Schedule of Activities (SoA). Corrected reporting time regarding pregnancy. 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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