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    Clinical Trial Results:
    A randomised, double-blind, parallel group, multicentre study of Fluticasone Furoate/GW642444 Inhalation Powder, Fluticasone Furoate Inhalation Powder alone, and Fluticasone Propionate alone in the treatment of persistent asthma in adults and adolescents

    Summary
    EudraCT number
    		 2010-019594-14
    Trial protocol
    		 DE   PL   Outside EU/EEA  
    Global end of trial date
    18 Oct 2011

    Results information
    Results version number
    		 v2(current)
    This version publication date
    08 Mar 2016
    First version publication date
    31 Jul 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction of full data set

    Trial information

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    Trial identification
    Sponsor protocol code
    0HZA106829
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01134042
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Dec 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Oct 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to compare the efficacy and safety of Fluticasone Furoate (FF)/GW642444 Inhalation Powder 200 microgram (mcg)/25 mcg administered once daily each evening to FF Inhalation Powder 200 mcg administered alone once daily each evening in adolescent and adult subjects 12 years of age and older with persistent bronchial asthma over a 24 week treatment period.
    Protection of trial subjects
    The following steps were taken to protect trial participants: 1). Only participants meeting all of the inclusion criteria and none of the exclusion criteria were randomized to investigational medication. 2). All participants enrolled into the study were provided rescue medication for use as necessary. 3). The investigator or treating physician could have unblinded a participant’s treatment assignment in the case of an emergency, when knowledge of the study treatment was essential for the appropriate clinical management or welfare of the participant.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jun 2010
    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
    Romania: 241
    Country: Number of subjects enrolled
    Japan: 106
    Country: Number of subjects enrolled
    Poland: 163
    Country: Number of subjects enrolled
    Germany: 122
    Country: Number of subjects enrolled
    Russian Federation: 246
    Country: Number of subjects enrolled
    United States: 328
    Worldwide total number of subjects
    1206
    EEA total number of subjects
    526
    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)
    65
    Adults (18-64 years)
    991
    From 65 to 84 years
    150
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants (par.) meeting eligibility criteria at the Screening visit entered a 4-week Run-in Period for completion of Baseline (BL) safety evaluations and to obtain BL measures of asthma status. Par. were then randomized to a 24-week Treatment Period. 1206 par. were screened, 587 were randomized, and 586 received >=1 dose of study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FF 200 µg OD
    Arm description
    		 Participants received FF 200 microgram (µg) inhalation powder via a Dry Powder Inhaler (DPI) once daily (OD) in the evening plus placebo via the DISKUS/ACCUHALER twice daily (BID), for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
    Arm type
    		 Experimental

    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
    200 µg once daily

    Arm title
    		 FF/VI 200/25 µg OD
    Arm description
    		 Participants received Fluticasone Furoate/Vilanterol (FF/VI) 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
    Arm type
    		 Experimental

    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
    200 µg/25 µg once daily

    Arm title
    		 FP 500 µg BID
    Arm description
    		 Participants received Fluticasone Propionate (FP) 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    fluticasone propionate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    500 µg twice daily

    Number of subjects in period 1 [1]
    		FF 200 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Started
    194
    197
    195
    Completed
    146
    169
    161
    Not completed
    48
    28
    34
         Physician decision
    4
    8
    1
         Consent withdrawn by subject
    13
    4
    7
         Adverse event, non-fatal
    3
    7
    2
         Lost to follow-up
    2
    -
    1
         Lack of efficacy
    21
    6
    18
         Protocol deviation
    5
    3
    5
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline data were collected in members of the Intent-to-Treat (ITT) Population, comprised of all participants who were randomized to treatment who received at least one dose of study medication. Randomized participants were assumed to have received study medication unless definitive evidence to the contrary existed. A total of 1206 participants were screened (enrolled), 587 were randomized, and 586 received at least one dose of study medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FF 200 µg OD
    Reporting group description
    		 Participants received FF 200 microgram (µg) inhalation powder via a Dry Powder Inhaler (DPI) once daily (OD) in the evening plus placebo via the DISKUS/ACCUHALER twice daily (BID), for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.

    Reporting group title
    FF/VI 200/25 µg OD
    Reporting group description
    		 Participants received Fluticasone Furoate/Vilanterol (FF/VI) 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.

    Reporting group title
    FP 500 µg BID
    Reporting group description
    		 Participants received Fluticasone Propionate (FP) 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.

    Reporting group values
    		 FF 200 µg OD FF/VI 200/25 µg OD FP 500 µg BID Total
    Number of subjects
    		 194 197 195 586
    Age categorical
    Units: Subjects
    Age continuous
    Baseline data were collected in members of the Intent-to-Treat (ITT) Population, comprised of all participants who were randomized to treatment who received at least one dose of study medication. Randomized participants were assumed to have received study medication unless definitive evidence to the contrary existed.
    Units: years
        arithmetic mean (standard deviation)
    		 44.6 ± 14.33 46.6 ± 15.05 47.3 ± 14.06 -
    Gender categorical
    Baseline data were collected in members of the Intent-to-Treat (ITT) Population, comprised of all participants who were randomized to treatment who received at least one dose of study medication. Randomized participants were assumed to have received study medication unless definitive evidence to the contrary existed.
    Units: Subjects
        Female
    		 113 116 116 345
        Male
    		 81 81 79 241
    Race, Customized
    Baseline data were collected in members of the Intent-to-Treat (ITT) Population, comprised of all participants who were randomized to treatment who received at least one dose of study medication. Randomized participants were assumed to have received study medication unless definitive evidence to the contrary existed.
    Units: Subjects
        African American/African Heritage (HER)
    		 16 16 19 51
        American Indian or Alaska Native
    		 0 0 1 1
        Japanese/East Asian HER/South East Asian HER
    		 12 15 13 40
        White
    		 165 165 162 492
        African American/African Heritage and White
    		 1 1 0 2

    End points

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    End points reporting groups
    Reporting group title
    FF 200 µg OD
    Reporting group description
    		 Participants received FF 200 microgram (µg) inhalation powder via a Dry Powder Inhaler (DPI) once daily (OD) in the evening plus placebo via the DISKUS/ACCUHALER twice daily (BID), for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.

    Reporting group title
    FF/VI 200/25 µg OD
    Reporting group description
    		 Participants received Fluticasone Furoate/Vilanterol (FF/VI) 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.

    Reporting group title
    FP 500 µg BID
    Reporting group description
    		 Participants received Fluticasone Propionate (FP) 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.

    Primary: Change from Baseline in clinic visit trough (pre-bronchodilator and pre-dose) forced expiratory volume in one second (FEV1) at the end of the 24-week Treatment Period

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    End point title
    		 Change from Baseline in clinic visit trough (pre-bronchodilator and pre-dose) forced expiratory volume in one second (FEV1) at the end of the 24-week Treatment Period
    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 is defined as the clinic visit (pre-bronchodilator and pre-dose) FEV1 measurement taken at the clinic visit while still on treatment. Pre-dose and pre-rescue albuterol/salbutamol trough FEV1 was measured electronically by spirometry in the evening at the Baseline (BL) through Week 24 clinic visits. The highest of 3 technically acceptable measurements was recorded. BL was the pre-dose value obtained at Visit 3. Change from BL was calculated as the Week 24 value minus the Baseline value. The analysis was performed using an Analysis of Covariance (ANCOVA) model with covariates of BL trough FEV1, country, sex, age, and treatment group.The last observation carried forward (LOCF) method was used to impute missing data, in which the last non-missing post-BL on-treatment measurement at scheduled clinic visits was used to impute the missing measurements.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    		 FF 200 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    186 [1]
    187 [2]
    190 [3]
    Units: Liters
        least squares mean (standard error)
    0.201 ± 0.0303
    0.394 ± 0.0302
    0.183 ± 0.03
    Notes
    [1] - Intent-to-Treat (ITT) Population: randomized participants who received >=1 dose of study medication
    [2] - Intent-to-Treat (ITT) Population: randomized participants who received >=1 dose of study medication
    [3] - Intent-to-Treat (ITT) Population: randomized participants who received >=1 dose of study medication
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This is a comparison of FF/VI 200/25 μg OD v FF 200 μg OD
    Comparison groups
    FF/VI 200/25 µg OD v FF 200 µg OD
    Number of subjects included in analysis
    373
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.193
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.108
         upper limit
    		 0.277
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    FF/VI 200/25 µg OD v FP 500 µg BID
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.127
         upper limit
    		 0.294
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    FF 200 µg OD v FP 500 µg BID
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.018
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.066
         upper limit
    		 0.102
    Notes
    [4] - Non-inferiority is demonstrated if the lower limit of the confidence interval (CI: 0.025, 1-sided significance level) for the mean difference in change from Baseline in clinic visit trough FEV1 of FF 200 µg OD versus FP 500 µg BID was greater than -125 milliliters.

    Primary: Change from Baseline in weighted mean serial FEV1 over 0-24 hours post-dose at Week 24

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    End point title
    		 Change from Baseline in weighted mean serial FEV1 over 0-24 hours post-dose at Week 24
    End point description
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Serial FEV1 measurements were taken electronically by spirometry at the Baseline and Week 24 clinic visits. Weighted mean was calculated using the 24-hour serial FEV1 measurements that included the pre-dose assessment (within 5 minutes prior to dosing) and the post-dose assessments after 5, 15, and 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23, and 24 hours. At each time point, the highest of 3 technically acceptable measurements was recorded. Baseline was the value obtained at Visit 3. Change from Baseline was calculated as the average Week 24 FEV1 value minus the Baseline value.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    		 FF 200 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    83 [5]
    89 [6]
    86 [7]
    Units: Liters
        least squares mean (standard error)
    0.328 ± 0.0493
    0.464 ± 0.047
    0.258 ± 0.0483
    Notes
    [5] - ITT Population. Data were calculated in participants for whom serial FEV1 at Week 24 was performed.
    [6] - ITT Population. Data were calculated in participants for whom serial FEV1 at Week 24 was performed.
    [7] - ITT Population. Data were calculated in participants for whom serial FEV1 at Week 24 was performed.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FF 200 µg OD v FF/VI 200/25 µg OD
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.048
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.136
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.001
         upper limit
    		 0.27
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    FP 500 µg BID v FF/VI 200/25 µg OD
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.206
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.073
         upper limit
    		 0.339

    Secondary: Change from Baseline in the percentage of rescue-free and symptom-free 24-hour periods during the 24-week Treatment Period

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    End point title
    		 Change from Baseline in the percentage of rescue-free and symptom-free 24-hour periods during the 24-week Treatment Period
    End point description
    The number of inhalations of rescue bronchodilator, albuterol/salbutamol inhalation aerosol, used during the day and night was recorded by the participants in a daily electronic diary (eDiary). Similarly, asthma symptoms were recorded in a daily eDairy by the participants every day in the morning and evening before taking any rescue or study medication and before the peak expiratory flow measurement. A 24-hour period in which a participant’s responses to both the morning and evening assessments indicated no use of rescue medication/symptoms was considered to be rescue free/symptom free. The Baseline value was derived from the last 7 days of the daily eDiary prior to the randomization of the participant. Change from Baseline was calculated as the averaged value during the 24-week Treatment Period minus the Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 FF 200 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    193 [8]
    197 [9]
    194 [10]
    Units: Percentage of periods
    least squares mean (standard error)
        Rescue-free 24-hour periods
    26.6 ± 2.45
    38.2 ± 2.42
    31.9 ± 2.45
        Symptom-free 24-hour periods
    21 ± 2.32
    29.3 ± 2.29
    24.5 ± 2.31
    Notes
    [8] - ITT Population. Only those participants available at the specified time points were analyzed.
    [9] - ITT Population. Only those participants available at the specified time points were analyzed.
    [10] - ITT Population. Only those participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Change from Baseline in the total Asthma Quality of Life Questionnaire (AQLQ) (+12) score at Week 12 and Week 24

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    End point title
    		 Change from Baseline in the total Asthma Quality of Life Questionnaire (AQLQ) (+12) score at Week 12 and Week 24
    End point description
    The AQLQ is a disease-specific, self-administered quality of life questionnaire used to evaluate the impact of asthma treatments on the quality of life of asthma sufferers. The AQLQ for 12 years and older (AQLQ [+12]) is a modified version of the AQLQ for use in asthma patients between the age of 12 and 70. The AQLQ contains 32 items in 4 domains: activity limitation (11 items), symptoms (12 items), emotional function (5 items), and environmental stimuli (4 items). For the 32 items on the questionnaire, the response format consists of a seven-point scale, where a value of 1 indicates “total impairment” and a value of 7 indicates “no impairment.” The AQLQ total score is defined as the average of the scores from all 32 questions; thus, the total score ranges from 1 (indicates "total impairment") to 7 (indicates "no impairment"). Baseline was the total score obtained at Visit 3. Change from Baseline was calculated as the total score at Weeks 12 and 24 minus the total score at Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, and Week 24
    End point values
    		 FF 200 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    194 [11]
    197 [12]
    195 [13]
    Units: Scores on a scale
    least squares mean (standard error)
        Week 12, n=154, 180, 163
    0.66 ± 0.061
    0.74 ± 0.056
    0.74 ± 0.059
        Week 24, n=140, 167, 156
    0.88 ± 0.071
    0.93 ± 0.065
    0.9 ± 0.068
    Notes
    [11] - ITT Population. Available participants were analyzed (represented by n=X, X, X in category titles).
    [12] - ITT Population. Available participants were analyzed (represented by n=X, X, X in category titles).
    [13] - ITT Population. Available participants were analyzed (represented by n=X, X, X in category titles).
    No statistical analyses for this end point

    Secondary: Clinic visit 12-hour post-dose FEV1at Week 24

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    End point title
    		 Clinic visit 12-hour post-dose FEV1at Week 24
    End point description
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. 12-hour post-dose FEV1 measurements were taken electronically by spirometry at the Week 24 clinic visit. The highest of 3 technically acceptable measurements was recorded.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 FF 200 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    82 [14]
    93 [15]
    87 [16]
    Units: Liters
        arithmetic mean (standard deviation)
    2.611 ± 0.8437
    2.683 ± 0.9758
    2.262 ± 0.7786
    Notes
    [14] - ITT Population. Data were analyzed in participants for whom serial FEV1 at Week 24 was performed.
    [15] - ITT Population. Data were analyzed in participants for whom serial FEV1 at Week 24 was performed.
    [16] - ITT Population. Data were analyzed in participants for whom serial FEV1 at Week 24 was performed.
    No statistical analyses for this end point

    Secondary: Change from Baseline in weighted mean serial FEV1 over 0 to 4 hours post-dose at Week 24

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    End point title
    		 Change from Baseline in weighted mean serial FEV1 over 0 to 4 hours post-dose at Week 24
    End point description
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Serial FEV1 measurements were taken electronically by spirometry at Baseline. Weighted mean was calculated using the 4-hour serial FEV1 measurements that included the pre-dose assessment (within 5 minutes prior to dosing) and post-dose assessments after 5, 15, and 30 minutes and 1, 2, 3, and 4 hours. At each time point, the highest of 3 technically acceptable measurements was recorded. Baseline was the value obtained at Visit 3. Change from Baseline was calculated as the average Week 24 FEV1 value minus the Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 FF 200 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    83 [17]
    89 [18]
    86 [19]
    Units: Liters
        arithmetic mean (standard deviation)
    0.363 ± 0.469
    0.492 ± 0.5671
    0.256 ± 0.4679
    Notes
    [17] - ITT Population. Data were calculated in participants for whom serial FEV1 at Week 24 was performed.
    [18] - ITT Population. Data were calculated in participants for whom serial FEV1 at Week 24 was performed.
    [19] - ITT Population. Data were calculated in participants for whom serial FEV1 at Week 24 was performed.
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in daily morning trough (AM) and evening (PM) Peak Expiratory Flow (PEF) averaged over the first 12 weeks and 24 weeks of the 24-week Treatment Period

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    End point title
    		 Mean change from Baseline in daily morning trough (AM) and evening (PM) Peak Expiratory Flow (PEF) averaged over the first 12 weeks and 24 weeks of the 24-week Treatment Period
    End point description
    PEF is a measure of lung function and is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF was measured by the participants using a hand-held electronic peak flow meter each morning and evening prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. Trough PEF is the PEF measured approximately 24 hours after the last administration of study drug. Change from Baseline (defined as the last 7 days prior to randomization of the participants) was calculated as the value of the averaged daily trough AM/PM PEF over 12 weeks and 24 weeks of the 24-week Treatment Period (at Weeks 12 and 24) minus the Baseline value. ITT Population. Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT Population.
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 12 and Week 24
    End point values
    		 FF 200 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    194 [20]
    197 [21]
    195 [22]
    Units: Liters/minute (L/min)
    least squares mean (standard error)
        AM PEF, Week 1 to 12, n=193, 197, 195
    15.1 ± 2.82
    48.1 ± 2.78
    17.1 ± 2.8
        AM PEF, Week 1 to 24, n=193, 197, 195
    18.2 ± 2.97
    51.8 ± 2.94
    18.8 ± 2.95
        PM PEF, Week 1 to 12, 192, 197, 194
    7.5 ± 2.8
    36.6 ± 2.75
    12.6 ± 2.78
        PM PEF, Week 1 to 24, 192, 197, 194
    9.1 ± 2.98
    39.8 ± 2.93
    13.6 ± 2.96
    Notes
    [20] - ITT Population. Available participants were analyzed (represented by n=X, X, X in category titles).
    [21] - ITT Population. Available participants were analyzed (represented by n=X, X, X in category titles).
    [22] - ITT Population. Available participants were analyzed (represented by n=X, X, X in category titles).
    No statistical analyses for this end point

    Secondary: The number of participants who withdrew due to lack of efficacy during the 24-week Treatment Period

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    End point title
    		 The number of participants who withdrew due to lack of efficacy during the 24-week Treatment Period
    End point description
    The number of participants whose primary reason for withdrawal was lack of efficacy was analyzed.
    End point type
    Secondary
    End point timeframe
    From the first dose of the study medication up to Week 24/Early Withdrawal
    End point values
    		 FF 200 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    194 [23]
    197 [24]
    195 [25]
    Units: Participants
    21
    6
    18
    Notes
    [23] - ITT Population
    [24] - ITT Population
    [25] - ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Asthma Control Test (ACT) scores at Week 12 and Week 24

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    End point title
    		 Change from Baseline in the Asthma Control Test (ACT) scores at Week 12 and Week 24
    End point description
    The ACT is a 5-item questionnaire developed as a measure of the participant's asthma control. Questions are designed to be self-completed by the participant and include the following: In the past 4 weeks, "How much of the time did your asthma keep you from getting as much done at work, school or at home?", "How often have you had shortness of breath?", "How often did your asthma symptoms wake you up at night or earlier than usual in the morning?", "How often have you used your rescue inhaler or nebulizer medication (such as albuterol)?" and "How would you rate your asthma control"? The ACT total score is defined as the sum of the scores from all 5 questions, provided all questions have been answered; thus, the total score ranges from 5 (poor control of asthma) to 25 (complete control of asthma). A score of 20 or higher indicates well-controlled asthma. Change from Baseline was calculated as the total score at Week 12 and Week 24 minus the total score at Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, and Week 24
    End point values
    		 FF 200 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    194 [26]
    197 [27]
    195 [28]
    Units: Scores on a scale
    least squares mean (standard error)
        Week 12, n=164, 183, 169
    3.9 ± 0.29
    4.8 ± 0.27
    3.9 ± 0.28
        Week 24, n=147, 170, 162
    5.2 ± 0.3
    5.5 ± 0.28
    4.7 ± 0.29
    Notes
    [26] - ITT Population. Available participants were analyzed (represented by n=X, X, X in category titles).
    [27] - ITT Population. Available participants were analyzed (represented by n=X, X, X in category titles).
    [28] - ITT Population. Available participants were analyzed (represented by n=X, X, X in category titles).
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated Global Assessment of Change Questionnaire responses at Weeks 4, 12, and 24

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    End point title
    		 Number of participants with the indicated Global Assessment of Change Questionnaire responses at Weeks 4, 12, and 24
    End point description
    At the end of Week 4, Week 8, and Week 24/Early Withdrawal, the Global Assessment of Change Questionnaire that assesses changes in asthma symptoms (AS) and rescue medication use (RMU) was completed by the participants. The number of participants who chose the following answers to the questionnaire were determined: much better, somewhat better, a little better, the same, a little worse, somewhat worse, much worse (to assess the changes in asthma symptoms); much less often, somewhat less often, a little less often, the same, a little more often, somewhat more often, much more often (to assess the changes in the frequency of rescue medication use). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT Population.
    End point type
    Secondary
    End point timeframe
    Week 4, Week 12, and Week 24
    End point values
    		 FF 200 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    194 [29]
    197 [30]
    195 [31]
    Units: Participants
        Week 4, AS: Much better, n=174, 191, 180
    37
    58
    35
        Week 4, AS: Somewhat better, n=174, 191, 180
    47
    65
    49
        Week 4, AS: A little better, n=174, 191, 180
    43
    34
    40
        Week 4, AS: The same, n=174, 191, 180
    35
    25
    44
        Week 4, AS: A little worse, n=174, 191, 180
    8
    7
    6
        Week 4, AS: Somewhat worse, n=174, 191, 180
    2
    2
    3
        Week 4, AS: Much worse, n=174, 191, 180
    2
    0
    3
        Week 4, RMU: Much less often, n=174, 191, 180
    49
    71
    42
        Week 4, RMU: Somewhat less often, n=174, 191, 180
    29
    48
    41
        Week 4, RMU: A little less often, n=174, 191, 180
    42
    38
    45
        Week 4, RMU: The same, n=174, 191, 180
    34
    27
    37
        Week 4, RMU: A little more often, n=174, 191, 180
    14
    4
    9
        Week 4, RMU: Somewhat more often, n=174, 191, 180
    5
    2
    3
        Week 4, RMU: Much more often, n=174, 191, 180
    1
    1
    3
        Week 12, AS: Much better, n=162, 183, 165
    60
    78
    54
        Week 12, AS: Somewhat better, n=162, 183, 165
    43
    51
    52
        Week 12, AS: A little better, n=162, 183, 165
    27
    33
    34
        Week 12, AS: The same, n=162, 183, 165
    23
    15
    16
        Week 12, AS: A little worse, n=162, 183, 165
    8
    5
    6
        Week 12, AS: Somewhat worse, n=162, 183, 165
    0
    1
    3
        Week 12, AS: Much worse, n=162, 183, 165
    1
    0
    0
        Week 12, RMU: Much less often, n=162, 183, 164
    66
    90
    59
        Week12, RMU: Somewhat less often, n=162, 183, 164
    31
    36
    37
        Week12, RMU: A little less often, n=162, 183, 164
    28
    24
    40
        Week12, RMU: The same, n=162, 183, 164
    26
    24
    20
        Week12, RMU: A little more often, n=162, 183, 164
    7
    8
    6
        Week12, RMU: Somewhat more often, n=162, 183, 164
    2
    0
    1
        Week12, RMU: Much more often, n=162, 183, 164
    2
    1
    1
        Week 24, AS: Much better, n=146, 168, 162
    64
    89
    62
        Week 24, AS: Somewhat better, n=146, 168, 162
    43
    37
    52
        Week 24, AS: A little better, n=146, 168, 162
    22
    23
    17
        Week 24, AS: The same, n=146, 168, 162
    11
    14
    23
        Week 24, AS: A little worse, n=146, 168, 162
    3
    4
    4
        Week 24, AS: Somewhat worse, n=146, 168, 162
    2
    1
    2
        Week 24, AS: Much worse, n=146, 168, 162
    1
    0
    2
        Week 24, RMU: Much less often, n=146, 168, 162
    68
    87
    69
        Week 24, RMU: Somewhat less often, n=146, 168, 162
    33
    38
    37
        Week 24, RMU: A little less often, n=146, 168, 162
    29
    22
    26
        Week 24, RMU: The same, n=146, 168, 162
    12
    16
    19
        Week 24, RMU: A little more often, n=146, 168, 162
    1
    3
    8
        Week 24, RMU: Somewhat more often, n=146, 168, 162
    3
    1
    1
        Week 24, RMU: Much more often, n=146, 168, 162
    0
    1
    2
    Notes
    [29] - ITT Population. Available participants were analyzed (represented by n=X, X, X in category titles).
    [30] - ITT Population. Available participants were analyzed (represented by n=X, X, X in category titles).
    [31] - ITT Population. Available participants were analyzed (represented by n=X, X, X in category titles).
    No statistical analyses for this end point

    Secondary: Number of the indicated unscheduled asthma-related healthcare visits during the Treatment Period

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    End point title
    		 Number of the indicated unscheduled asthma-related healthcare visits during the Treatment Period
    End point description
    All unscheduled asthma-related visits to a physician’s office, visits to urgent care, visits to the emergency department, and hospitalizations (ICU=intensive care unit; GW=general ward) associated with severe asthma exacerbations or other asthma-related healthcare issues were recorded.
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 24/Withdrawal Visit
    End point values
    		 FF 200 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    194 [32]
    197 [33]
    195 [34]
    Units: Number of visits
    arithmetic mean (standard deviation)
        Number of Home Visits (Day)
    0 ± 0.07
    0 ± 0
    0 ± 0
        Number of Home Visits (Night)
    0 ± 0
    0 ± 0
    0 ± 0
        Number of Physician Office/Practice Visits
    0 ± 0.1
    0 ± 0
    0.1 ± 0.45
        Number of Urgent Care/Outpatient Clinic Visits
    0 ± 0
    0 ± 0
    0 ± 0
        Number of Emergency Room Visits
    0 ± 0.07
    0 ± 0
    0 ± 0
        Number of Inpatient Hospitalization Days (ICU)
    0 ± 0
    0 ± 0
    0 ± 0
        Number of Inpatient Hospitalization (GW) Days
    0 ± 0.29
    0 ± 0
    0 ± 0
    Notes
    [32] - ITT Population
    [33] - ITT Population
    [34] - ITT Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the treatment period (up to Week 24).
    Adverse event reporting additional description
    An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    FF 200 µg OD
    Reporting group description
    		 Participants received FF 200 microgram (µg) inhalation powder via a Dry Powder Inhaler (DPI) once daily (OD) in the evening plus placebo via the DISKUS/ACCUHALER twice daily (BID), for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.

    Reporting group title
    FF/VI 200/25 µg OD
    Reporting group description
    		 Participants received Fluticasone Furoate/Vilanterol (FF/VI) 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.

    Reporting group title
    FP 500 µg BID
    Reporting group description
    		 Participants received Fluticasone Propionate (FP) 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.

    Serious adverse events
    		 FF 200 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 194 (0.52%)
    6 / 197 (3.05%)
    2 / 195 (1.03%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thyroid cancer
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 197 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Limb traumatic amputation
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 197 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 197 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 197 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 197 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 197 (0.00%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 197 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 197 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 197 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 FF 200 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 194 (34.02%)
    62 / 197 (31.47%)
    73 / 195 (37.44%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 194 (6.70%)
    11 / 197 (5.58%)
    15 / 195 (7.69%)
         occurrences all number
    21
    12
    25
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    2 / 194 (1.03%)
    6 / 197 (3.05%)
    4 / 195 (2.05%)
         occurrences all number
    2
    6
    5
    Oropharyngeal pain
         subjects affected / exposed
    8 / 194 (4.12%)
    4 / 197 (2.03%)
    7 / 195 (3.59%)
         occurrences all number
    10
    5
    7
    Cough
         subjects affected / exposed
    6 / 194 (3.09%)
    3 / 197 (1.52%)
    13 / 195 (6.67%)
         occurrences all number
    6
    3
    14
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    2 / 194 (1.03%)
    1 / 197 (0.51%)
    7 / 195 (3.59%)
         occurrences all number
    2
    1
    7
    Pharyngitis
         subjects affected / exposed
    2 / 194 (1.03%)
    4 / 197 (2.03%)
    6 / 195 (3.08%)
         occurrences all number
    2
    4
    7
    Sinusitis
         subjects affected / exposed
    7 / 194 (3.61%)
    3 / 197 (1.52%)
    4 / 195 (2.05%)
         occurrences all number
    7
    3
    5
    Bronchitis
         subjects affected / exposed
    6 / 194 (3.09%)
    7 / 197 (3.55%)
    6 / 195 (3.08%)
         occurrences all number
    6
    7
    6
    Influenza
         subjects affected / exposed
    8 / 194 (4.12%)
    5 / 197 (2.54%)
    7 / 195 (3.59%)
         occurrences all number
    9
    5
    8
    Respiratory tract infection viral
         subjects affected / exposed
    7 / 194 (3.61%)
    7 / 197 (3.55%)
    7 / 195 (3.59%)
         occurrences all number
    9
    8
    8
    Nasopharyngitis
         subjects affected / exposed
    27 / 194 (13.92%)
    25 / 197 (12.69%)
    39 / 195 (20.00%)
         occurrences all number
    34
    33
    60

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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