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    Clinical Trial Results:
    A multi-centre, randomised, double-blind, placebo-controlled, crossover study to investigate the efficacy, safety, and tolerability of repeat doses of inhaled GSK2269557 in adults with persistent, uncontrolled asthma

    Summary
    EudraCT number
    		 2014-003808-77
    Trial protocol
    		 DE  
    Global end of trial date
    28 Sep 2016

    Results information
    Results version number
    		 v2
    This version publication date
    10 Mar 2018
    First version publication date
    04 Jun 2017
    Other versions
    		 v1 , v3
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    201543
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy of inhaledGSK2269557 administered once daily for 28 days in subjects with persistent uncontrolled asthma, compared with placebo.
    Protection of trial subjects
    The study protocol has included the following stopping criteria: - Liver Chemistry Stopping Criteria - QTc Stopping Criteria - Other Safety stopping criteria like Unacceptable adverse events related to study drug or study procedures. Clinically significant and relevant changes in laboratory parameters or ECG recordings. Paradoxical bronchospasm Pregnancy (female subjects) - Efficacy stopping criteria - A subjects may withdraw from study treatment at any time at his/her own request, or may be withdrawn at any time at the discretion of the investigator for safety, behavioural or administrative reasons.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Oct 2015
    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: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    47
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Eligible participants entered the 2 week Run-in phase and participants who met the randomization eligibility criteria entered into the 4 week Double-blind treatment period (DBTP) 1 followed by a 4-week wash-out period, 4 weeks DBTP 2 and a 2 week follow-up phase. The total duration of participation in the study was 16 weeks.

    Pre-assignment
    Screening details
    		 A total of 108 participants with persistent uncontrolled asthma, currently not treated with an inhaled corticosteroid (ICS) or long acting beta2 agonist (LABA) were screened, of these, 58 were screen failures and 50 entered the Run-in phase. All 50 par. were randomized into the study and received study treatments.

    Period 1
    Period 1 title
    Treatment Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo, then GSK2269557
    Arm description
    		 Participants received placebo drug once daily via dry powder inhaler for 28 days during Treatment Period 1. After a washout period of 4 weeks, participants received GSK2269557 1000 micrograms (µg) drug once daily via dry powder inhaler for 28 days during Treatment Period 2. In addition, salbutamol was provided to participants to use on an as-needed basis for relief of asthma symptoms.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GSK2269557
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations of GSK269557 were administered every day before breakfast by using DISKUS dry powder inhaler (DPI). Inhalations were taken approximately 30 seconds apart.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations of lactose were administered every day before breakfast by using DISKUS DPI. Inhalations were taken approximately 30 seconds apart.

    Arm title
    		 GSK2269557, then Placebo
    Arm description
    		 Participants received GSK2269557 1000 µg drug once daily via dry powder inhaler for the 28 days during Treatment Period 1. After a washout period of 4 weeks, participants received placebo drug once daily via dry powder inhaler for 28 days during Treatment Period 2. In addition, salbutamol was provided to participants to use on an as-needed basis for relief of asthma symptoms.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GSK2269557
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations of GSK269557 were administered every day before breakfast by using DISKUS dry powder inhaler (DPI). Inhalations were taken approximately 30 seconds apart.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations of lactose were administered every day before breakfast by using DISKUS DPI. Inhalations were taken approximately 30 seconds apart.

    Number of subjects in period 1
    		Placebo, then GSK2269557 GSK2269557, then Placebo
    Started
    24
    26
    Completed
    22
    23
    Not completed
    2
    3
         Other: Reached stopping criteria
    2
    -
         Adverse event, non-fatal
    -
    2
         Protocol deviation
    -
    1
    Period 2
    Period 2 title
    Washout period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo, then GSK2269557
    Arm description
    		 The two treatment periods were separated by a four-week wash-out period in which all participants did not receive study medication, but were provided a salbutamol inhaler for symptomatic relief of asthma symptoms.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 GSK2269557, then Placebo
    Arm description
    		 The two treatment periods were separated by a four-week wash-out period in which all participants did not receive study medication, but were provided a salbutamol inhaler for symptomatic relief of asthma symptoms.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Placebo, then GSK2269557 GSK2269557, then Placebo
    Started
    22
    23
    Completed
    22
    23
    Period 3
    Period 3 title
    Treatment period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo, then GSK2269557
    Arm description
    		 Participants received placebo drug once daily via dry powder inhaler for 28 days during Treatment Period 1. After a washout period of 4 weeks, participants received GSK2269557 1000 micrograms (µg) drug once daily via dry powder inhaler for 28 days during Treatment Period 2. In addition, salbutamol was provided to participants to use on an as-needed basis for relief of asthma symptoms.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GSK2269557
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations of GSK269557 were administered every day before breakfast by using DISKUS dry powder inhaler (DPI). Inhalations were taken approximately 30 seconds apart.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations of lactose were administered every day before breakfast by using DISKUS DPI. Inhalations were taken approximately 30 seconds apart.

    Arm title
    		 GSK2269557, then Placebo
    Arm description
    		 Participants received GSK2269557 1000 µg drug once daily via dry powder inhaler for the 28 days during Treatment Period 1. After a washout period of 4 weeks, participants received placebo drug once daily via dry powder inhaler for 28 days during Treatment Period 2. In addition, salbutamol was provided to participants to use on an as-needed basis for relief of asthma symptoms.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GSK2269557
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations of GSK269557 were administered every day before breakfast by using DISKUS dry powder inhaler (DPI). Inhalations were taken approximately 30 seconds apart.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations of lactose were administered every day before breakfast by using DISKUS DPI. Inhalations were taken approximately 30 seconds apart.

    Number of subjects in period 3
    		Placebo, then GSK2269557 GSK2269557, then Placebo
    Started
    22
    23
    Completed
    22
    20
    Not completed
    0
    3
         Other: Reached stopping criteria
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period 1
    Reporting group description
    		 Treatment Period 1

    Reporting group values
    		 Treatment Period 1 Total
    Number of subjects
    		 50
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.5 ( 13.86 ) -
    Gender categorical
    Units: Subjects
        Female
    		 28 28
        Male
    		 22 22
    Race/Ethnicity, Customized
    Units: Subjects
        White - White/Caucasian/European Heritage
    		 50 50

    End points

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    End points reporting groups
    Reporting group title
    Placebo, then GSK2269557
    Reporting group description
    		 Participants received placebo drug once daily via dry powder inhaler for 28 days during Treatment Period 1. After a washout period of 4 weeks, participants received GSK2269557 1000 micrograms (µg) drug once daily via dry powder inhaler for 28 days during Treatment Period 2. In addition, salbutamol was provided to participants to use on an as-needed basis for relief of asthma symptoms.

    Reporting group title
    GSK2269557, then Placebo
    Reporting group description
    		 Participants received GSK2269557 1000 µg drug once daily via dry powder inhaler for the 28 days during Treatment Period 1. After a washout period of 4 weeks, participants received placebo drug once daily via dry powder inhaler for 28 days during Treatment Period 2. In addition, salbutamol was provided to participants to use on an as-needed basis for relief of asthma symptoms.
    Reporting group title
    Placebo, then GSK2269557
    Reporting group description
    		 The two treatment periods were separated by a four-week wash-out period in which all participants did not receive study medication, but were provided a salbutamol inhaler for symptomatic relief of asthma symptoms.

    Reporting group title
    GSK2269557, then Placebo
    Reporting group description
    		 The two treatment periods were separated by a four-week wash-out period in which all participants did not receive study medication, but were provided a salbutamol inhaler for symptomatic relief of asthma symptoms.
    Reporting group title
    Placebo, then GSK2269557
    Reporting group description
    		 Participants received placebo drug once daily via dry powder inhaler for 28 days during Treatment Period 1. After a washout period of 4 weeks, participants received GSK2269557 1000 micrograms (µg) drug once daily via dry powder inhaler for 28 days during Treatment Period 2. In addition, salbutamol was provided to participants to use on an as-needed basis for relief of asthma symptoms.

    Reporting group title
    GSK2269557, then Placebo
    Reporting group description
    		 Participants received GSK2269557 1000 µg drug once daily via dry powder inhaler for the 28 days during Treatment Period 1. After a washout period of 4 weeks, participants received placebo drug once daily via dry powder inhaler for 28 days during Treatment Period 2. In addition, salbutamol was provided to participants to use on an as-needed basis for relief of asthma symptoms.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who received matching placebo once daily via dry powder inhaler for 28 days in either treatment period 1 or 2.

    Subject analysis set title
    GSK2269557 1000 µg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who received GSK2269557 1000 µg once daily via dry powder inhaler for 28 days in either treatment period 1 or 2.

    Primary: Change from Baseline in trough forced expiratory volume in one second (FEV1) at Day 28 in Intent-To-Treat (ITT) Population

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    End point title
    		 Change from Baseline in trough forced expiratory volume in one second (FEV1) at Day 28 in Intent-To-Treat (ITT) Population
    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 the maximum volume of air that can be forced out in one second after taking a deep breath approximately 24 hours after the last administration of study drug. FEV1 was measured using a spirometer. Data was collected pre-dose in the clinic at Baseline, Day 7, Day 14 and Day 28. Change from Baseline is calculated as post-Baseline value minus Baseline value where Baseline is defined as Day 1 (pre-dose). The analysis was performed on the ITT Population which comprised of all participants who received at least one dose of trial medication and have at least one post-dose efficacy assessment. Six participants had entered the study without spirometric evidence of disease, and were excluded from the ITT population prior to unblinding.
    End point type
    Primary
    End point timeframe
    Up to Day 28 for each treatment period
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    37 [1]
    39
    Units: Liters
    median (confidence interval 95%)
        Liters
    0.027 (-0.066 to 0.117)
    0.035 (-0.061 to 0.124)
    Notes
    [1] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The data entered as the 95% confidence interval represents the 95% equi-tailed credible interval. The posterior median difference is calculated as GSK2269557 1000 μg minus Placebo. The total number of participants included in the analysis is 84; however, the value calculated by the system (76) is incorrect.
    Comparison groups
    GSK2269557 1000 µg v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.57 [3]
    Method
    		 Bayesian repeated measures model
    Parameter type
    		 Posterior median difference.
    Point estimate
    0.007
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.083
         upper limit
    		 0.102
    Variability estimate
    Standard deviation
    Dispersion value
    0.0468
    Notes
    [2] - Non-informative priors used for all modelling parameters. Unstructured covariance matrix fitted.
    [3] - The data entered for the p-value represents the posterior probability that the true treatment difference is greater than zero.

    Primary: Change from Baseline in trough forced expiratory volume in one second (FEV1) at Day 28 in Per Protocol (PP) Population

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    End point title
    		 Change from Baseline in trough forced expiratory volume in one second (FEV1) at Day 28 in Per Protocol (PP) Population
    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 the maximum volume of air that can be forced out in one second after taking a deep breath approximately 24 hours after the last administration of study drug. FEV1 was measured using a spirometer. Data was collected pre-dose in the clinic at Baseline, Day 7, Day 14 and Day 28. Change from Baseline is calculated as post-Baseline value minus Baseline value where Baseline is defined as Day 1 (pre-dose). The analysis was performed on the PP Population which comprised of all participants in the ITT Population not identified as major protocol violators.
    End point type
    Primary
    End point timeframe
    Up to Day 28 for each treatment period
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    35 [4]
    37
    Units: Liters
    median (confidence interval 95%)
        Liters
    0.029 (-0.073 to 0.119)
    0.042 (-0.058 to 0.132)
    Notes
    [4] - PP Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The data entered as the 95% confidence interval represents the 95% equi-tailed credible interval. The posterior median difference is calculated as GSK2269557 1000 μg minus Placebo. The total number of participants included in the analysis is 78; however, the value calculated by the system (72) is incorrect.
    Comparison groups
    Placebo v GSK2269557 1000 µg
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.61 [6]
    Method
    		 Bayesian repeated measures model
    Parameter type
    		 Posterior median difference.
    Point estimate
    0.013
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.084
         upper limit
    		 0.113
    Variability estimate
    Standard deviation
    Dispersion value
    0.0501
    Notes
    [5] - Non-informative priors used for all modelling parameters. Unstructured covariance matrix fitted.
    [6] - The data entered for the p-value represents the posterior probability that the true treatment difference is greater than zero.

    Secondary: Weighted mean (0-4 hours) FEV1 at Day 28

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    End point title
    		 Weighted mean (0-4 hours) FEV1 at Day 28
    End point description
    The weighted mean FEV1 on Day 28 was calculated using data collected pre-dose and at 1 hour, 2 hours, 3 hours, and 4 hours post-dose. The weighted mean FEV1 was derived by calculating the average area under the curve using the trapezoidal rule, and then dividing by the relevant time interval.
    End point type
    Secondary
    End point timeframe
    Day 28 for each treatment period
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    38 [7]
    40
    Units: Liters
    median (confidence interval 95%)
        Liters
    2.672 (2.556 to 2.783)
    2.722 (2.607 to 2.836)
    Notes
    [7] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The data entered as the 95% confidence interval represents the 95% equi-tailed credible interval. The posterior median difference is calculated as GSK2269557 1000 μg minus Placebo. The total number of participants included in the analysis is 84; however, the value calculated by the system (78) is incorrect.
    Comparison groups
    GSK2269557 1000 µg v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.731 [9]
    Method
    		 Bayesian model
    Parameter type
    		 Posterior median difference
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.111
         upper limit
    		 0.21
    Variability estimate
    Standard deviation
    Dispersion value
    0.0818
    Notes
    [8] - Non-informative priors used for all modelling parameters. Unstructured covariance matrix fitted.
    [9] - The data entered for the p-value represents the posterior probability that the true treatment difference is greater than zero.

    Secondary: Change from Baseline in trough FEV1 at Day 7 and Day 14

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    End point title
    		 Change from Baseline in trough FEV1 at Day 7 and Day 14
    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. The trough FEV1 is the maximum volume of air that can be forced out in one second after taking a deep breath approximately 24 hrs after the last administration of study drug. Change from Baseline values were calculated as post-Baseline values minus Baseline value where Baseline was defined as Day 1 (pre-dose). The number of participants with data available at the specified time points are represented by n=X in the category titles.
    End point type
    Secondary
    End point timeframe
    Day 7 and Day 14 for each treatment period
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    42 [10]
    42
    Units: Liters
    median (confidence interval 95%)
        Day 7; n= 39, 40
    0.012 (-0.102 to 0.131)
    0.003 (-0.113 to 0.119)
        Day 14; n= 38,41
    0.016 (-0.086 to 0.116)
    0.040 (-0.061 to 0.137)
    Notes
    [10] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Day 7. The data entered as the 95% confidence interval represents the 95% equi-tailed credible interval. The posterior median difference is calculated as GSK2269557 1000 μg minus Placebo.
    Comparison groups
    Placebo v GSK2269557 1000 µg
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.44 [12]
    Method
    		 Bayesian repeated measures model
    Parameter type
    		 Posterior median difference
    Point estimate
    -0.009
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.151
         upper limit
    		 0.131
    Variability estimate
    Standard deviation
    Dispersion value
    0.0712
    Notes
    [11] - Non-informative priors used for all modelling parameters. Unstructured covariance matrix fitted.
    [12] - The data entered for the p-value represents the posterior probability that the true treatment difference is greater than zero.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Day 14. The data entered as the 95% confidence interval represents the 95% equi-tailed credible interval. The posterior median difference is calculated as GSK2269557 1000 μg minus Placebo.
    Comparison groups
    Placebo v GSK2269557 1000 µg
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.66 [14]
    Method
    		 Bayesian repeated measures model
    Parameter type
    		 Posterior median difference
    Point estimate
    0.024
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.087
         upper limit
    		 0.137
    Variability estimate
    Standard deviation
    Dispersion value
    0.057
    Notes
    [13] - Non-informative priors used for all modelling parameters. Unstructured covariance matrix fitted.
    [14] - The data entered for the p-value represents the posterior probability that the true treatment difference is greater than zero.

    Secondary: Change from Baseline in Forced Vital Capacity (FVC) at Day 7, Day 14 and Day 28

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    End point title
    		 Change from Baseline in Forced Vital Capacity (FVC) at Day 7, Day 14 and Day 28
    End point description
    FVC is defined as the total amount of air exhaled during the FEV test. Data was collected pre-dose at Baseline (Day 1), Day 7, Day 14 and Day 28. Change from Baseline was calculated as the post-Baseline value minus the Baseline value where Baseline was defined as Day 1 (pre-dose). The number of participants with data available at the specified time points are represented by n=X in the category titles.
    End point type
    Secondary
    End point timeframe
    Day 7, Day 14 and Day 28 for each treatment period
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    42 [15]
    42
    Units: Liter
    median (confidence interval 95%)
        Day 7; n= 39,40
    0.036 (-0.075 to 0.146)
    0.015 (-0.097 to 0.126)
        Day 14; n= 38,41
    -0.002 (-0.110 to 0.107)
    0.038 (-0.069 to 0.146)
        Day 28; n= 37,39
    0.017 (-0.092 to 0.124)
    0.054 (-0.052 to 0.159)
    Notes
    [15] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Day 7. The data entered as the 95% confidence interval represents the 95% equi-tailed credible interval. The posterior median difference is calculated as GSK2269557 1000 μg minus Placebo.
    Comparison groups
    GSK2269557 1000 µg v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.35 [17]
    Method
    		 Bayesian repeated measures model
    Parameter type
    		 Posterior median difference
    Point estimate
    -0.021
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 0.099
    Variability estimate
    Standard deviation
    Dispersion value
    0.0609
    Notes
    [16] - Non-informative priors used for all modelling parameters. Unstructured covariance matrix fitted.
    [17] - The data entered for the p-value represents the posterior probability that the true treatment difference is greater than zero.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Day 14. The data entered as the 95% confidence interval represents the 95% equi-tailed credible interval. The posterior median difference is calculated as GSK2269557 1000 μg minus Placebo.
    Comparison groups
    GSK2269557 1000 µg v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.76 [19]
    Method
    		 Bayesian repeated measures model
    Parameter type
    		 Posterior median difference
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.071
         upper limit
    		 0.156
    Variability estimate
    Standard deviation
    Dispersion value
    0.0578
    Notes
    [18] - Non-informative priors used for all modelling parameters. Unstructured covariance matrix fitted.
    [19] - The data entered for the p-value represents the posterior probability that the true treatment difference is greater than zero.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Day 28. The data entered as the 95% confidence interval represents the 95% equi-tailed credible interval. The posterior median difference is calculated as GSK2269557 1000 μg minus Placebo.
    Comparison groups
    GSK2269557 1000 µg v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.76 [21]
    Method
    		 Bayesian repeated measures model
    Parameter type
    		 Posterior median difference
    Point estimate
    0.038
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.073
         upper limit
    		 0.148
    Variability estimate
    Standard deviation
    Dispersion value
    0.0559
    Notes
    [20] - Non-informative priors used for all modelling parameters. Unstructured covariance matrix fitted.
    [21] - The data entered for the p-value represents the posterior probability that the true treatment difference is greater than zero.

    Secondary: Change from Baseline in FEV1/FVC at Day 7, Day 14 and Day 28

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    End point title
    		 Change from Baseline in FEV1/FVC at Day 7, Day 14 and Day 28
    End point description
    FEV1 and FVC are measures of lung function. FEV1 is defined as the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the total amount of air exhaled during the FEV test. Change from Baseline in FEV1/FVC at Day 7, Day 14 and Day 28 was calculated as post-Baseline value minus Baseline value where Baseline was defined as Day 1 (pre-dose). The number of participants with data available at the specified time points are represented by n=X in the category titles.
    End point type
    Secondary
    End point timeframe
    Day 7, Day 14 and Day 28 for each treatment period
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    42 [22]
    42
    Units: Percentage
    median (confidence interval 95%)
        Day 7; n= 39,40
    -0.956 (-2.337 to 0.495)
    -0.855 (-2.285 to 0.517)
        Day 14; n= 38,41
    -0.456 (-1.944 to 0.986)
    -0.444 (-1.899 to 0.992)
        Day 28; n= 37,39
    -0.691 (-2.050 to 0.638)
    -0.791 (-2.163 to 0.516)
    Notes
    [22] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Day 7. The data entered as the 95% confidence interval represents the 95% equi-tailed credible interval. The posterior median difference is calculated as GSK2269557 1000 μg minus Placebo.
    Comparison groups
    Placebo v GSK2269557 1000 µg
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.56 [24]
    Method
    		 Bayesian repeated measures model
    Parameter type
    		 Posterior median difference
    Point estimate
    0.083
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.102
         upper limit
    		 1.346
    Variability estimate
    Standard deviation
    Dispersion value
    0.6175
    Notes
    [23] - Non-informative priors used for all modelling parameters. Unstructured covariance matrix fitted.
    [24] - The data entered for the p-value represents the posterior probability that the true treatment difference is greater than zero.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Day 14. The data entered as the 95% confidence interval represents the 95% equi-tailed credible interval. The posterior median difference is calculated as GSK2269557 1000 μg minus Placebo.
    Comparison groups
    Placebo v GSK2269557 1000 µg
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 0.51 [26]
    Method
    		 Bayesian repeated measures model
    Parameter type
    		 Posterior median difference
    Point estimate
    0.014
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.271
         upper limit
    		 1.341
    Variability estimate
    Standard deviation
    Dispersion value
    0.6672
    Notes
    [25] - Non-informative priors used for all modelling parameters. Unstructured covariance matrix fitted.
    [26] - The data entered for the p-value represents the posterior probability that the true treatment difference is greater than zero.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Day 28. The data entered as the 95% confidence interval represents the 95% equi-tailed credible interval. The posterior median difference is calculated as GSK2269557 1000 μg minus Placebo.
    Comparison groups
    Placebo v GSK2269557 1000 µg
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.41 [28]
    Method
    		 Bayesian repeated measures model
    Parameter type
    		 Posterior median difference
    Point estimate
    -0.113
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.125
         upper limit
    		 0.908
    Variability estimate
    Standard deviation
    Dispersion value
    0.5148
    Notes
    [27] - Non-informative priors used for all modelling parameters. Unstructured covariance matrix fitted.
    [28] - The data entered for the p-value represents the posterior probability that the true treatment difference is greater than zero.

    Secondary: Change from Baseline in Asthma Control Test (ACT) score at Day 28

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    End point title
    		 Change from Baseline in Asthma Control Test (ACT) score at Day 28
    End point description
    The total ACT score is the sum of five-item questionnaires developed as a measurement of asthma control. Total score can range from five (worse control) to 25 (full control), with higher scores reflecting greater asthma control. Total ACT score at Day 1 (Baseline) and Day 28 in both Treatment Periods was used for this analysis. Change from Baseline in ACT was calculated as post-Baseline value minus Baseline value where Baseline was defined as Day 1 (pre-dose).
    End point type
    Secondary
    End point timeframe
    Up to Day 28 for each treatment period
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    38 [29]
    40
    Units: Score on a scale
    median (confidence interval 95%)
        Score on a scale
    1.4 (0.5 to 2.2)
    1.9 (1.0 to 2.7)
    Notes
    [29] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The data entered as the 95% confidence interval represents the 95% equi-tailed credible interval. The posterior median difference is calculated as GSK2269557 1000 μg minus Placebo. The total number of participants included in the analysis is 84; however, the value calculated by the system (78) is incorrect.
    Comparison groups
    GSK2269557 1000 µg v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [30]
    P-value
    		 = 0.81 [31]
    Method
    		 Bayesian model
    Parameter type
    		 Posterior median difference
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 1.7
    Variability estimate
    Standard deviation
    Dispersion value
    0.59
    Notes
    [30] - Non-informative priors used for all modelling parameters. Unstructured covariance matrix fitted.
    [31] - The data entered for the p-value represents the posterior probability that the true treatment difference is greater than zero.

    Secondary: Change from Baseline in daily FEV1 averaged over the treatment period

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    End point title
    		 Change from Baseline in daily FEV1 averaged over the treatment period
    End point description
    Triplicate measurements of FEV1 were collected in an eDiary pre-dose before breakfast [ante meridiem (AM)], and approximately 12 hours later at evening [post-meridiem (PM)]. The average change from Baseline was calculated by summing the total value of the endpoint (i.e. change from Baseline) within the time period of interest and dividing by the number of days with non-missing data for that endpoint to obtain an average for each subject. The AM Baseline is the Day 1 AM value, the PM Baseline is the last PM reading prior to taking the first dose of blinded study medication within that Treatment Period.
    End point type
    Secondary
    End point timeframe
    Up to Day 28 for each treatment period
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    42 [32]
    42
    Units: Liter
    arithmetic mean (standard deviation)
        AM; n= 38, 40
    0.000 ( 0.2019 )
    0.065 ( 0.2974 )
        PM; n= 34, 39
    0.013 ( 0.2634 )
    0.115 ( 0.3802 )
    Notes
    [32] - ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in daily Peak Expiratory Flow (PEF) averaged over the treatment period

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    End point title
    		 Change from Baseline in daily Peak Expiratory Flow (PEF) averaged over the treatment period
    End point description
    Triplicate measurements of PEF were collected in an eDiary pre-dose before breakfast (AM), and approximately 12 hours later at evening (PM). The average change from Baseline was calculated by summing the total value of the endpoint (i.e. change from Baseline) within the time period of interest and dividing by the number of days with non-missing data for that endpoint to obtain an average for each subject. The AM Baseline is the Day 1 AM value, the PM Baseline is the last PM reading prior to taking the first dose of blinded study medication within that Treatment Period.
    End point type
    Secondary
    End point timeframe
    Up to Day 28 for each treatment period
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    42 [33]
    42
    Units: Liter/minute
    arithmetic mean (standard deviation)
        AM; n= 38,40
    -4.8 ( 32.44 )
    14.2 ( 46.11 )
        PM; n= 34, 39
    9.8 ( 36.05 )
    29.8 ( 64.28 )
    Notes
    [33] - ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in trough Fractional exhaled Nitric Oxide (FeNO) at Day 7, Day 14 and Day 28

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    End point title
    		 Change from Baseline in trough Fractional exhaled Nitric Oxide (FeNO) at Day 7, Day 14 and Day 28
    End point description
    Participants with asthma have high levels of NO in their exhaled breath. Evaluation of FeNO is a quantitative, noninvasive method of measuring airway inflammation to assess airway diseases including asthma. FeNO was measured in the clinic using a handheld electronic device. Change from Baseline for Day 7, Day 14 and Day 28 was calculated as the post-Baseline value minus the Baseline value where Baseline was defined as Day 1 (pre-dose). The number of participants with data available at the specified time points are represented by n=X in the category titles.
    End point type
    Secondary
    End point timeframe
    Day 7, Day 14 and Day 28 for each treatment period
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    42 [34]
    42
    Units: Part per billion (PPB)
    median (confidence interval 95%)
        Day 7; n= 38,34
    1.03 (0.93 to 1.13)
    0.91 (0.82 to 1.01)
        Day 14; n= 34,35
    0.99 (0.89 to 1.11)
    0.95 (0.85 to 1.05)
        Day 28; n= 34,34
    1.03 (0.91 to 1.17)
    1.03 (0.91 to 1.17)
    Notes
    [34] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Day 7. The data entered as the 95% confidence interval represents the 95% equi-tailed credible interval. The posterior median ratio is calculated as GSK2269557 1000 μg/ Placebo.
    Comparison groups
    GSK2269557 1000 µg v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 = 0.97 [36]
    Method
    		 Bayesian repeated measures model
    Parameter type
    		 Posterior median ratio
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1
    Variability estimate
    Standard deviation
    Dispersion value
    0.063
    Notes
    [35] - Non-informative priors used for all modelling parameters. Unstructured covariance matrix fitted.
    [36] - The data entered for the p-value represents the posterior probability that the true treatment ratio is less than 1.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Day 14. The data entered as the 95% confidence interval represents the 95% equi-tailed credible interval. The posterior median ratio is calculated as GSK2269557 1000 μg/ Placebo.
    Comparison groups
    GSK2269557 1000 µg v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 = 0.76 [38]
    Method
    		 Bayesian repeated measures model
    Parameter type
    		 Posterior median ratio
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.09
    Variability estimate
    Standard deviation
    Dispersion value
    0.071
    Notes
    [37] - Non-informative priors used for all modelling parameters. Unstructured covariance matrix fitted.
    [38] - The data entered for the p-value represents the posterior probability that the true treatment ratio is less than 1.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Day 28. The data entered as the 95% confidence interval represents the 95% equi-tailed credible interval. The posterior median ratio is calculated as GSK2269557 1000 μg/ Placebo.
    Comparison groups
    GSK2269557 1000 µg v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [39]
    P-value
    		 = 0.51 [40]
    Method
    		 Bayesian repeated measures model
    Parameter type
    		 Posterior median ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.18
    Variability estimate
    Standard deviation
    Dispersion value
    0.085
    Notes
    [39] - Non-informative priors used for all modelling parameters. Unstructured covariance matrix fitted.
    [40] - The data entered for the p-value represents the posterior probability that the true treatment ratio is less than one.

    Secondary: Mean number of inhalations per day of rescue medication (salbutamol) over the treatment period

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    End point title
    		 Mean number of inhalations per day of rescue medication (salbutamol) over the treatment period
    End point description
    Daily recordings of rescue medication use were collected in an eDiary by participants. The mean number of inhalations per day of rescue medication was calculated for each participant as number of inhalations over the time period of interest divided by number of days when rescue medication was taken over the time period of interest.
    End point type
    Secondary
    End point timeframe
    Up to Day 28 for each treatment period
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    38 [41]
    39
    Units: Inhalations/day
    arithmetic mean (standard deviation)
        Number
    3.0 ( 1.86 )
    2.7 ( 1.53 )
    Notes
    [41] - ITT Population
    No statistical analyses for this end point

    Secondary: Percentage of rescue free days over the treatment period

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    End point title
    		 Percentage of rescue free days over the treatment period
    End point description
    Daily recordings of rescue medication use were collected in an eDiary by participants. Percentage of rescue free days was calculated as the number of rescue free days divided by length of treatment period.
    End point type
    Secondary
    End point timeframe
    Up to Day 28 for each treatment period
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    42 [42]
    42
    Units: Percentage
    arithmetic mean (standard deviation)
        Percentage
    49.5 ( 35.04 )
    47.3 ( 34.79 )
    Notes
    [42] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of participants with Adverse Events (AEs)

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    End point title
    		 Number of participants with Adverse Events (AEs)
    End point description
    An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The analysis was performed on Safety Population which comprised of all participants who were randomized into the study.
    End point type
    Secondary
    End point timeframe
    From the Start of IP to Follow-Up (Week 16)
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    47 [43]
    48
    Units: Participants
        Participants
    18
    28
    Notes
    [43] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with abnormal values of clinical chemistry parameters

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    End point title
    		 Number of participants with abnormal values of clinical chemistry parameters
    End point description
    Blood samples were collected from participants for evaluation of clinical chemistry parameters by Potential Clinical Importance Criteria. The clinical chemistry parameters included albumin, calcium, creatinine, glucose, potassium and sodium. Participants were counted in the category that their value changes to (low, normal or high), unless there is no change in their category. The number of participants with data available at the specified data points are represented by n=X in the category titles.
    End point type
    Secondary
    End point timeframe
    From start of IP up to Week 14
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    47 [44]
    48
    Units: Participants
        Albumin; Day 1; Change to low; n= 47, 48
    0
    0
        Albumin; Day 14; Change to low; n= 42, 48
    0
    0
        Albumin; Day 28; Change to low; n= 41, 45
    0
    0
        Calcium; Day 1; Change to low; n= 47, 48
    0
    0
        Calcium; Day 1; Change to high; n= 47, 48
    0
    0
        Calcium; Day 14; Change to low; n= 42, 48
    0
    0
        Calcium; Day 14; Change to high; n= 42, 48
    0
    0
        Calcium; Day 28; Change to high; n= 40, 45
    0
    0
        Calcium; Day 28; Change to low; n= 40, 45
    0
    0
        Glucose; Day 1; Change to low; n= 47, 48
    0
    0
        Glucose; Day 1; change to high; n= 47, 48
    0
    0
        Glucose; Day 14; Change to low; n= 42, 48
    1
    0
        Glucose; Day 14; change to high; n= 42, 48
    0
    0
        Glucose; Day 28; Change to low; n= 41, 45
    0
    0
        Glucose; Day 28; Change to high; n= 41, 45
    0
    0
        Potassium; Day 1; Change to low; n= 47, 48
    0
    0
        Potassium; Day 1; Change to high; n= 47, 48
    0
    0
        Potassium; Day 14; Change to low; n= 42, 48
    0
    0
        Potassium; Day 14; Change to high; n= 42, 48
    0
    0
        Potassium; Day 28; Change to low; n= 40, 45
    0
    0
        Potassium; Day 28; Change to high; n= 40, 45
    0
    0
        Sodium; Day 1; Change to low; n= 47, 48
    0
    0
        Sodium; Day 1; Change to high; n= 47, 48
    0
    0
        Sodium; Day 14; Change to low; n= 42, 48
    0
    0
        Sodium; Day 14; Change to high; n= 42, 48
    0
    0
        Sodium; Day 28; Change to low; n= 41, 45
    0
    0
        Sodium; Day 28; Change to high; n= 41, 45
    0
    0
        Hematocrit; Day 1; Change to high; n= 46, 47
    0
    0
        Hematocrit; Day 14; Change to high; n= 43, 47
    0
    0
        Hematocrit; Day 28; Change to high; n= 42, 44
    0
    0
        Hemoglobin; Day 1; Change to high; n= 46, 47
    0
    0
        Hemoglobin; Day 14; Change to high; n= 43, 47
    0
    0
        Hemoglobin; Day 28; Change to high; n= 42, 44
    0
    0
        Lymphocytes; Day 1; Change to low; n= 46, 47
    0
    0
        Lymphocytes; Day 14; Change to low; n= 43, 47
    0
    0
        Lymphocytes; Day 28; Change to low; n= 42, 44
    0
    0
        Platelet count; Day 1; Change to low; n= 46, 47
    0
    0
        Platelet count; Day 1; Change to high; n= 46, 47
    0
    0
        Platelet count; Day 14; Change to low; n= 43, 47
    0
    0
        Platelet count; Day 14; Change to high; n= 43, 47
    0
    0
        Platelet count; Day 28; Change to low; n= 42, 43
    0
    0
        Platelet count; Day 28; Change to high; n= 42, 43
    0
    0
        Total neutrophils; Day 1; Change to low; n= 46, 47
    0
    0
        Total neutrophils;Day 14; Change to low; n= 43, 47
    0
    1
        Total neutrophils; Day 28; Change to low; n= 42,44
    0
    0
        WBC; Day 1; Change to low; n= 46, 47
    0
    0
        WBC; Day 1; Change to high; n= 46, 47
    0
    0
        WBC; Day 14; Change to low; n= 43, 47
    0
    0
        WBC; Day 14; Change to high; n= 43, 47
    0
    0
        WBC; Day 28; Change to low; n= 42, 44
    0
    0
        WBC; Day 28; Change to high; n= 42, 44
    0
    0
    Notes
    [44] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with abnormal values of hematology parameters

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    End point title
    		 Number of participants with abnormal values of hematology parameters
    End point description
    Blood samples were collected from participants for evaluation of hematology parameters by Potential Clinical Importance Criteria. The hematology parameters included hematocrit, hemoglobin, lymphocytes, total neutrophils, platelets and white blood cells (WBC). Participants were counted in the category that their value changes to (low, normal or high), unless there is no change in their category. The number of participants with data available at the specified data points are represented by n=X in the category titles.
    End point type
    Secondary
    End point timeframe
    From start of IP up to Week 14
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    47 [45]
    48
    Units: Participants
        Hematocrit; Day 1; Change to high; n= 46, 47
    0
    0
        Hematocrit; Day 14; Change to high; n= 43, 47
    0
    0
        Hematocrit; Day 28; Change to high; n= 42, 44
    0
    0
        Hemoglobin; Day 1; Change to high; n= 46, 47
    0
    0
        Hemoglobin; Day 14; Change to high; n= 43, 47
    0
    0
        Hemoglobin; Day 28; Change to high; n= 42, 44
    0
    0
        Lymphocytes; Day 1; Change to low; n= 46, 47
    0
    0
        Lymphocytes; Day 14; Change to low; n= 43, 47
    0
    0
        Lymphocytes; Day 28; Change to low; n= 42, 44
    0
    0
        Platelet count; Day 1; Change to low; n= 46, 47
    0
    0
        Platelet count; Day 1; Change to high; n= 46, 47
    0
    0
        Platelet count; Day 14; Change to low; n= 43, 47
    0
    0
        Platelet count; Day 14; Change to high; n= 43, 47
    0
    0
        Platelet count; Day 28; Change to low; n= 42, 43
    0
    0
        Platelet count; Day 28; Change to high; n= 42, 43
    0
    0
        Total neutrophils; Day 1; Change to low; n= 46, 47
    0
    0
        Total neutrophils;Day 14; Change to low; n= 43, 47
    0
    1
        Total neutrophils; Day 28; Change to low; n= 42,44
    0
    0
        WBC; Day 1; Change to low; n= 46, 47
    0
    0
        WBC; Day 1; Change to high; n= 46, 47
    0
    0
        WBC; Day 14; Change to low; n= 43, 47
    0
    0
        WBC; Day 14; Change to high; n= 43, 47
    0
    0
        WBC; Day 28; Change to low; n= 42, 44
    0
    0
        WBC; Day 28; Change to high; n= 42, 44
    0
    0
    Notes
    [45] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with abnormal vital sign values

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    End point title
    		 Number of participants with abnormal vital sign values
    End point description
    Number of participants with abnormal values of vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate were evaluated. Vital signs outside the range of potential clinical importance are presented at the indicated timepoints: Day 7, Day 14, Day 28 and follow-up/Early withdrawal. The number of participants with data available at the specified data points are represented by n=X in the category titles.
    End point type
    Secondary
    End point timeframe
    From start of IP up to Week 14
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    47 [46]
    48
    Units: Participants
        DBP; Day 7; Change to low; n= 46, 46
    0
    0
        DBP; Day 7; Change to high; n= 46, 46
    0
    0
        DBP; Day 14; Change to low; n= 43, 48
    0
    0
        DBP; Day 14; Change to high; n= 43, 48
    1
    0
        DBP; Day 28; Change to low; n= 42, 45
    0
    0
        DBP; Day 28; Change to high; n= 42, 45
    0
    1
        SBP; Day 7; Change to low; n= 46, 46
    0
    0
        SBP; Day 7; Change to high; n= 46, 46
    0
    0
        SBP; Day 14; Change to low; n= 43, 48
    0
    0
        SBP; Day 14; Change to high; n= 43, 48
    1
    0
        SBP; Day 28; Change to low; n= 42, 45
    0
    0
        SBP; Day 28; Change to high; n= 42, 45
    0
    0
        Heart rate; Day 7; Change to low; n= 46, 46
    0
    0
        Heart rate; Day 7; Change to high; n= 46, 46
    0
    0
        Heart rate; Day 14; Change to low; n= 43, 48
    0
    0
        Heart rate; Day 14; Change to high; n= 43, 48
    0
    0
        Heart rate; Day 28; Change to low; n= 42, 45
    0
    0
        Heart rate; Day 28; Change to high; n= 42, 45
    0
    0
    Notes
    [46] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with abnormal electrocardiogram (ECG) findings

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    End point title
    		 Number of participants with abnormal electrocardiogram (ECG) findings
    End point description
    Single measurements of 12-lead ECGs were obtained after 5 minutes rest in a semi-supine position at Baseline (Day 1 pre dose) , Day 7, Day 28 pre-dose in each treatment period using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc). ECG values were recorded as abnormal not clinically significant (NCS) and abnormal clinically significant (CS). The number of participants with data available at the specified data points are represented by n= X in the category titles.
    End point type
    Secondary
    End point timeframe
    Up to Day 28 for each treatment period
    End point values
    		 Placebo GSK2269557 1000 µg
    Number of subjects analysed
    47 [47]
    48
    Units: Participants
        Day 1; abnormal NCS; n= 47,48
    2
    5
        Day 1; abnormal CS; n= 47,48
    0
    0
        Day 7; abnormal NCS; n= 46,46
    1
    4
        Day 7; abnormal CS; n= 46,46
    0
    0
        Day 28; abnormal NCS; n= 42, 45
    0
    3
        Day 28; abnormal CS; n= 42,45
    0
    0
        Any time Post-Baseline; abnormal NCS; n= 47,48
    1
    6
        Any time Post Baseline; abnormal CS; n= 47,48
    0
    0
    Notes
    [47] - Safety Population
    No statistical analyses for this end point

    Secondary: Plasma concentration of GSK2269557

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    End point title
    		 Plasma concentration of GSK2269557
    End point description
    Blood samples were collected from participants for pharmacokinetic (PK) analysis at Day 7, Day 14 and Day 28 pre dose. On Day 28 samples were also collected between 5-10 minutes post dose and between 2.5-3.5 hours post dose. The analysis was performed on PK Population which comprised of participants in the ITT Population for whom a PK sample was obtained and analyzed. The number of participants with data available at the specified data points are represented by n= X in the category titles.
    End point type
    Secondary
    End point timeframe
    Pre dose at Day 7 and Day 14. At Day 28 pre dose, 5-10 minutes and 2.5-3.5 hours post dose
    End point values
    		 GSK2269557 1000 µg
    Number of subjects analysed
    42 [48]
    Units: pg per Milliliter (Pg/mL)
    geometric mean (confidence interval 95%)
        Day 7; pre dose; n= 40
    555.7 (446.2 to 692.0)
        Day 14; pre dose; n= 40
    520.7 (380.3 to 712.9)
        Day 28; pre dose; n= 38
    649.2 (519.9 to 810.8)
        Day 28; 5-10 minutes post dose; n= 40
    1188.8 (990.5 to 1426.8)
        Day 28; 2.5-3.5 hours post dose; n= 40
    1170.8 (976.1 to 1404.4)
    Notes
    [48] - PK Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up 2 weeks after the last dose (total study duration was 16 weeks)
    Adverse event reporting additional description
    AEs and SAEs were collected in Safety Population which comprised of all participants who were randomized.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants who received matching placebo once daily via dry powder inhaler for 28 days in either treatment period 1 or 2.

    Reporting group title
    GSK2269557 1000 µg
    Reporting group description
    		 Participants who received GSK2269557 1000 µg once daily via dry powder inhaler for 28 days in either treatment period 1 or 2.

    Serious adverse events
    		 Placebo GSK2269557 1000 µg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 48 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo GSK2269557 1000 µg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 47 (27.66%)
    19 / 48 (39.58%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 47 (8.51%)
    2 / 48 (4.17%)
         occurrences all number
    6
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 47 (8.51%)
    17 / 48 (35.42%)
         occurrences all number
    4
    18
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 47 (14.89%)
    2 / 48 (4.17%)
         occurrences all number
    7
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Feb 2016
    Removal of instruction on the need for precautionary measures to protect against potential photosensitive effects of GSK2269557; Addition of 2 secondary efficacy endpoints; Clarification to the requirements surrounding pregnancy testing at screening compared to other time points; Addition of nicotine replacement or containing products to the prohibited medicines list; Alignment of background information to reflect the current status of ongoing clinical investigations pertaining to this investigational medicinal product.

    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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