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    Clinical Trial Results:
    HZA106853: A dose-ranging study of vilanterol (VI) inhalation powder in children aged 5-11 years with asthma on a background of inhaled corticosteroid therapy.

    Summary
    EudraCT number
    		 2011-003337-34
    Trial protocol
    		 DE   Outside EU/EEA   PL   SK  
    Global end of trial date
    28 Apr 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    28 Mar 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    HZA106853
    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 8664357343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, +1 8664357343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000431-PIP01-08
    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
    11 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the dose response, efficacy and safety of three doses of VI inhalation powder administered once daily in the evening in children aged 5-11 years with persistent uncontrolled asthma over a 4 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). Subject lung function, as measured by morning (AM) and evening (PM) peak expiratory flow (PEF), was monitored for stability through the use of a daily electronic diary. 4). 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
    27 Mar 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 51
    Country: Number of subjects enrolled
    Slovakia: 32
    Country: Number of subjects enrolled
    Germany: 38
    Country: Number of subjects enrolled
    South Africa: 12
    Country: Number of subjects enrolled
    Ukraine: 39
    Country: Number of subjects enrolled
    Peru: 150
    Country: Number of subjects enrolled
    Puerto Rico: 6
    Country: Number of subjects enrolled
    Argentina: 225
    Country: Number of subjects enrolled
    United States: 239
    Country: Number of subjects enrolled
    Philippines: 82
    Country: Number of subjects enrolled
    Georgia: 18
    Country: Number of subjects enrolled
    Chile: 114
    Country: Number of subjects enrolled
    Mexico: 153
    Country: Number of subjects enrolled
    Japan: 49
    Worldwide total number of subjects
    1208
    EEA total number of subjects
    121
    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)
    1208
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 1208 participants (par.) were screened; 760 were enrolled/entered the Run-in Phase, 463 were randomized, and 2 received study medication (SM) but weren't randomized/included in the Intent-to-Treat (ITT) Population (randomized to treatment and receiving >=1 SM dose). 7 randomized par. didn't receive SM; hence, 456 par. comprised the ITT Population.

    Pre-assignment
    Screening details
    		 Participants who met the eligibility criteria at screening (Visit 1) entered the Run-in Phase for completion of Baseline safety evaluations and measures of asthma status. Participants meeting all randomization criteria at Visit 3 were randomized to 1 of 4 treatment arms. The total duration of study participation was up to a maximum of 9 weeks.

    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
    		 Placebo
    Arm description
    		 Participants received placebo once daily (OD) in the evening from a dry powder inhaler for 4 weeks in addition to open-label fluticasone propionate (FP) 100 micrograms (µg) twice daily (BID). Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo once daily via a dry powder inhaler

    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
    100 µg twice daily via a dry powder inhaler

    Arm title
    		 VI 6.25 µg OD
    Arm description
    		 Participants received vilanterol (VI) 6.25 µg OD in the evening from a dry powder inhaler for 4 weeks in addition to open-label FP 100 µg BID. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    6.25 µg once daily via a dry powder inhaler

    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
    100 µg twice daily via a dry powder inhaler

    Arm title
    		 VI 12.5 µg OD
    Arm description
    		 Participants received VI 12.5 µg OD in the evening from a dry powder inhaler for 4 weeks in addition to open-label FP 100 µg BID. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    12.5 µg once daily via a dry powder inhaler

    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
    100 µg twice daily via a dry powder inhaler

    Arm title
    		 VI 25 µg OD
    Arm description
    		 Participants received VI 25 µg OD in the evening from a dry powder inhaler for 4 weeks in addition to open-label FP 100 µg BID. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    25 µg (micrograms) once daily via a dry powder inhaler

    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
    100 µg twice daily via a dry powder inhaler

    Number of subjects in period 1 [1]
    		Placebo VI 6.25 µg OD VI 12.5 µg OD VI 25 µg OD
    Started
    115
    114
    113
    114
    Completed
    93
    93
    99
    90
    Not completed
    22
    21
    14
    24
         Physician decision
    1
    2
    -
    2
         Consent withdrawn by subject
    -
    1
    -
    -
         Adverse event, non-fatal
    -
    1
    -
    1
         Lost to follow-up
    -
    1
    1
    1
         Lack of efficacy
    18
    15
    12
    17
         Protocol deviation
    3
    1
    1
    3
    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: 1208 participants (par.) were screened; 760 were enrolled/entered the Run-in Phase, 463 were randomized, and 2 received study medication (SM) but weren't randomized/included in the Intent-to-Treat (ITT) Population (randomized to treatment and receiving >=1 SM dose). 7 randomized par. didn't receive SM; hence, 456 par. comprised the ITT Population.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo once daily (OD) in the evening from a dry powder inhaler for 4 weeks in addition to open-label fluticasone propionate (FP) 100 micrograms (µg) twice daily (BID). Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.

    Reporting group title
    VI 6.25 µg OD
    Reporting group description
    		 Participants received vilanterol (VI) 6.25 µg OD in the evening from a dry powder inhaler for 4 weeks in addition to open-label FP 100 µg BID. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.

    Reporting group title
    VI 12.5 µg OD
    Reporting group description
    		 Participants received VI 12.5 µg OD in the evening from a dry powder inhaler for 4 weeks in addition to open-label FP 100 µg BID. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.

    Reporting group title
    VI 25 µg OD
    Reporting group description
    		 Participants received VI 25 µg OD in the evening from a dry powder inhaler for 4 weeks in addition to open-label FP 100 µg BID. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.

    Reporting group values
    		 Placebo VI 6.25 µg OD VI 12.5 µg OD VI 25 µg OD Total
    Number of subjects
    		 115 114 113 114 456
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8 ± 1.81 8 ± 1.95 7.9 ± 1.74 7.9 ± 1.72 -
    Gender categorical
    Units: Subjects
        Female
    		 50 43 42 45 180
        Male
    		 65 71 71 69 276
    Race, customized
    Units: Subjects
        African American/African Heritage
    		 5 5 5 3 18
        American Indian or Alaska Native
    		 16 21 17 18 72
        Asian - Japanese Heritage
    		 5 5 5 5 20
        Asian - South East Asian Heritage
    		 1 1 2 1 5
        White - Arabic/North African Heritage
    		 1 1 0 1 3
        White - White/Caucasian/European Heritage
    		 67 62 55 61 245
        Mixed Race
    		 20 19 29 25 93

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo once daily (OD) in the evening from a dry powder inhaler for 4 weeks in addition to open-label fluticasone propionate (FP) 100 micrograms (µg) twice daily (BID). Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.

    Reporting group title
    VI 6.25 µg OD
    Reporting group description
    		 Participants received vilanterol (VI) 6.25 µg OD in the evening from a dry powder inhaler for 4 weeks in addition to open-label FP 100 µg BID. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.

    Reporting group title
    VI 12.5 µg OD
    Reporting group description
    		 Participants received VI 12.5 µg OD in the evening from a dry powder inhaler for 4 weeks in addition to open-label FP 100 µg BID. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.

    Reporting group title
    VI 25 µg OD
    Reporting group description
    		 Participants received VI 25 µg OD in the evening from a dry powder inhaler for 4 weeks in addition to open-label FP 100 µg BID. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.

    Primary: Change from Baseline in daily pre-dose evening (PM) peak expiratory flow (PEF) from participant electronic daily diary averaged over the 4-week Treatment Period

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    End point title
    		 Change from Baseline in daily pre-dose evening (PM) peak expiratory flow (PEF) from participant electronic daily diary averaged over the 4-week Treatment Period
    End point description
    PEF 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 evening prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use each morning. The best of three measurements was recorded. Change from Baseline was calculated as the value of the averaged daily PM PEF over the 4-week Treatment Period minus the Baseline value. The Baseline PEF value is defined as the average of the last 7 days of the Run-in Phase. The analysis was performed using an analysis of covariance (ANCOVA) model with covariates of Baseline, region, sex, age, and treatment. Only those participants contributing data per the daily eDiary were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline; Week 1 up to Week 4
    End point values
    		 Placebo VI 6.25 µg OD VI 12.5 µg OD VI 25 µg OD
    Number of subjects analysed
    113 [1]
    113 [2]
    112 [3]
    110 [4]
    Units: Liters per minute (L/min)
        least squares mean (standard error)
    215.9 ± 2.53
    221.4 ± 2.53
    222.4 ± 2.54
    220.3 ± 2.56
    Notes
    [1] - ITT Population: participants randomized to treatment who received >=1 dose of study medication
    [2] - ITT Population: participants randomized to treatment who received >=1 dose of study medication
    [3] - ITT Population: participants randomized to treatment who received >=1 dose of study medication
    [4] - ITT Population: participants randomized to treatment who received >=1 dose of study medication
    Statistical analysis title
    		 Statistical Analysis #1
    Comparison groups
    Placebo v VI 25 µg OD
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.227 [5]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 11.4
    Notes
    [5] - Inference for VI 12.5 µg versus (vs) placebo was dependent upon statistical significance (SS) having first been achieved for VI 25 µg vs placebo; inference for VI 6.25 µg vs placebo was dependent on SS having been achieved for VI 12.5 µg vs placebo.
    Statistical analysis title
    		 Statistical Analysis #2
    Comparison groups
    Placebo v VI 12.5 µg OD
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.073
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 13.5
    Statistical analysis title
    		 Statistical Analysis #3
    Comparison groups
    Placebo v VI 6.25 µg OD
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.127
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 12.5

    Secondary: Change from Baseline in evening clinic visit trough (pre-bronchodilator and pre-dose) forced expiratory volume in one second (FEV1) at the end of the 4-week Treatment Period in children who could perform the maneuver

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    End point title
    		 Change from Baseline in evening clinic visit trough (pre-bronchodilator and pre-dose) forced expiratory volume in one second (FEV1) at the end of the 4-week Treatment Period in children who could perform the maneuver
    End point description
    Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 is defined as a pre-dose FEV1 measurement taken at a clinic visit while still on treatment. Change from Baseline in trough FEV1 at the end of the 4-week Treatment Period was defined using the pre-dose FEV1 measurement taken at the Week 4 clinic visit. Change from Baseline was calculated as the Week 4 trough FEV1 value minus the Baseline value. The Baseline FEV1 value is defined as the value at Visit 3 (randomization). The analysis was performed using an ANCOVA model with covariates of Baseline trough FEV1, region, sex, age, and treatment. The last observation carried forward (LOCF) method was used to impute missing data, in which the last non-missing post-Baseline on-treatment measurement at scheduled clinic visits was used to impute the missing measurements.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 4
    End point values
    		 Placebo VI 6.25 µg OD VI 12.5 µg OD VI 25 µg OD
    Number of subjects analysed
    85 [6]
    83 [7]
    86 [8]
    86 [9]
    Units: Liters
        least squares mean (standard error)
    0.223 ± 0.0287
    0.166 ± 0.0292
    0.24 ± 0.0285
    0.193 ± 0.0288
    Notes
    [6] - ITT Population. Only those participants available at the specified time points were analyzed.
    [7] - ITT Population. Only those participants available at the specified time points were analyzed.
    [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.
    Statistical analysis title
    		 Statistical Analysis #1
    Comparison groups
    Placebo v VI 6.25 µg OD
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.057
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.138
         upper limit
    		 0.024
    Statistical analysis title
    		 Statistical Analysis #2
    Comparison groups
    Placebo v VI 12.5 µg OD
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.017
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.063
         upper limit
    		 0.096
    Statistical analysis title
    		 Statistical Analysis #3
    Comparison groups
    Placebo v VI 25 µg OD
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.051

    Secondary: Change from Baseline in the percentage of rescue-free 24-hour periods during the 4-week Treatment Period

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    End point title
    		 Change from Baseline in the percentage of rescue-free 24-hour periods during the 4-week Treatment Period
    End point description
    The number of inhalations of rescue albuterol/salbutamol inhalation aerosol (medication used to relieve symptoms immediately) used during the day and night) was recorded by the participants in a daily diary. A 24-hour period in which a participant’s responses to both the morning and evening assessments indicated no use of rescue medication was considered as rescue free. Participants who were rescue free for 24-hour periods during the 4-week Treatment Period were assessed. The Baseline value was derived from the last 7 days of the daily diary prior to the randomization of the participant. Change from Baseline is calculated as the average value during the 4-week Treatment Period minus the value at Baseline. The Baseline value is defined as the value at Visit 3 (randomization). Analysis was performed using ANCOVA with covariates of Baseline, region, sex, age, and treatment.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 1 up to Week 4
    End point values
    		 Placebo VI 6.25 µg OD VI 12.5 µg OD VI 25 µg OD
    Number of subjects analysed
    113 [10]
    113 [11]
    112 [12]
    110 [13]
    Units: Percentage of rescue-free 24-hr periods
        least squares mean (standard error)
    14.4 ± 2.97
    12.2 ± 2.97
    15.8 ± 2.98
    23.1 ± 3.01
    Notes
    [10] - ITT population. Only those participants available at the specified time points were analyzed.
    [11] - ITT population. Only those participants available at the specified time points were analyzed.
    [12] - ITT population. Only those participants available at the specified time points were analyzed.
    [13] - ITT population. Only those participants available at the specified time points were analyzed.
    Statistical analysis title
    		 Statistical Analysis #1
    Comparison groups
    Placebo v VI 6.25 µg OD
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.5
         upper limit
    		 6
    Statistical analysis title
    		 Statistical Analysis #2
    Comparison groups
    Placebo v VI 12.5 µg OD
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.9
         upper limit
    		 9.6
    Statistical analysis title
    		 Statistical Analysis #3
    Comparison groups
    Placebo v VI 25 µg OD
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 17

    Secondary: Change from Baseline in daily morning (AM) PEF averaged over the 4-week Treatment Period

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    End point title
    		 Change from Baseline in daily morning (AM) PEF averaged over the 4-week Treatment Period
    End point description
    PEF 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 prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. Change from Baseline was calculated as the value of the averaged daily AM PEF over the 4-week Treatment Period (at Week 4) minus the Baseline value. The Baseline value is defined as the value at Visit 3 (randomization). The analysis was performed using an ANCOVA model with covariates of Baseline, region, sex, age, and treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 1 up to Week 4
    End point values
    		 Placebo VI 6.25 µg OD VI 12.5 µg OD VI 25 µg OD
    Number of subjects analysed
    114 [14]
    113 [15]
    112 [16]
    110 [17]
    Units: L/min
        least squares mean (standard error)
    6.4 ± 2.42
    12 ± 2.43
    13.9 ± 2.44
    13.7 ± 2.46
    Notes
    [14] - ITT Population. Only those participants available at the specified time points were analyzed.
    [15] - ITT Population. Only those participants available at the specified time points were analyzed.
    [16] - ITT Population. Only those participants available at the specified time points were analyzed.
    [17] - ITT Population. Only those participants available at the specified time points were analyzed.
    Statistical analysis title
    		 Statistical Analysis #1
    Comparison groups
    VI 6.25 µg OD v Placebo
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 12.3
    Statistical analysis title
    		 Statistical Analysis #2
    Comparison groups
    Placebo v VI 12.5 µg OD
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 14.2
    Statistical analysis title
    		 Statistical Analysis #3
    Comparison groups
    Placebo v VI 25 µg OD
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 14

    Secondary: Change from Baseline in evening (PM) PEF over the last 7 days of the Treatment Period (Week 4)

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    End point title
    		 Change from Baseline in evening (PM) PEF over the last 7 days of the Treatment Period (Week 4)
    End point description
    PEF 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 evening prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. Change from Baseline is calculated as the value over the last 7 days of the Treatment Period minus the Baseline value. The Baseline value is defined as the value at Visit 3 (randomization). The analysis was performed using an ANCOVA model with covariates of Baseline, region, sex, age, and treatment group. The LOCF method was used to impute missing data, in which the last non-missing post-Baseline on-treatment measurement at scheduled clinic visits was used to impute the missing measurements.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 4
    End point values
    		 Placebo VI 6.25 µg OD VI 12.5 µg OD VI 25 µg OD
    Number of subjects analysed
    113 [18]
    113 [19]
    112 [20]
    110 [21]
    Units: L/min
        least squares mean (standard error)
    5.9 ± 3.44
    9.4 ± 3.44
    13.7 ± 3.45
    11.1 ± 3.48
    Notes
    [18] - ITT Population. Only those participants available at the specified time points were analyzed.
    [19] - ITT Population. Only those participants available at the specified time points were analyzed.
    [20] - ITT Population. Only those participants available at the specified time points were analyzed.
    [21] - ITT Population. Only those participants available at the specified time points were analyzed.
    Statistical analysis title
    		 Statistical Analysis #1
    Comparison groups
    Placebo v VI 6.25 µg OD
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.1
         upper limit
    		 13.1
    Statistical analysis title
    		 Statistical Analysis #2
    Comparison groups
    Placebo v VI 12.5 µg OD
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 17.4
    Statistical analysis title
    		 Statistical Analysis #3
    Comparison groups
    Placebo v VI 25 µg OD
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 14.9

    Secondary: Change from Baseline in AM PEF over the last 7 days of the Treatment Period (Week 4)

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    End point title
    		 Change from Baseline in AM PEF over the last 7 days of the Treatment Period (Week 4)
    End point description
    PEF 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 prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. Change from Baseline is calculated as the value of the averaged daily AM PEF over the 4-week Treatment Period (at Week 4) minus the Baseline value. The Baseline value is defined as the value at Visit 3 (randomization). The analysis was performed using an ANCOVA model with covariates of Baseline, region, sex, age, and treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 4
    End point values
    		 Placebo VI 6.25 µg OD VI 12.5 µg OD VI 25 µg OD
    Number of subjects analysed
    114 [22]
    113 [23]
    112 [24]
    110 [25]
    Units: L/min
        least squares mean (standard error)
    7.4 ± 3.45
    13.3 ± 3.47
    17 ± 3.48
    14.4 ± 3.51
    Notes
    [22] - ITT Population. Only those participants available at the specified time points were analyzed.
    [23] - ITT Population. Only those participants available at the specified time points were analyzed.
    [24] - ITT Population. Only those participants available at the specified time points were analyzed.
    [25] - ITT Population. Only those participants available at the specified time points were analyzed.
    Statistical analysis title
    		 Statistical Analysis #1
    Comparison groups
    Placebo v VI 6.25 µg OD
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.7
         upper limit
    		 15.6
    Statistical analysis title
    		 Statistical Analysis #2
    Comparison groups
    Placebo v VI 12.5 µg OD
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 19.3
    Statistical analysis title
    		 Statistical Analysis #3
    Comparison groups
    Placebo v VI 25 µg OD
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 16.7

    Secondary: Change from Baseline in the percentage of symptom-free 24-hour periods during the 4-week Treatment Period

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    End point title
    		 Change from Baseline in the percentage of symptom-free 24-hour periods during the 4-week Treatment Period
    End point description
    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 PEF measurement. A 24-hour (hr) period in which a participant’s responses to both the morning and evening assessments indicated no symptoms was considered to be symptom free. The Baseline symptom-free value is defined as the value at Visit 3 (randomization). Change from Baseline was calculated as the averaged value during the 4-week Treatment Period minus the Baseline value. The analysis was performed using an ANCOVA model with covariates of Baseline, region, sex, age, and treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 1 up to Week 4
    End point values
    		 Placebo VI 6.25 µg OD VI 12.5 µg OD VI 25 µg OD
    Number of subjects analysed
    113 [26]
    113 [27]
    112 [28]
    110 [29]
    Units: Percentage of symptom-free 24-hr periods
        least squares mean (standard error)
    9.9 ± 2.65
    10.1 ± 2.65
    18.3 ± 2.66
    19.7 ± 2.69
    Notes
    [26] - ITT Population. Only those participants available at the specified time points were analyzed.
    [27] - ITT Population. Only those participants available at the specified time points were analyzed.
    [28] - ITT Population. Only those participants available at the specified time points were analyzed.
    [29] - ITT Population. Only those participants available at the specified time points were analyzed.
    Statistical analysis title
    		 Statistical Analysis #1
    Comparison groups
    Placebo v VI 6.25 µg OD
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.2
         upper limit
    		 7.5
    Statistical analysis title
    		 Statistical Analysis #2
    Comparison groups
    Placebo v VI 12.5 µg OD
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 15.7
    Statistical analysis title
    		 Statistical Analysis #3
    Comparison groups
    Placebo v VI 25 µg OD
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.3
         upper limit
    		 17.2

    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 study medication until the follow-up visit (up to 9 weeks).
    Adverse event reporting additional description
    On-treatment SAEs and non-serious AEs are reported for members of the ITT Population, comprised of all participants who were randomized to treatment and received at least one dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo once daily (OD) in the evening from a dry powder inhaler for 4 weeks in addition to open-label fluticasone propionate (FP) 100 micrograms (µg) twice daily (BID). Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.

    Reporting group title
    VI 6.25 OD
    Reporting group description
    		 Participants received vilanterol (VI) 6.25 µg OD in the evening from a dry powder inhaler for 4 weeks in addition to open-label FP 100 µg BID. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.

    Reporting group title
    VI 12.5 OD
    Reporting group description
    		 Participants received VI 12.5 µg OD in the evening from a dry powder inhaler for 4 weeks in addition to open-label FP 100 µg BID. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.

    Reporting group title
    VI 25 OD
    Reporting group description
    		 Participants received VI 25 µg OD in the evening from a dry powder inhaler for 4 weeks in addition to open-label FP 100 µg BID. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication.

    Serious adverse events
    		 Placebo VI 6.25 OD VI 12.5 OD VI 25 OD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 114 (0.00%)
    0 / 113 (0.00%)
    1 / 114 (0.88%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 114 (0.00%)
    0 / 113 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Placebo VI 6.25 OD VI 12.5 OD VI 25 OD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 115 (8.70%)
    17 / 114 (14.91%)
    12 / 113 (10.62%)
    11 / 114 (9.65%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 115 (3.48%)
    6 / 114 (5.26%)
    2 / 113 (1.77%)
    2 / 114 (1.75%)
         occurrences all number
    4
    8
    3
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 115 (6.96%)
    8 / 114 (7.02%)
    10 / 113 (8.85%)
    9 / 114 (7.89%)
         occurrences all number
    8
    8
    11
    9
    Influenza
         subjects affected / exposed
    0 / 115 (0.00%)
    4 / 114 (3.51%)
    0 / 113 (0.00%)
    0 / 114 (0.00%)
         occurrences all number
    0
    4
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jun 2012
    This amendment was implemented to remove the requirement that participants must achieve a reversibility of 12% at Visit 1. This amendment also includes changes to the inhaled corticosteroid (ICS) doses allowed prior to Visit 1 and addresses the re-screening of participants found to be ineligible prior to this amendment. Additional edits were made to the statistical sections to the effect that the primary analysis will be the pairwise comparison of each dose regimen of vilanterol with placebo.
    14 Dec 2012
    The purpose of this amendment was to allow for the-re-screening of participants who failed Visit 1 criteria. Additional edits were made to the statistical sections to the effect that the primary analysis will be the comparison of each dose regimen of vilanterol with placebo.
    19 Sep 2013
    The purpose of this amendment was to implement a change to the time point for the primary endpoint (from an endpoint assessment to the average over the treatment period) and to the analysis for the primary endpoint.

    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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