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    Clinical Trial Results:
    A randomised, double-blind, parallel group, multicentre, stratified, study evaluating the efficacy and safety of once daily fluticasone furoate/vilanterol inhalation powder compared to once daily fluticasone furoate inhalation powder in the treatment of asthma in participants aged 5 to 17 years old (inclusive) currently uncontrolled on inhaled corticosteroids

    Summary
    EudraCT number
    		 2016-004086-87
    Trial protocol
    		 DE   ES   IT   PL   Outside EU/EEA   LT   HU   BG   RO  
    Global end of trial date
    25 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Sep 2022
    First version publication date
    28 Sep 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    HZA107116
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03248128
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom, TW8 9GS
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 May 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Apr 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and efficacy study of fluticasone furoate/vilanterol (FF/VI) fixed dose combination (FDC) compared to FF alone in subjects with asthma
    Protection of trial subjects
    Not Applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Oct 2017
    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
    Argentina: 307
    Country: Number of subjects enrolled
    Bulgaria: 53
    Country: Number of subjects enrolled
    Canada: 132
    Country: Number of subjects enrolled
    Japan: 117
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Italy: 62
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Romania: 48
    Country: Number of subjects enrolled
    Lithuania: 14
    Country: Number of subjects enrolled
    Poland: 311
    Country: Number of subjects enrolled
    Mexico: 190
    Country: Number of subjects enrolled
    Russian Federation: 330
    Country: Number of subjects enrolled
    South Africa: 331
    Country: Number of subjects enrolled
    United States: 452
    Country: Number of subjects enrolled
    China: 3
    Worldwide total number of subjects
    2402
    EEA total number of subjects
    540
    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)
    1778
    Adolescents (12-17 years)
    624
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 2402 participants screened, 906 participants were randomised, of which 4 participants did not receive study treatment. 902 participants received at least 1 dose of study medication creating the intent to treat (ITT) Population.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Participants who received FF/ VI FDC
    Arm description
    		 5-11 years old pediatric population were administered FF/VI as a FDC of 50/25 micrograms (mcg) and the 12-17 years old adolescent population received 100/25 mcg once daily via ELLIPTA dry powder inhaler (DPI). Each participant, in addition used albuterol/salbutamol (inhalation aerosol or nebuliser) as required throughout the entire study period as rescue medication for symptomatic relief of asthma symptoms.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Participants aged 5-17 years who received FF/ VI FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants aged 5 to 11 years received FDC of 50 mcg/ 25 mcg and 12 to 17 years received FDC of 100 mcg/ 25 mcg of FF/VI. Both age groups received dose once daily in the morning via ELLIPTA DPI.

    Arm title
    		 Participants who received FF
    Arm description
    		 5-11 years old pediatric population were administered FF/VI as a monotherapy of 50 mcg and the 12-17 years old adolescent population received 100 mcg once daily via ELLIPTA DPI. Each participant, in addition used albuterol/salbutamol (inhalation aerosol or nebuliser) as required throughout the entire study period as rescue medication for symptomatic relief of asthma symptoms.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Participants aged 5-17 years who received FF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants aged 5 to 11 years received 50 mcg and aged 12 to 17 years received 100 mcg of FF. Both age groups received dose once daily in the morning via ELLIPTA DPI.

    Number of subjects in period 1 [1]
    		Participants who received FF/ VI FDC Participants who received FF
    Started
    454
    448
    Completed
    433
    431
    Not completed
    21
    17
         Consent withdrawn by subject
    16
    14
         Site Closed
    4
    3
         Lost to follow-up
    1
    -
    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: 2402 participants were screened, 906 patients were randomized of which 4 participants did not receive study treatment. 902 participants received at least 1 dose of study medication creating the ITT Population for which baseline characteristics are reported.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Participants who received FF/ VI FDC
    Reporting group description
    		 5-11 years old pediatric population were administered FF/VI as a FDC of 50/25 micrograms (mcg) and the 12-17 years old adolescent population received 100/25 mcg once daily via ELLIPTA dry powder inhaler (DPI). Each participant, in addition used albuterol/salbutamol (inhalation aerosol or nebuliser) as required throughout the entire study period as rescue medication for symptomatic relief of asthma symptoms.

    Reporting group title
    Participants who received FF
    Reporting group description
    		 5-11 years old pediatric population were administered FF/VI as a monotherapy of 50 mcg and the 12-17 years old adolescent population received 100 mcg once daily via ELLIPTA DPI. Each participant, in addition used albuterol/salbutamol (inhalation aerosol or nebuliser) as required throughout the entire study period as rescue medication for symptomatic relief of asthma symptoms.

    Reporting group values
    		 Participants who received FF/ VI FDC Participants who received FF Total
    Number of subjects
    		 454 448 902
    Age categorical
    Units: Subjects
        >=5 years to <=7 years
    		 102 100 202
        >=8 years to <=11 years
    		 235 236 471
        >=12 years to <=17 years
    		 117 112 229
    Sex: Female, Male
    Units: Participants
        Female
    		 165 191 356
        Male
    		 289 257 546
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    		 34 40 74
        American Indian or Alaska Native
    		 22 29 51
        Asian
    		 32 26 58
        Multiple
    		 31 33 64
        White
    		 335 320 655
    Age, Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 9.9 ± 3.02 10.0 ± 2.97 -

    End points

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    End points reporting groups
    Reporting group title
    Participants who received FF/ VI FDC
    Reporting group description
    		 5-11 years old pediatric population were administered FF/VI as a FDC of 50/25 micrograms (mcg) and the 12-17 years old adolescent population received 100/25 mcg once daily via ELLIPTA dry powder inhaler (DPI). Each participant, in addition used albuterol/salbutamol (inhalation aerosol or nebuliser) as required throughout the entire study period as rescue medication for symptomatic relief of asthma symptoms.

    Reporting group title
    Participants who received FF
    Reporting group description
    		 5-11 years old pediatric population were administered FF/VI as a monotherapy of 50 mcg and the 12-17 years old adolescent population received 100 mcg once daily via ELLIPTA DPI. Each participant, in addition used albuterol/salbutamol (inhalation aerosol or nebuliser) as required throughout the entire study period as rescue medication for symptomatic relief of asthma symptoms.

    Subject analysis set title
    Participants receiving FF/ VI FDC (5-11 year old population)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subset of the ITT Population for pediatric participants of age 11 years and younger at Screening who were administered FF/VI as a FDC of 50/25 mcg.

    Subject analysis set title
    Participants receiving FF (5-11 year old population)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subset of the ITT Population for pediatric participants of age 11 years and younger at Screening who were administered FF as a monotherapy of 50 mcg.

    Primary: Absolute weighted mean of forced expiratory volume in 1 second (FEV1) (0-4 hours) at week 12 in 5-17 years old population

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    End point title
    		 Absolute weighted mean of forced expiratory volume in 1 second (FEV1) (0-4 hours) at week 12 in 5-17 years old population
    End point description
    Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second using a standardized calibrated spirometer. Weighted mean FEV1 was derived using the post-dose assessments (after 30 minutes and 1, 2, 3, 4 hours) with their actual times and using the pre-dose assessment as the 0 hour measurement. ITT (5-17 years old) included all randomized participants who received at least one dose of study treatment. Only those participants with data available at specified time points have been analyzed.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Participants who received FF/ VI FDC Participants who received FF
    Number of subjects analysed
    397
    399
    Units: Litres
        arithmetic mean (standard deviation)
    2.082 ± 0.7598
    1.994 ± 0.6998
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using analysis of covariance (ANCOVA) with covariates of baseline, region, sex, age and treatment.
    Comparison groups
    Participants who received FF/ VI FDC v Participants who received FF
    Number of subjects included in analysis
    796
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.083
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.037
         upper limit
    		 0.129

    Primary: Change from baseline in mean pre-dose morning peak expiratory flow (AM PEF) in 5-11 years old population

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    End point title
    		 Change from baseline in mean pre-dose morning peak expiratory flow (AM PEF) in 5-11 years old population
    End point description
    PEF was defined as the maximum speed of expiration of a participant. PEF was measured 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. The best of three measurements were recorded in the electronic patient diary. The mean morning PEF was calculated for each participant as an averaged mean over weeks 1-12 of the treatment period. Baseline was defined as the average of measurements with a non-missing value from Day -6 to Day 1 of pre-dose. Intent-to treat (ITT) (5- 11 years old) was a subset of the ITT (5-17 Years Old) population for participants 11 years old and younger at screening (Visit 1). Only those participants with data available at specified time points have been analyzed.
    End point type
    Primary
    End point timeframe
    Baseline and Week 1-12
    End point values
    		 Participants receiving FF/ VI FDC (5-11 year old population) Participants receiving FF (5-11 year old population)
    Number of subjects analysed
    336
    335
    Units: Litres per minute (L/min)
        arithmetic mean (standard deviation)
    11.9 ± 37.63
    8.9 ± 35.62
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using ANCOVA with covariates of baseline, region, sex, age and treatment.
    Comparison groups
    Participants receiving FF/ VI FDC (5-11 year old population) v Participants receiving FF (5-11 year old population)
    Number of subjects included in analysis
    671
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.228
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 8.4

    Secondary: Change from baseline in mean pre-dose AM PEF in 5-17 years old population

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    End point title
    		 Change from baseline in mean pre-dose AM PEF in 5-17 years old population
    End point description
    PEF was defined as the maximum speed of expiration of a participant. PEF was measured 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. The best of three measurements were recorded in the daily diary. The mean morning PEF was calculated for each participant as an averaged mean over weeks 1-12 of the treatment period. Baseline was defined as the average of measurements with a non-missing value from Day -6 to Day 1 of pre-dose. Analysed population was ITT (5-17 years old). Only those participants with data available at specified time points has been analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 1-12
    End point values
    		 Participants who received FF/ VI FDC Participants who received FF
    Number of subjects analysed
    453
    447
    Units: L/min
        arithmetic mean (standard deviation)
    14.9 ± 39.94
    9.3 ± 38.95
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using ANCOVA with covariates of baseline, region, sex, age and treatment.
    Comparison groups
    Participants who received FF/ VI FDC v Participants who received FF
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    6.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 10.9

    Secondary: Absolute weighted mean of FEV1 (0-4 hours) at week 12 in 5-11 years old population

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    End point title
    		 Absolute weighted mean of FEV1 (0-4 hours) at week 12 in 5-11 years old population
    End point description
    Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second using a standardized calibrated spirometer. Weighted mean FEV1 was derived using the post-dose assessments (after 30 minutes and 1, 2, 3, 4 hours) with their actual times and using the pre-dose assessment as the 0 hour measurement. ITT (5- 11 years old). Only those participants with data available at specified time points has been analyzed.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Participants receiving FF/ VI FDC (5-11 year old population) Participants receiving FF (5-11 year old population)
    Number of subjects analysed
    286
    289
    Units: Litres
        arithmetic mean (standard deviation)
    1.772 ± 0.0161
    1.700 ± 0.0160
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using ANCOVA with covariates of baseline, region, sex, age and treatment.
    Comparison groups
    Participants receiving FF/ VI FDC (5-11 year old population) v Participants receiving FF (5-11 year old population)
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.073
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.028
         upper limit
    		 0.118

    Secondary: Change from baseline in the percentage of rescue-free 24-hour periods over weeks 1-12 of the treatment period in 5-17 years old population

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    End point title
    		 Change from baseline in the percentage of rescue-free 24-hour periods over weeks 1-12 of the treatment period in 5-17 years old population
    End point description
    The number of inhalations of rescue albuterol/salbutamol aerosol used during the day and night were recorded in a daily electronic diary. Percentages of rescue-free 24-hour periods was calculated based on the number of 24-hour periods on which a participant recorded no use of albuterol/salbutamol divided by the length of the time period being assessed (with non-missing values of rescue medication recorded, respectively). A 24-hour period in which the response of participants to both the morning and evening assessments indicated no use of rescue medication was considered as rescue free. Baseline was calculated from the evening (Day -7 to Day -1) and morning (Day -6 to Day 1) measurements. Change from Baseline was calculated as the averaged value during the 12-week treatment period minus the Baseline value. Analysed population was ITT (5-17 years old). Only those participants with data available at specified time points has been analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 1-12
    End point values
    		 Participants who received FF/ VI FDC Participants who received FF
    Number of subjects analysed
    453
    447
    Units: Percentage
        arithmetic mean (standard deviation)
    25.9 ± 33.78
    25.8 ± 36.55
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using ANCOVA with covariates of baseline, region, sex, age and treatment.
    Comparison groups
    Participants who received FF/ VI FDC v Participants who received FF
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.87
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 3.8

    Secondary: Change from baseline in the percentage of symptom-free 24-hour periods over weeks 1-12 of the treatment period in 5-17 years old population

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    End point title
    		 Change from baseline in the percentage of symptom-free 24-hour periods over weeks 1-12 of the treatment period in 5-17 years old population
    End point description
    The symptom-free days were recorded in a daily electronic diary every day in the morning and evening before taking any rescue or study medication and before the PEF measurement. Percentages of symptom-free 24-hour periods was calculated based on the number of 24-hour periods on which a participant recorded no symptoms divided by the length of the time period being assessed (with non-missing values of rescue medication recorded, respectively). A 24-hour period in which the response of participants to both the morning and evening assessments indicated no symptoms was considered as symptom free. Baseline was calculated from evening (Day -7 to Day -1) and morning (Day -6 to Day 1) measurements. Change from Baseline was calculated as the averaged value during the 12-week treatment period minus the Baseline value. Analysed population was ITT (5-17 years old). Only those participants with data available at specified time points has been analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 1-12
    End point values
    		 Participants who received FF/ VI FDC Participants who received FF
    Number of subjects analysed
    453
    447
    Units: Percentage
        arithmetic mean (standard deviation)
    25.7 ± 32.77
    24.6 ± 34.62
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using ANCOVA with covariates of baseline, region, sex, age and treatment.
    Comparison groups
    Participants who received FF/ VI FDC v Participants who received FF
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.988
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.2
         upper limit
    		 4.1

    Secondary: Change from baseline in morning (AM) FEV1 at week 12 in 5-17 years old population

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    End point title
    		 Change from baseline in morning (AM) FEV1 at week 12 in 5-17 years old population
    End point description
    Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Morning FEV1 was measured using the pre-dose serial spirometry assessment at the Week 12. Baseline was defined as the pre-dose assessment with a non missing value on Visit 2 (Day -5). Analysed population was ITT (5-17 years old). Only those participants with data available at specified time points have been analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Participants who received FF/ VI FDC Participants who received FF
    Number of subjects analysed
    417
    413
    Units: Litres
        arithmetic mean (standard deviation)
    0.312 ± 0.3865
    0.275 ± 0.3512
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using a repeated measures analysis adjusted for baseline, region, sex, age, treatment, visit, visit by baseline interaction and visit by treatment group interaction
    Comparison groups
    Participants who received FF v Participants who received FF/ VI FDC
    Number of subjects included in analysis
    830
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.124
    Method
    		 Repeated measures analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.035
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.08

    Secondary: Change from Baseline in asthma control questionnaire (ACQ-5) Score at week 24 in 5-17 years old population

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    End point title
    		 Change from Baseline in asthma control questionnaire (ACQ-5) Score at week 24 in 5-17 years old population
    End point description
    Asthma control as measured by improvements in ACQ-5, a five-item questionnaire with response options for each question rated from 0 to 6 scale. A score of 0 indicates well controlled asthma and a score of 6 indicates extremely poorly controlled asthma. Individual questions (concerning nocturnal awakening, waking in the morning, activity limitation, shortness of breath and wheeze) are equally weighted and the ACQ-5 score is calculated as the mean of these 5 item responses. A lower mean score indicates greater asthma control and higher mean score indicates lesser asthma control. Baseline was defined as the pre-dose assessment with a non missing value on Visit 3 (Day 1). Analysed population was ITT (5-17 years old). Only those participants with data available at specified time points has been analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Participants who received FF/ VI FDC Participants who received FF
    Number of subjects analysed
    385
    378
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.21 ± 0.935
    -1.09 ± 0.976
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using a repeated measures ANCOVA adjusted for baseline, region, sex, age, treatment, visit, visit by baseline interaction and visit by treatment group interaction.
    Comparison groups
    Participants who received FF/ VI FDC v Participants who received FF
    Number of subjects included in analysis
    763
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.91
    Method
    		 Repeated measures analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.09

    Secondary: Change from baseline in the percentage of rescue-free 24-hour periods over weeks 1-12 of the treatment period in 5-11 years old population

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    End point title
    		 Change from baseline in the percentage of rescue-free 24-hour periods over weeks 1-12 of the treatment period in 5-11 years old population
    End point description
    The number of inhalations of rescue albuterol/salbutamol aerosol used during the day and night were recorded in a daily electronic diary. Percentages of rescue-free 24-hour periods was calculated based on the number of 24-hour periods on which a participant recorded no use of albuterol/salbutamol divided by the length of the time period being assessed (with non-missing values of rescue medication recorded, respectively). A 24-hour period in which the response of participants to both the morning and evening assessments indicated no use of rescue medication was considered as rescue free. Baseline was calculated from the evening (Day -7 to Day -1) and morning (Day -6 to Day 1) measurements. Change from Baseline was calculated as the averaged value during the 12-week treatment period minus the Baseline value. Analysed population was ITT (5- 11 years old). Only those participants with data available at specified time points has been analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 1-12
    End point values
    		 Participants receiving FF/ VI FDC (5-11 year old population) Participants receiving FF (5-11 year old population)
    Number of subjects analysed
    336
    335
    Units: Percentage
        arithmetic mean (standard deviation)
    27.3 ± 34.4
    25.6 ± 37.03
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using ANCOVA with covariates of baseline, region, sex, age and treatment.
    Comparison groups
    Participants receiving FF/ VI FDC (5-11 year old population) v Participants receiving FF (5-11 year old population)
    Number of subjects included in analysis
    671
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.614
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 6.2

    Secondary: Change from baseline in the percentage of symptom-free 24-hour periods over weeks 1-12 of the treatment period in 5-11 years old population

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    End point title
    		 Change from baseline in the percentage of symptom-free 24-hour periods over weeks 1-12 of the treatment period in 5-11 years old population
    End point description
    The symptom-free days were recorded in a daily electronic diary every day in the morning and evening before taking any rescue or study medication and before the PEF measurement. Percentages of symptom-free 24-hour periods was calculated based on the number of 24-hour periods on which a participant recorded no symptoms divided by the length of the time period being assessed (with non-missing values of rescue medication recorded, respectively). A 24-hour period in which the response of participants to both the morning and evening assessments indicated no symptoms was considered as symptom free. Baseline was calculated from evening (Day -7 to Day -1) and morning (Day -6 to Day 1) measurements. Change from Baseline was calculated as the averaged value during the 12-week treatment period minus the Baseline value. Analysed population was ITT (5- 11 years old). Only those participants with data available at specified time points has been analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 1-12
    End point values
    		 Participants receiving FF/ VI FDC (5-11 year old population) Participants receiving FF (5-11 year old population)
    Number of subjects analysed
    336
    335
    Units: Percentage
        arithmetic mean (standard deviation)
    27.2 ± 833.16
    25.8 ± 34.94
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using ANCOVA with covariates of baseline, region, sex, age and treatment.
    Comparison groups
    Participants receiving FF/ VI FDC (5-11 year old population) v Participants receiving FF (5-11 year old population)
    Number of subjects included in analysis
    671
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.594
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 6.3

    Secondary: Change from baseline in morning (AM) FEV1 at week 12 in 5-11 years old population

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    End point title
    		 Change from baseline in morning (AM) FEV1 at week 12 in 5-11 years old population
    End point description
    Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Morning FEV1 was measured using the pre-dose serial spirometry assessment at the Week 12. Baseline was defined as the pre-dose assessment with a non missing value on Visit 2 (Day -5). Analysed population was ITT (5- 11 years old). Only those participants with data available at specified time points have been analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Participants receiving FF/ VI FDC (5-11 year old population) Participants receiving FF (5-11 year old population)
    Number of subjects analysed
    307
    304
    Units: Litres
        arithmetic mean (standard deviation)
    0.263 ± 0.3029
    0.245 ± 0.3192
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using a repeated measures analysis adjusted for baseline, region, sex, age, treatment, visit, visit by baseline interaction and visit by treatment group interaction.
    Comparison groups
    Participants receiving FF/ VI FDC (5-11 year old population) v Participants receiving FF (5-11 year old population)
    Number of subjects included in analysis
    611
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.226
    Method
    		 Repeated measures analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.028
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.017
         upper limit
    		 0.073

    Secondary: Change from baseline in ACQ-5 Score at week 24 in 5-11 years old population

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    End point title
    		 Change from baseline in ACQ-5 Score at week 24 in 5-11 years old population
    End point description
    Asthma control as measured by improvements in ACQ-5, a five-item questionnaire with response options for each question rated from 0 to 6 scale. A score of 0 indicates well controlled asthma and a score of 6 indicates extremely poorly controlled asthma. Individual questions (concerning nocturnal awakening, waking in the morning, activity limitation, shortness of breath and wheeze) are equally weighted and the ACQ-5 score is calculated as the mean of these 5 item responses. A lower mean score indicates greater asthma control and higher mean score indicates lesser asthma control. Baseline was defined as the pre-dose assessment with a non missing value on Visit 3 (Day 1). Analysed population was ITT (5- 11 years old). Only those participants with data available at specified time points has been analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Participants receiving FF/ VI FDC (5-11 year old population) Participants receiving FF (5-11 year old population)
    Number of subjects analysed
    291
    286
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.25 ± 0.944
    -1.13 ± 0.975
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using a repeated measures analysis adjusted for baseline, region, sex, age, treatment, visit, visit by baseline interaction and visit by treatment group interaction.
    Comparison groups
    Participants receiving FF/ VI FDC (5-11 year old population) v Participants receiving FF (5-11 year old population)
    Number of subjects included in analysis
    577
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.663
    Method
    		 Repeated measures analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.09

    Secondary: Number of participants with adverse events (AEs) and serious adverse events (SAEs) in 5-17 years old population

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    End point title
    		 Number of participants with adverse events (AEs) and serious adverse events (SAEs) in 5-17 years old population
    End point description
    An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect and important medical events may jeopardize the participant or may require medical or surgical intervention/SOC to prevent one of the other outcomes mentioned before. Analysed population was ITT (5-17 years old).
    End point type
    Secondary
    End point timeframe
    Up to week 25
    End point values
    		 Participants who received FF/ VI FDC Participants who received FF
    Number of subjects analysed
    454
    448
    Units: Participants
        AEs
    183
    164
        SAEs
    5
    5
    No statistical analyses for this end point

    Secondary: Number of participants with abnormal electrocardiogram (ECG) findings in 5-17 years old population

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    End point title
    		 Number of participants with abnormal electrocardiogram (ECG) findings in 5-17 years old population
    End point description
    A single 12-lead ECG was obtained using an ECG machine that automatically calculates the heartrate and measures PR, QRS, QT, and QT interval corrected (QTc). Analysed population was ITT (5-17 years old). Only those participants with data available at specified time points has been analyzed.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Participants who received FF/ VI FDC Participants who received FF
    Number of subjects analysed
    402
    398
    Units: Participants
    64
    49
    No statistical analyses for this end point

    Secondary: Change from baseline in fasting glucose in 5-17 years old population

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    End point title
    		 Change from baseline in fasting glucose in 5-17 years old population
    End point description
    Blood samples were collected for evaluation of fasting blood glucose pre and post-treatment. Baseline was defined as Visit 1 (Screening). Analysed population was ITT (5- 11 years old). Only those participants with data available at specified time point have been analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Participants who received FF/ VI FDC Participants who received FF
    Number of subjects analysed
    370
    388
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.12 ± 0.587
    -0.15 ± 0.626
    No statistical analyses for this end point

    Secondary: Number of participants with incidence of an asthma exacerbation over the 24-week treatment period in 5-17 years old population

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    End point title
    		 Number of participants with incidence of an asthma exacerbation over the 24-week treatment period in 5-17 years old population
    End point description
    Asthma exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension or injection) for at least three days or a single depot corticosteroid injection or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. Analysed population was ITT (5-17 years old)
    End point type
    Secondary
    End point timeframe
    Up to week 24
    End point values
    		 Participants who received FF/ VI FDC Participants who received FF
    Number of subjects analysed
    454
    448
    Units: Participants
    33
    38
    No statistical analyses for this end point

    Secondary: Number of participants with AEs and SAEs in 5-11 years old population

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    End point title
    		 Number of participants with AEs and SAEs in 5-11 years old population
    End point description
    An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect and important medical events may jeopardize the participant or may require medical or surgical intervention/Standard of care (SOC) to prevent one of the other outcomes mentioned before. Analysed population was ITT (5-11 years old).
    End point type
    Secondary
    End point timeframe
    Up to week 25
    End point values
    		 Participants receiving FF/ VI FDC (5-11 year old population) Participants receiving FF (5-11 year old population)
    Number of subjects analysed
    337
    336
    Units: Participants
        AEs
    133
    122
        SAEs
    4
    4
    No statistical analyses for this end point

    Secondary: Number of participants with abnormal ECG findings in 5-11 years old population

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    End point title
    		 Number of participants with abnormal ECG findings in 5-11 years old population
    End point description
    A single 12-lead ECG was obtained using an ECG machine that automatically calculates the heartrate and measures PR, QRS, QT, and QTc. Analysed population was ITT (5-11 years old). Only those participants with data available at specified time points has been analyzed.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Participants receiving FF/ VI FDC (5-11 year old population) Participants receiving FF (5-11 year old population)
    Number of subjects analysed
    303
    298
    Units: Participants
    53
    40
    No statistical analyses for this end point

    Secondary: Change from baseline in fasting glucose in 5-11 years old population

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    End point title
    		 Change from baseline in fasting glucose in 5-11 years old population
    End point description
    Blood samples were collected for evaluation of fasting blood glucose pre and post-treatment. Baseline was defined as Visit 1 (screening). Analysed population was ITT (5- 11 years old). Only those participants with data available at specified time point have been analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Participants receiving FF/ VI FDC (5-11 year old population) Participants receiving FF (5-11 year old population)
    Number of subjects analysed
    274
    288
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.13 ± 0.563
    -0.17 ± 0.638
    No statistical analyses for this end point

    Secondary: Number of participants with any incidence of asthma exacerbation over the 24-week treatment period in 5-11 years old population

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    End point title
    		 Number of participants with any incidence of asthma exacerbation over the 24-week treatment period in 5-11 years old population
    End point description
    Asthma exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension or injection) for at least three days or a single depot corticosteroid injection or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. Analysis was performed on the ITT (5-11 years old) population.
    End point type
    Secondary
    End point timeframe
    Up to week 24
    End point values
    		 Participants receiving FF/ VI FDC (5-11 year old population) Participants receiving FF (5-11 year old population)
    Number of subjects analysed
    337
    336
    Units: Participants
    27
    32
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All cause mortality, Non-serious adverse events (Non-SAEs) and serious adverse events (SAEs) were collected up to 25 weeks (which included one week of follow up contact after completion of the treatment period).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Participants aged 5-17 years who received FF/ VI FDC
    Reporting group description
    		 Participants aged 5 to 11 years received FDC of 50 mcg/ 25 mcg and 12 to 17 years received FDC of 100 mcg/ 25 mcg of FF/VI. Both age groups received dose once daily in the morning via ELLIPTA dry powder inhaler (DPI).

    Reporting group title
    Participants aged 5-17 years who received FF
    Reporting group description
    		 Participants aged 5 to 11 years received 50 mcg and aged 12 to 17 years received 100 mcg of FF. Both age groups received dose once daily in the morning via ELLIPTA DPI.

    Serious adverse events
    		 Participants aged 5-17 years who received FF/ VI FDC Participants aged 5-17 years who received FF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 454 (1.10%)
    5 / 448 (1.12%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 448 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 454 (0.44%)
    3 / 448 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 448 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    1 / 454 (0.22%)
    0 / 448 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Helicobacter gastritis
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 448 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 454 (0.00%)
    1 / 448 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Participants aged 5-17 years who received FF/ VI FDC Participants aged 5-17 years who received FF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    107 / 454 (23.57%)
    71 / 448 (15.85%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 454 (3.08%)
    9 / 448 (2.01%)
         occurrences all number
    23
    13
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic
         subjects affected / exposed
    19 / 454 (4.19%)
    6 / 448 (1.34%)
         occurrences all number
    22
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    47 / 454 (10.35%)
    34 / 448 (7.59%)
         occurrences all number
    60
    42
    Rhinitis
         subjects affected / exposed
    15 / 454 (3.30%)
    6 / 448 (1.34%)
         occurrences all number
    16
    6
    Upper respiratory tract infection
         subjects affected / exposed
    32 / 454 (7.05%)
    25 / 448 (5.58%)
         occurrences all number
    42
    27

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jun 2019
    Amendment 01: The aim of this amendment was to aid in the recruitment of participants in this study. The changes will allow flexibility to perform spirometry maneuvers during screening especially in the younger participants.
    10 Dec 2019
    Amendment 02: The changes in this amendment took into account the variability in asthma by allowing re-screening, and also by increasing the maximum permitted FEV1 at screening and randomisation to 100% predicted normal. These changes were made to help with recruitment of this population.
    13 Jan 2020
    Amendment 03: The aim of this amendment was to specify that Visit 4 to no longer be considered optional parent only visit. As Visit 4 is the first visit after randomization to study treatment, it is considered an important visit at which to collect clinical data.
    24 Aug 2020
    Amendment 04: The aim was to allow the option for certain visits to either be conducted at home by a qualified nurse or replaced by video-calls with the site, when appropriate and if permitted by local regulations.

    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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