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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Triple-Dummy, Placebo-Controlled, Parallel Group, Four-Week Study Assessing the Efficacy of Fluticasone Propionate Aqueous Nasal Spray 200mcg QD versus Montelukast 10mg QD in Adolescent and Adult Subjects with Asthma and Seasonal Allergic Rhinitis Who are Receiving ADVAIR™ DISKUS™ 100/50mcg BID or Placebo BID

    Summary
    EudraCT number
    		 2015-004867-35
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    16 Jun 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jan 2017
    First version publication date
    25 Jan 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ADA103578
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Sep 2007
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jun 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study are to show that fluticasone propionate/salmeterol combination product 100/50mcg (FSC) BID (available as ADVAIR DISKUS) is superior to montelukast 10mg (MON) QD (available as Singulair) as monotherapy for asthma, and that MON administered concurrently with FSC adds no additional benefit to FSC alone in improving asthma control in a population of subjects with allergic asthma. A secondary objective is to demonstrate that in the presence of FSC, FPANS 200mcg QD (available as FLONASE) was superior to MON for control of rhinitis symptoms in a population of subjects with allergic asthma.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Sep 2005
    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
    United States: 1177
    Worldwide total number of subjects
    1177
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    90
    Adults (18-64 years)
    1053
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants having diagnosed as persistent asthma, for at least three months, who fulfilled eligibility criteria were enrolled for the study. Six hundred sixty (660) subjects were randomly assigned to one of the four double-blind study treatments

    Pre-assignment
    Screening details
    		 Study was conducted at 71 investigational centers in United States. Subjects replaced their current short-acting beta 2-agonist with albuterol to be used as needed throughout the study. After screening, subjects entered a 7-14 day run-in period during which they continued use of their pre-study controller therapy

    Period 1
    Period 1 title
    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
    		 FSC 100/50mcg (BID)+FPANS (200mcg) QD
    Arm description
    		 Participants received fluticasone propionate/salmeterol (FSC) 100/50microgram (mcg) inhalation powder twice daily (BID) and fluticasone propionate aqueous nasal spray (FPANS) 200mcg once daily (QD) and placebo capsule once daily for four weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone propionate/salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    100/50mcg twice a day

    Investigational medicinal product name
    Fluticasone propionate aqueous nasal spray
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Nasal use
    Dosage and administration details
    200mcg once daily

    Arm title
    		 FSC 100/50mcg (BID) +MON 10mg (QD)
    Arm description
    		 Participants received fluticasone propionate/salmeterol 100/50mcg Inhalation powder twice daily, Montelukast (MON) 10mg capsule once daily and vehicle placebo nasal spray once daily for four weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fluticasone propionate/salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    100/50mcg twice a day

    Investigational medicinal product name
    Montelukast
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10mg once daily

    Arm title
    		 FSC 100/50mcg (BID)
    Arm description
    		 Participants received fluticasone propionate/salmeterol 100/50mcg Inhalation powder twice daily, vehicle placebo nasal spray once daily and placebo capsule once daily for four weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone propionate/salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    100/50mcg twice a day

    Arm title
    		 MON 10mg (QD)
    Arm description
    		 Participants received Montelukast 10mg capsule once daily, placebo via dry powder inhaler BID, and vehicle placebo nasal spray QD for four weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Montelukast
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10mg once daily

    Number of subjects in period 1 [1]
    		FSC 100/50mcg (BID)+FPANS (200mcg) QD FSC 100/50mcg (BID) +MON 10mg (QD) FSC 100/50mcg (BID) MON 10mg (QD)
    Started
    168
    165
    157
    170
    Completed
    139
    139
    125
    134
    Not completed
    29
    26
    32
    36
         Consent withdrawn by subject
    -
    1
    -
    4
         Physician decision
    -
    -
    1
    -
         Adverse event, non-fatal
    5
    2
    3
    2
         Other; reasons not specified
    7
    8
    12
    13
         Other; Exacerbation
    1
    1
    2
    5
         Lost to follow-up
    1
    2
    -
    -
         Protocol deviation
    6
    3
    3
    1
         Other; Non-compliance
    9
    9
    11
    10
         Lack of efficacy
    -
    -
    -
    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: Although 1177 participants enrolled, a total of 660 subjects comprised the Intent-To-Treat population randomized into the study. Sixty three (63) sites randomized a total of 396 subjects into a Per Protocol population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FSC 100/50mcg (BID)+FPANS (200mcg) QD
    Reporting group description
    		 Participants received fluticasone propionate/salmeterol (FSC) 100/50microgram (mcg) inhalation powder twice daily (BID) and fluticasone propionate aqueous nasal spray (FPANS) 200mcg once daily (QD) and placebo capsule once daily for four weeks.

    Reporting group title
    FSC 100/50mcg (BID) +MON 10mg (QD)
    Reporting group description
    		 Participants received fluticasone propionate/salmeterol 100/50mcg Inhalation powder twice daily, Montelukast (MON) 10mg capsule once daily and vehicle placebo nasal spray once daily for four weeks.

    Reporting group title
    FSC 100/50mcg (BID)
    Reporting group description
    		 Participants received fluticasone propionate/salmeterol 100/50mcg Inhalation powder twice daily, vehicle placebo nasal spray once daily and placebo capsule once daily for four weeks.

    Reporting group title
    MON 10mg (QD)
    Reporting group description
    		 Participants received Montelukast 10mg capsule once daily, placebo via dry powder inhaler BID, and vehicle placebo nasal spray QD for four weeks.

    Reporting group values
    		 FSC 100/50mcg (BID)+FPANS (200mcg) QD FSC 100/50mcg (BID) +MON 10mg (QD) FSC 100/50mcg (BID) MON 10mg (QD) Total
    Number of subjects
    		 168 165 157 170
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.2 ± 13.12 36.6 ± 12.47 37.4 ± 13.85 36.7 ± 13.9 -
    Gender categorical
    Units:
        Female
    		 116 120 108 108 452
        Male
    		 52 45 49 62 208
    Race, Customized
    Please note: The unknown category is used to present 1 participant who is missing from the study's demographic table in arm: FSC 100/50mcg (BID)+FPANS (200mcg) QD. There is no further explanation provided about the 1 missing participant data.
    Units: Subjects
        African American/African Heritage
    		 18 19 22 19 78
        American Indian or Alaska Native
    		 3 3 0 3 9
        Asian - Central/South Asian Heritage
    		 2 3 1 2 8
        Asian - East Asian Heritage
    		 1 2 1 0 4
        Asian - Japanese Heritage
    		 0 2 0 0 2
        Asian - South East Asian Heritage
    		 1 3 1 1 6
        Native Hawaiian or other Pacific Islander
    		 1 1 1 1 4
        White - Arabic/North African Heritage
    		 2 1 0 2 5
        White - White/Caucasian/European Heritage
    		 137 130 129 142 538
        White - Mixed Race
    		 1 0 0 0 1
        Mixed Race
    		 1 1 2 0 4
        Unknown
    		 1 0 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    FSC 100/50mcg (BID)+FPANS (200mcg) QD
    Reporting group description
    		 Participants received fluticasone propionate/salmeterol (FSC) 100/50microgram (mcg) inhalation powder twice daily (BID) and fluticasone propionate aqueous nasal spray (FPANS) 200mcg once daily (QD) and placebo capsule once daily for four weeks.

    Reporting group title
    FSC 100/50mcg (BID) +MON 10mg (QD)
    Reporting group description
    		 Participants received fluticasone propionate/salmeterol 100/50mcg Inhalation powder twice daily, Montelukast (MON) 10mg capsule once daily and vehicle placebo nasal spray once daily for four weeks.

    Reporting group title
    FSC 100/50mcg (BID)
    Reporting group description
    		 Participants received fluticasone propionate/salmeterol 100/50mcg Inhalation powder twice daily, vehicle placebo nasal spray once daily and placebo capsule once daily for four weeks.

    Reporting group title
    MON 10mg (QD)
    Reporting group description
    		 Participants received Montelukast 10mg capsule once daily, placebo via dry powder inhaler BID, and vehicle placebo nasal spray QD for four weeks.

    Primary: Change from baseline in morning peak expiratory flow to assess superiority

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    End point title
    		 Change from baseline in morning peak expiratory flow to assess superiority
    End point description
    Peak expiratory flow (PEF) was measured by the participant between clinic visits using the device used for spirometry assessments. Change from baseline is calculated as endpoint value minus baseline value where endpoint was defined as the average of the last (week 4) week’s worth of data. Superiority analysis was performed by comparing the values between treatment groups. The Intent-to-Treat (ITT) population was defined as all subjects randomized to double-blind treatment
    End point type
    Primary
    End point timeframe
    Baseline and Week 4
    End point values
    		 FSC 100/50mcg (BID)+FPANS (200mcg) QD FSC 100/50mcg (BID) +MON 10mg (QD) FSC 100/50mcg (BID) MON 10mg (QD)
    Number of subjects analysed
    165 [1]
    161 [2]
    154 [3]
    162 [4]
    Units: Liter per minute (L/min)
        geometric mean (standard error)
    20.8 ± 3.31
    28.7 ± 3.06
    28.9 ± 3.99
    -2.2 ± 3.5
    Notes
    [1] - Intent-to-treat (ITT) population.
    [2] - ITT Population
    [3] - ITT Population
    [4] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    MON 10mg (QD) v FSC 100/50mcg (BID)
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least square mean difference
    Point estimate
    29.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 20.1
         upper limit
    		 39.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.92

    Primary: Mean change from baseline in morning peak expiratory flow to assess equivalence

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    End point title
    		 Mean change from baseline in morning peak expiratory flow to assess equivalence
    End point description
    PEF was measured by the participant between clinic visits using the device used for spirometry assessments. Change from baseline is calculated as endpoint value minus baseline value where endpoint was defined as the average of the last (week 4) week’s worth of data. Equivalence comparison was significant if Confidence interval falls entirely within (-18, 18) and contains zero. Per protocol (PP) population is defined as analysis can only be restricted to the participants who fulfill the protocol in the terms of the eligibility, interventions, and outcome assessment.
    End point type
    Primary
    End point timeframe
    Baseline and Week 4
    End point values
    		 FSC 100/50mcg (BID)+FPANS (200mcg) QD FSC 100/50mcg (BID) +MON 10mg (QD) FSC 100/50mcg (BID) MON 10mg (QD)
    Number of subjects analysed
    105 [5]
    115 [6]
    78 [7]
    98 [8]
    Units: Liter per minute (L/min)
        geometric mean (standard error)
    20.8 ± 3.84
    32.4 ± 3.66
    37 ± 6.75
    1.9 ± 4.61
    Notes
    [5] - Per protocol population
    [6] - Per protocol population
    [7] - Per protocol population
    [8] - Per protocol population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FSC 100/50mcg (BID) +MON 10mg (QD) v FSC 100/50mcg (BID)
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [9]
    P-value
    		 = 0.006
    Method
    		 ANCOVA
    Parameter type
    		 Least square mean difference
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.4
         upper limit
    		 14.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.02
    Notes
    [9] - Equivalence comparison is significant if CI falls entirely within (-18, 18) and contains zero.

    Secondary: Change from baseline in daytime total nasal symptom scores.

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    End point title
    		 Change from baseline in daytime total nasal symptom scores.
    End point description
    Nasal symptoms were evaluated by the subject using 4-point (0 to 3) categorical scale, where 0-none, 1-mild, 2-moderate and 3-severe. The scores of the four component daytime symptoms (nasal congestion, itching, rhinorrhea, and sneezing) were summed to create a Daytime Total Nasal Symptom Score (D-TNSS) for each day. Change from baseline was calculated as Weeks 1-2 values minus baseline value, where values between week 1 and week 2 were averaged for Week 1-2 value. Confidence intervals and p-values are corrected for multiplicity using Hochberg’s method.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 1-2
    End point values
    		 FSC 100/50mcg (BID)+FPANS (200mcg) QD FSC 100/50mcg (BID) +MON 10mg (QD) FSC 100/50mcg (BID) MON 10mg (QD)
    Number of subjects analysed
    167 [10]
    162 [11]
    155 [12]
    167 [13]
    Units: Scores
        geometric mean (standard error)
    -3.3 ± 0.18
    -2.5 ± 0.16
    -2.3 ± 0.17
    -2.4 ± 0.15
    Notes
    [10] - ITT Population
    [11] - ITT Population
    [12] - ITT Population
    [13] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FSC 100/50mcg (BID)+FPANS (200mcg) QD v FSC 100/50mcg (BID) +MON 10mg (QD)
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least square mean difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 -0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.22

    Secondary: Change from baseline in night time total nasal symptoms.

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    End point title
    		 Change from baseline in night time total nasal symptoms. [14]
    End point description
    Nasal symptoms were evaluated by the subject using 4-point (0 to 3) categorical scale, where 0-none, 1-mild, 2-moderate and 3-severe. The sum of symptom scores assessing AM nasal congestion upon wakening, difficulty in going to sleep due to nasal symptoms, and night time awakenings due to nasal symptoms. Change from baseline was calculated as Weeks 1-2 values minus baseline value, where values between week 1 and week 2 were averaged for Week 1-2 value. Confidence intervals and p-values are corrected for multiplicity using Hochberg’s method.
    End point type
    Secondary
    End point timeframe
    Baseline to weeks 1-2
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis is presented as available. Statistical analysis is not available for all the baseline period arms.
    End point values
    		 FSC 100/50mcg (BID)+FPANS (200mcg) QD FSC 100/50mcg (BID) +MON 10mg (QD)
    Number of subjects analysed
    167 [15]
    161 [16]
    Units: Scores
        geometric mean (standard error)
    -2.1 ± 0.13
    -1.8 ± 0.12
    Notes
    [15] - ITT Population
    [16] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FSC 100/50mcg (BID)+FPANS (200mcg) QD v FSC 100/50mcg (BID) +MON 10mg (QD)
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15

    Secondary: Change from baseline at endpoint in predose AM FEV1

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    End point title
    		 Change from baseline at endpoint in predose AM FEV1 [17]
    End point description
    Forced expiratory volume in one second (FEV1) was evaluated. Change from baseline is calculated as endpoint value minus baseline value where baseline FEV1 was defined as the measure recorded on the morning of Day 1, just prior to randomization and endpoint was defined as the last available on-treatment FEV1 measure. Confidence intervals and p-values are corrected for multiplicity using Hochberg’s method.
    End point type
    Secondary
    End point timeframe
    Baseline and week 4
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis is presented as available. Statistical analysis is not available for all the baseline period arms.
    End point values
    		 FSC 100/50mcg (BID) MON 10mg (QD)
    Number of subjects analysed
    143 [18]
    153 [19]
    Units: Liter (L)
        geometric mean (standard error)
    0.21 ± 0.0277
    0.057 ± 0.026
    Notes
    [18] - ITT Population
    [19] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FSC 100/50mcg (BID) v MON 10mg (QD)
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least square mean difference
    Point estimate
    0.131
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.056
         upper limit
    		 0.207
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0335

    Secondary: Mean change from baseline in predose morning (AM) FEV1 to assess equivalence

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    End point title
    		 Mean change from baseline in predose morning (AM) FEV1 to assess equivalence [20]
    End point description
    Forced expiratory volume in one second (FEV1) was evaluated. Change from baseline is calculated as endpoint value minus baseline value where baseline FEV1 was defined as the measure recorded on the morning of Day 1, just prior to randomization and endpoint was defined as the last available on-treatment FEV1 measure. Confidence intervals and p-values are corrected for multiplicity using Hochberg’s method
    End point type
    Secondary
    End point timeframe
    Baseline and week 4
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis is presented as available. Statistical analysis is not available for all the baseline period arms.
    End point values
    		 FSC 100/50mcg (BID) +MON 10mg (QD) FSC 100/50mcg (BID)
    Number of subjects analysed
    113 [21]
    77 [22]
    Units: Liter (L)
        geometric mean (standard error)
    0.217 ± 0.0253
    0.219 ± 0.0376
    Notes
    [21] - Per protocol (PP) population
    [22] - PP Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FSC 100/50mcg (BID) +MON 10mg (QD) v FSC 100/50mcg (BID)
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [23]
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least square mean difference
    Point estimate
    0.053
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.156
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0429
    Notes
    [23] - Equivalence comparison is significant if CI falls entirely within (-0.2, 0.2) and contains zero.

    Secondary: Change from baseline in the asthma symptom free-days

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    End point title
    		 Change from baseline in the asthma symptom free-days [24]
    End point description
    Subject rated overall satisfaction with treatment was analyzed by Percentage of Asthma Symptom-free Days. Change from baseline is calculated as endpoint value minus baseline value, where, Endpoint is defined as the average of the last seven days’ worth of data. Confidence intervals and p-values are corrected for multiplicity using Hochberg’s method.
    End point type
    Secondary
    End point timeframe
    Baseline and week 4
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis is presented as available. Statistical analysis is not available for all the baseline period arms.
    End point values
    		 FSC 100/50mcg (BID) MON 10mg (QD)
    Number of subjects analysed
    155 [25]
    161 [26]
    Units: Percentage
        geometric mean (standard error)
    32.1 ± 2.99
    13.9 ± 2.43
    Notes
    [25] - ITT Population
    [26] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FSC 100/50mcg (BID) v MON 10mg (QD)
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least sqaure mean difference
    Point estimate
    18.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.7
         upper limit
    		 28.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.09

    Secondary: Change from baseline in asthma symptom-free days

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    End point title
    		 Change from baseline in asthma symptom-free days [27]
    End point description
    Subject rated overall satisfaction with treatment was analyzed by Percentage of Asthma Symptom-free Days. Change from baseline is calculated as endpoint value minus baseline value, where, Endpoint is defined as the average of the last seven days’ worth of data. Confidence intervals and p-values are corrected for multiplicity using Hochberg’s method.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis is presented as available. Statistical analysis is not available for all the baseline period arms.
    End point values
    		 FSC 100/50mcg (BID) +MON 10mg (QD) FSC 100/50mcg (BID)
    Number of subjects analysed
    115 [28]
    78 [29]
    Units: Percentage
        geometric mean (standard error)
    37.3 ± 3.72
    35.7 ± 4.18
    Notes
    [28] - PP Population
    [29] - PP Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Equivalence comparison is significant if CI falls entirely within (-15.7, 15.7) and contains zero.
    Comparison groups
    FSC 100/50mcg (BID) +MON 10mg (QD) v FSC 100/50mcg (BID)
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.017
    Method
    		 ANCOVA
    Parameter type
    		 Least square mean difference
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.6
         upper limit
    		 14.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.69

    Secondary: Change from baseline in the percentage of albuterol-free-days

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    End point title
    		 Change from baseline in the percentage of albuterol-free-days [30]
    End point description
    Overall satisfaction with treatment was analyzed by percentage of albuterol-free-days (puffs/24hour [hr]). Change from baseline is calculated as endpoint value minus baseline value, where, Endpoint is defined as the average of the last seven days’ worth of data. Confidence intervals and p-values are corrected for multiplicity using Hochberg’s method.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis is presented as available. Statistical analysis is not available for all the baseline period arms.
    End point values
    		 FSC 100/50mcg (BID) MON 10mg (QD)
    Number of subjects analysed
    155 [31]
    161 [32]
    Units: Percentage
        geometric mean (standard error)
    37 ± 3.18
    21.4 ± 2.83
    Notes
    [31] - ITT Population
    [32] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FSC 100/50mcg (BID) v MON 10mg (QD)
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least square mean difference
    Point estimate
    15.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.5
         upper limit
    		 24.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.22

    Secondary: Change from baseline in percentage of Albuterol-free days .

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    End point title
    		 Change from baseline in percentage of Albuterol-free days . [33]
    End point description
    Overall satisfaction with treatment was analyzed by Percentage of albuterol-free-days (puffs/24hr). Change from baseline is calculated as endpoint value minus baseline value, where, Endpoint is defined as the average of the last seven days’ worth of data. Confidence intervals and p-values are corrected for multiplicity using Hochberg’s method.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis is presented as available. Statistical analysis is not available for all the baseline period arms.
    End point values
    		 FSC 100/50mcg (BID) +MON 10mg (QD) FSC 100/50mcg (BID)
    Number of subjects analysed
    115 [34]
    78 [35]
    Units: Percentage
        geometric mean (standard error)
    39.1 ± 3.73
    43.4 ± 4.54
    Notes
    [34] - PP Population
    [35] - PP Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FSC 100/50mcg (BID) +MON 10mg (QD) v FSC 100/50mcg (BID)
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [36]
    P-value
    		 = 0.007
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.8
         upper limit
    		 10
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.95
    Notes
    [36] - Equivalence comparison is significant if CI falls entirely within (-19.5, 19.5) and contains zero.

    Secondary: Subject Rated Overall Satisfaction with Treatment.

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    End point title
    		 Subject Rated Overall Satisfaction with Treatment.
    End point description
    Subject-rated overall satisfaction with treatment (related to percentage of asthma symptom-free days). The satisfaction category ranged from very dissatisfied to very satisfied. The measurement type refers to the number of participants.
    End point type
    Secondary
    End point timeframe
    At Week 4
    End point values
    		 FSC 100/50mcg (BID)+FPANS (200mcg) QD FSC 100/50mcg (BID) +MON 10mg (QD) FSC 100/50mcg (BID) MON 10mg (QD)
    Number of subjects analysed
    95
    106
    71
    96
    Units: Participants
    number (not applicable)
        Very dissatisfied
    0
    0
    1
    6
        Dissatisfied
    3
    4
    3
    14
        Slightly dissatisfied
    11
    7
    12
    9
        Neutral
    12
    15
    8
    16
        Slight satisfied
    14
    19
    16
    11
        Satisfied
    29
    39
    22
    33
        Very satisfied
    26
    22
    9
    7
    No statistical analyses for this end point

    Secondary: Change from baseline in evening (PM) peak expiratory flow.

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    End point title
    		 Change from baseline in evening (PM) peak expiratory flow. [37]
    End point description
    Evening peak expiratory flow (PM PEF) was measured using the device used for spirometry assessments. Change from baseline is calculated as endpoint value minus baseline value where endpoint was defined as the average of the last (week 4) week’s worth of data. Superiority analysis was performed by comparing the values between treatment groups.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    Notes
    [37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis is presented as available. Statistical analysis is not available for all the baseline period arms.
    End point values
    		 FSC 100/50mcg (BID) MON 10mg (QD)
    Number of subjects analysed
    155 [38]
    161 [39]
    Units: Liter per minutes
        geometric mean (standard error)
    18.3 ± 3.91
    -9.7 ± 3.38
    Notes
    [38] - ITT Population
    [39] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FSC 100/50mcg (BID) v MON 10mg (QD)
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least square mean difference
    Point estimate
    25.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 16.2
         upper limit
    		 35.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.85

    Secondary: Change from Baseline in Asthma Symptom Scores.

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    End point title
    		 Change from Baseline in Asthma Symptom Scores. [40]
    End point description
    Asthma symptom scores are diary-based asthma measures related to the proportion of asthma symptom-free days. Change from baseline is calculated as endpoint value minus baseline value where endpoint was defined as the average of the last (week 4) week’s worth of data. Superiority analysis was performed by comparing the values between treatment groups.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    Notes
    [40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis is presented as available. Statistical analysis is not available for all the baseline period arms.
    End point values
    		 FSC 100/50mcg (BID) MON 10mg (QD)
    Number of subjects analysed
    157 [41]
    170 [42]
    Units: Scores
        geometric mean (standard error)
    -1.3 ± 0.07
    -1 ± 0.09
    Notes
    [41] - ITT Population
    [42] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FSC 100/50mcg (BID) v MON 10mg (QD)
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least square mean difference
    Point estimate
    -0.346
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.539
         upper limit
    		 -0.152
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0985

    Secondary: Mean Change from Baseline in daily albuterol use.

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    End point title
    		 Mean Change from Baseline in daily albuterol use. [43]
    End point description
    Daily albuterol use (puffs/24hr) is a diary-based asthma measures. Change from baseline is calculated as endpoint value minus baseline value where endpoint was defined as the average of the last (week 4) week’s worth of data. Superiority analysis was performed by comparing the values between treatment groups.
    End point type
    Secondary
    End point timeframe
    Baseline to endpoint
    Notes
    [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis is presented as available. Statistical analysis is not available for all the baseline period arms.
    End point values
    		 FSC 100/50mcg (BID) MON 10mg (QD)
    Number of subjects analysed
    155 [44]
    161 [45]
    Units: Puffs per 24 hours
        geometric mean (standard error)
    -1.5 ± 0.14
    -1 ± 0.15
    Notes
    [44] - ITT Population
    [45] - ITT Population
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Daytime Nasal Congestion Symptom Score.

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    End point title
    		 Mean Change from Baseline in Daytime Nasal Congestion Symptom Score. [46]
    End point description
    Nasal congestion symptom score were evaluated by the subject using 4-point (0 to 3) categorical scale, where 0-none, 1-mild, 2-moderate and 3-severe. Change from baseline is calculated as treatment Week 1-2 value minus baseline value where Week 1-2 was defined as the average of data recorded from Day 2 to Day 15. Superiority analysis was performed by comparing the values between treatment groups.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 1-2
    Notes
    [46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis is presented as available. Statistical analysis is not available for all the baseline period arms.
    End point values
    		 FSC 100/50mcg (BID)+FPANS (200mcg) QD FSC 100/50mcg (BID) +MON 10mg (QD)
    Number of subjects analysed
    168 [47]
    165 [48]
    Units: Score on scale
        geometric mean (standard error)
    -0.8 ± 0.05
    -0.6 ± 0.04
    Notes
    [47] - ITT Population
    [48] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    FSC 100/50mcg (BID)+FPANS (200mcg) QD v FSC 100/50mcg (BID) +MON 10mg (QD)
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse event (SAE) and non serious adverse event (non-SAE) was analyzed up to 4 week of the study.
    Adverse event reporting additional description
    All AE were based on the ITT population. AEs were sorted by system organ class (SOC).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    FSC 100/50mcg (BID)+FPANS (200mcg) QD
    Reporting group description
    		 Participants received fluticasone propionate/salmeterol (FSC) 100/50microgram (mcg) Inhalation powder twice daily (BID) and fluticasone propionate aqueous nasal spray (FPANS) 200mcg once daily (QD) and placebo capsule once daily for four weeks.

    Reporting group title
    FSC 100/50mcg (BID) +MON 10mg (QD)
    Reporting group description
    		 Participants received fluticasone propionate/salmeterol 100/50mcg Inhalation powder twice daily, Montelukast (MON) 10mg capsule once daily and vehicle placebo nasal spray once daily for four weeks.

    Reporting group title
    FSC 100/50mcg (BID)
    Reporting group description
    		 Participants received fluticasone propionate/salmeterol 100/50mcg Inhalation powder twice daily, vehicle placebo nasal spray once daily and placebo capsule once daily for four weeks.

    Reporting group title
    MON 10mg (QD)
    Reporting group description
    		 Participants received Montelukast 10mg capsule once daily, placebo via dry powder inhaler BID, and vehicle placebo nasal spray QD for four weeks.

    Serious adverse events
    		 FSC 100/50mcg (BID)+FPANS (200mcg) QD FSC 100/50mcg (BID) +MON 10mg (QD) FSC 100/50mcg (BID) MON 10mg (QD)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 165 (0.00%)
    0 / 157 (0.00%)
    1 / 170 (0.59%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Pelvic fracture
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 165 (0.00%)
    0 / 157 (0.00%)
    1 / 170 (0.59%)
         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
    		 FSC 100/50mcg (BID)+FPANS (200mcg) QD FSC 100/50mcg (BID) +MON 10mg (QD) FSC 100/50mcg (BID) MON 10mg (QD)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 168 (7.74%)
    8 / 165 (4.85%)
    7 / 157 (4.46%)
    17 / 170 (10.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 168 (7.74%)
    8 / 165 (4.85%)
    7 / 157 (4.46%)
    17 / 170 (10.00%)
         occurrences all number
    15
    8
    7
    34

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jul 2005
    Replaced all instances of Ventolin Hydrofluoroalkane (HFA) with albuterol/salbutamol. Clarified selection method for best spirometry effort. Included complete rating scale for patient satisfaction with treatment questionnaire.
    17 Oct 2006
    Amended Sponsor Contact Information Page. Clarified Statistical Analyses sections.
    12 Jan 2007
    Increased number of randomized subjects, revised participating countries, expanded acceptable visit windows, and corrected administrative errors
    14 May 2007
    Amended Sponsor Contact Information Page, revised asthma therapy footnote to include ADVAIR HFA and Symbicort, and included ciclesonide as allowable prior asthma therapy

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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