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    Clinical Trial Results:
    A repeat-dose, open-label, randomized, incomplete block design in pediatric subjects with asthma, ages 4 - 11 years, to compare systemic exposure and pharmacodynamics of fluticasone propionate and salmeterol following Advair® HFA 45/21 mcg (2 inhalations), Advair HFA 45/21 mcg (2 inhalations) with Aerochamber Plus Spacer and Advair Diskus 100/50 twice daily.

    Summary
    EudraCT number
    		 2015-004866-27
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    02 Feb 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Dec 2016
    First version publication date
    19 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SAS105519
    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 4357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1-866 4357343, GSKClinicalSupportHD@gsk.com
    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
    11 Jul 2007
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Feb 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Feb 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to compare the systemic exposure and pharmacodynamics of therapeutic doses of Advair HFA
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Oct 2006
    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: 31
    Worldwide total number of subjects
    31
    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)
    31
    Adolescents (12-17 years)
    0
    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
    		 This was a repeat-dose, open-label randomized, incomplete block design study in pediatric participants with asthma, aged 4-11 years to compare systemic exposure and pharmacodynamics of Advair HFA (A), Advair DISKUS (B), and Advair HFA with Aerochamber Plus Spacer (C) in two treatment periods, with a follow-up period within 24 hours post last dose.

    Pre-assignment
    Screening details
    		 Following Baseline assessments, participants received Advair HFA 45/21 microgram (µg) (two inhalations), Advair DISKUS 100/50 µg (one inhlation), or Advair HFA with Aerochamber Plus Spacer 45/21 µg (two inhalations) twice daily for 21 days, in accordance with the treatment sequence to which they were randomized (AB,BA,AC,CA,BC,or CB).

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All study treatments
    Arm description
    		 Participants were randomized to one of the 6 possible treatment arms (AB, BC, AC, CA, BC, or CB): Treatment regimen A: two inhalations of ADVAIR HFA 45/21 µg, which was a combination of 45 µg of fluticasone propionate (FP) and 21 µg of salmeterol administered via a metered dose inhaler (MDI), treatment regimen B: Advair HFA 42/21 µg with Aerochamber Plus Spacer, or treatment regimen C: Adavir DISKUS 100/50 µg twice daily (BID) for 21 days (on outpatient basis except on Day 21) in both treatment periods without any washout period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ADVAIR HFA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Advair HFA 45/21 µg was supplied as an HFA-propelled 120-actuation MDI desgined to deliver approximately 21 µg salmeterol and 42 µg FP per actuation. Two inhalations from this device twice daily (BID) for 21 days.

    Investigational medicinal product name
    ADVAIR HFA with Aerochamber Plus Spacer
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Advair HFA 45/21 µg was supplied as supplied as a 6 mutli-dose powder inhaler (MDPI) to deliver 45 µg of salmeterol and 21 µg of fluticasone propionate (FP). Two inhalations from the DISKUS device twice daily (BID) for 21 days

    Investigational medicinal product name
    ADVAIR DISKUS
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of ADVAIR DISKUS 100/50mcg (Fluticasone, Salmeterol) will be administered twice daily for 21 days

    Number of subjects in period 1
    		All study treatments
    Started
    31
    Completed
    28
    Not completed
    3
         Consent withdrawn by subject
    2
         Missing
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study
    Reporting group description
    		 -

    Reporting group values
    		 Overall study Total
    Number of subjects
    		 31 31
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 7.16 ± 2.423 -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 24 24
    Race
    Units: Subjects
        AfricanAmerican/African Heritage
    		 2 2
        Asian-South East Asian Heritage
    		 1 1
        Native Hawaiian or Other Pacific Islander
    		 1 1
        White-Arabic/North African Heritage
    		 2 2
        White-White/Caucasian/European Heritage
    		 25 25

    End points

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    End points reporting groups
    Reporting group title
    All study treatments
    Reporting group description
    		 Participants were randomized to one of the 6 possible treatment arms (AB, BC, AC, CA, BC, or CB): Treatment regimen A: two inhalations of ADVAIR HFA 45/21 µg, which was a combination of 45 µg of fluticasone propionate (FP) and 21 µg of salmeterol administered via a metered dose inhaler (MDI), treatment regimen B: Advair HFA 42/21 µg with Aerochamber Plus Spacer, or treatment regimen C: Adavir DISKUS 100/50 µg twice daily (BID) for 21 days (on outpatient basis except on Day 21) in both treatment periods without any washout period.

    Subject analysis set title
    Advair HFA
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants were randomized to one of the 6 possible treatment arms (AB, BA, AC, CA, BC, or CB): two inhalations of ADVAIR HFA 45/21 µg , which was supplied as a HFA-propelled 120-actuation metered dose inhaler (MDI) desgined to deliver 45 µg of fluticasone propionate (FP) and 21 µg of salmeterol twice daily (BID) for 21 days (on outpatient basis except on Day 21) along with either Advair HFA with Aerochamber Plus Spacer or Adavir DISKUS. After this treatment period 1, participants received a repeat dosing of the same sequence for 21 days without any washout period.

    Subject analysis set title
    Advair HFA with Spacer
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants were randomized to one of the 6 possible treatment arms (AB, BA, AC, CA, BC, or CB): two inhalations of ADVAIR HFA 45/21 µg with Aerochamber Plus Spacer, which was supplied as a metered dose inhaler (MDI) designed to deliver 45 µg of FP and 21 µg of salmeterol twice daily (BID) for 21 days (on outpatient basis except on Day 21) along with either Advair HFA or Adavir DISKUS. After this treatment period 1, participants received a repeat dosing of the same sequence for 21 days without any washout period.

    Subject analysis set title
    Advair DISKUS
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants were randomized to one of the 6 possible treatment arms (AB, BA, AC, CA, BC or CB): one inhalation of ADVAIR DISKUS 100/50 µg, which was supplied as a 60-dose multi-dose powder inhaler (MPDI) designed to deliver 100 µg of FP and 50 µg of salmeterol twice daily (BID) for 21 days (on outpatient basis except on Day 21) along with either Advair HFA with Aerochamber Plus Spacer or Adavir HFA. After this treatment period 1, participants received a repeat dosing of the same sequence for 21 days without any washout period.

    Primary: Weighted mean serum cortisol (SC) over 0 to 12 hours (h; 0-12 h) post-dose for fluticasone propionate (FP)

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    End point title
    		 Weighted mean serum cortisol (SC) over 0 to 12 hours (h; 0-12 h) post-dose for fluticasone propionate (FP)
    End point description
    Participants' blood samples were collected and analyzed for SC levels. The serum cortisol weighted mean, calculated by dividing the area under the concentration curve (AUC) over the 0-12 h period by the sample collection time interval, was determined at Baseline and at the end of each treatment period. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title. Pharmacodynamic (PD) parameter population was defined as all participants who received treatment during both periods and for whom PD parameters were derived for both periods.
    End point type
    Primary
    End point timeframe
    Baseline and 0, 2, 4, 8, and 12 h post-dose on Day 21 of each treatment period
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [1]
    19 [2]
    20 [3]
    Units: Nanomoles per liter (nmol/L)
        geometric mean (confidence interval 95%)
    0.86 (0.77 to 0.96)
    0.78 (0.7 to 0.86)
    0.87 (0.79 to 0.97)
    Notes
    [1] - Pharmacodynamic (PD) Parameter Population
    [2] - Pharmacodynamic (PD) Parameter Population
    [3] - Pharmacodynamic (PD) Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair DISKUS v Advair HFA
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.062
    Notes
    [4] - If the two-sided CI for the ratio of geometric means for the two formulations is contained within the range of 0.7 to 1.43, the two formulations were deemed comparable.
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair DISKUS v Advair HFA with Spacer
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.061
    Notes
    [5] - If the two-sided CI for the ratio of geometric means for the two formulations is contained within the range of 0.7 to 1.43, the two formulations were deemed comparable.
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA with Spacer v Advair HFA
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.064
    Notes
    [6] - If the two-sided CI for the ratio of geometric means for the two formulations is contained within the range of 0.7 to 1.43, the two formulations were deemed comparable.

    Primary: Serum cortisol minimum (Cmin) over 0-12 h post-dose for FP

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    End point title
    		 Serum cortisol minimum (Cmin) over 0-12 h post-dose for FP
    End point description
    Blood samples of participants were collected for the evaluation of Cmin. Any differences in systemic exposure as a result of the absorbed steroid component of the three differing inhaled treatments should also result in differences in serum cortisol concentrations. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).
    End point type
    Primary
    End point timeframe
    At Baseline and 0, 2, 4, 8, and 12 h post-dose on Day 21 of each treatment period
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [7]
    19 [8]
    20 [9]
    Units: Nanomoles/liter (nmol/L)
        geometric mean (confidence interval 95%)
    0.9 (0.69 to 1.18)
    0.67 (0.52 to 0.87)
    1.09 (0.84 to 1.4)
    Notes
    [7] - Pharmacodynamic (PD) Parameter Population
    [8] - Pharmacodynamic (PD) Parameter Population
    [9] - Pharmacodynamic (PD) Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair HFA v Advair DISKUS
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.185
    Notes
    [10] - If the two-sided CI for the ratio of geometric means for the two formulations is contained within the range of 0.7 to 1.43, the two formulations were deemed comparable.
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair DISKUS v Advair HFA with Spacer
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.183
    Notes
    [11] - If the two-sided CI for the ratio of geometric means for the two formulations is contained within the range of 0.7 to 1.43, the two formulations were deemed comparable.
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA with Spacer v Advair HFA
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.189
    Notes
    [12] - If the two-sided CI for the ratio of geometric means for the two formulations is contained within the range of 0.7 to 1.43, the two formulations were deemed comparable.

    Secondary: Maximum mean change from Baseline of the QT Interval Corrected According to Bazett’s Formula (QTcB) at 9 hours post-dose

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    End point title
    		 Maximum mean change from Baseline of the QT Interval Corrected According to Bazett’s Formula (QTcB) at 9 hours post-dose
    End point description
    Twelve-lead electrocardiogram was performed to measure QTcB at Baseline, pre-dose and at 15 min, 45 min, 1.5 h, 3h, 6 h and 9 h post-dose on Day 21 of each treatment period and maximum value for QTcB was derived during the 0-9 h period. Baseline was defined as the derived parameter from the Baseline assessment. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title). Pharmacodynamic (PD) parameter population was defined as all participants who received treatment during both periods and for whom PD parameters were derived for both periods.
    End point type
    Secondary
    End point timeframe
    At Baseline, and pre-dose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [13]
    19 [14]
    20 [15]
    Units: Milliseconds (ms)
        arithmetic mean (standard error)
    3.6 ± 2.2
    -2.2 ± 2.14
    0.4 ± 2.08
    Notes
    [13] - Pharmacodynamic (PD) Parameter Population
    [14] - Pharmacodynamic (PD) Parameter Population
    [15] - Pharmacodynamic (PD) Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair HFA v Advair DISKUS
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of adjusted means
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 8.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.73
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair DISKUS v Advair HFA with Spacer
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of adjusted means
    Point estimate
    -2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8
         upper limit
    		 2.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.69
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA with Spacer v Advair HFA
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of adjusted means
    Point estimate
    -5.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.5
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.82

    Secondary: Weighted mean change from Baseline of the QT Interval Corrected According to Bazett’s Formula (QTcB) at 9 hours post-dose

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    End point title
    		 Weighted mean change from Baseline of the QT Interval Corrected According to Bazett’s Formula (QTcB) at 9 hours post-dose
    End point description
    Twelve-lead electrocardiograms were performed to measure QTcB at Baseline, pre-dose and 15 min, 45 min, 1.5 h, 3h, 6 h and 9 h post-dose on Day 21 of each treatment period. Baseline was defined as the derived parameter from the Baseline assessment. Weighted mean (WM) was derived by calculating the area under curve (AUC), and then dividing by the relevant time interval. The data are presented as the adjusted means of WM. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).
    End point type
    Secondary
    End point timeframe
    At Baseline, and pre-dose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [16]
    19 [17]
    20 [18]
    Units: Milliseconds (ms)
        arithmetic mean (standard error)
    5 ± 1.61
    0.1 ± 1.62
    1 ± 1.53
    Notes
    [16] - PD Parameter Population
    [17] - PD Parameter Population
    [18] - PD Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair HFA v Advair DISKUS
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of adjusted means
    Point estimate
    4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 7.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.9
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair DISKUS v Advair HFA with Spacer
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of adjusted means
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.9
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA with Spacer v Advair HFA
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of adjusted means
    Point estimate
    -4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.1
         upper limit
    		 -0.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.03

    Secondary: Maximum mean change from Baseline of the QT Interval Corrected According to Fridericia's Formula (QTcF) at 9 hours post-dose

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    End point title
    		 Maximum mean change from Baseline of the QT Interval Corrected According to Fridericia's Formula (QTcF) at 9 hours post-dose
    End point description
    Twelve-lead electrocardiograms (ECGs) were performed to measure QT interval corrected according to Fridericia's formula (QTcF) at Baseline, pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 3h, 6 h and 9 h post-dose on Day 21 of each treatment period and the maximum values for QTcF were derived during the 0-9 h period. Baseline was defined as the derived parameter from the Baseline assessment. The data are presented as adjusted means of the maximum QTcF. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).
    End point type
    Secondary
    End point timeframe
    At Baseline, and pre-dose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [19]
    19 [20]
    20 [21]
    Units: Milliseconds (ms)
        arithmetic mean (standard error)
    -0.9 ± 1.88
    -4 ± 1.83
    -4.4 ± 1.79
    Notes
    [19] - PD Parameter Population
    [20] - PD Parameter Population
    [21] - PD Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair HFA v Advair DISKUS
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of adjusted means
    Point estimate
    3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 8
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.26
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair DISKUS v Advair HFA with Spacer
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of adjusted means
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 5
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.24
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA with Spacer v Advair HFA
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of adjusted means
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.8
         upper limit
    		 1.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.35

    Secondary: Weighted mean change from Baseline of the QT Interval Corrected According to Fridericia's Formula (QTcF) at 9 hours post-dose

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    End point title
    		 Weighted mean change from Baseline of the QT Interval Corrected According to Fridericia's Formula (QTcF) at 9 hours post-dose
    End point description
    Twelve-lead ECGs (electrocardiograms) were performed to measure QTcF at Baseline, pre-dose and 15 minutes (min), 45 min, 1.5 h, 3h, 6 h and 9 h post-dose on Day 21 of each treatment period. Baseline was defined as the derived parameter from the Baseline assessment. Weighted mean (WM) was derived by calculating the AUC, and then dividing by the relevant time interval. Data are presented as the adjusted means of WM. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).
    End point type
    Secondary
    End point timeframe
    At Baseline, and pre-dose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [22]
    18 [23]
    20 [24]
    Units: Milliseconds (ms)
        arithmetic mean (standard error)
    1.9 ± 1.28
    -3.3 ± 1.28
    -3.6 ± 1.2
    Notes
    [22] - PD Parameter Population
    [23] - PD Parameter Population
    [24] - PD Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair HFA v Advair DISKUS
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of adjusted means
    Point estimate
    5.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.2
         upper limit
    		 8.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.65
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair DISKUS v Advair HFA with Spacer
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of adjusted means
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 3.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.65
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA with Spacer v Advair HFA
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of adjusted means
    Point estimate
    -5.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.7
         upper limit
    		 -1.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.74

    Secondary: Maximum mean change from Baseline of the supine heart rate at 9 hours post-dose

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    End point title
    		 Maximum mean change from Baseline of the supine heart rate at 9 hours post-dose
    End point description
    Heart rate was recorded at Screening, prior to dosing, and at 15 minutes, 45 minutes, 1.5, 3, 6 and 9 h post-dose on Day 21of each treatment period. Baseline was defined as the derived parameter from the Baseline assessment. Heart rate measurement was taken in a supine position having rested in this position for at least 10 min before each reading. The maximum observed value of heart rate was measured and data are presented as adjusted mean of maximum heart rate. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).
    End point type
    Secondary
    End point timeframe
    At Baseline, and pre-dose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [25]
    19 [26]
    20 [27]
    Units: Beats per minute (bpm)
        arithmetic mean (standard error)
    3.7 ± 2.31
    -0.1 ± 2.26
    4.8 ± 2.19
    Notes
    [25] - PD Parameter Population
    [26] - PD Parameter Population
    [27] - PD Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair HFA v Advair DISKUS
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of adjusted means
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.8
         upper limit
    		 4.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.82
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair DISKUS v Advair HFA with Spacer
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of adjusted means
    Point estimate
    -5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.6
         upper limit
    		 0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.79
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA with Spacer v Advair HFA
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of adjusted means
    Point estimate
    -3.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.8
         upper limit
    		 2.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.92

    Secondary: Weighted Mean change from Baseline of supine heart rate at 9 hours post-dose

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    End point title
    		 Weighted Mean change from Baseline of supine heart rate at 9 hours post-dose
    End point description
    Heart rate was recorded at Screening, prior to dosing, and at 15 min, 45 min, 1.5, 3, 6 and 9 h post-dose on Day 21of each treatment period. Baseline was defined as the derived parameter from the Baseline assessment. Heart rate measurement was taken in a supine position having rested in this position for at least 10 min before each reading. Weighted mean (WM) was derived by calculating the AUC, and then dividing by the relevant time interval. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).
    End point type
    Secondary
    End point timeframe
    At Baseline, and pre-dose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [28]
    18 [29]
    20 [30]
    Units: Bpm
        arithmetic mean (standard error)
    4.1 ± 1.52
    3.2 ± 1.53
    5.8 ± 1.44
    Notes
    [28] - PD Parameter Population
    [29] - PD Parameter Population
    [30] - PD Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair HFA v Advair DISKUS
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of treatment ratios
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.8
         upper limit
    		 2.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.03
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair DISKUS v Advair HFA with Spacer
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of treatment ratios
    Point estimate
    -2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.7
         upper limit
    		 1.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.03
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA with Spacer v Advair HFA
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of treatment ratios
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.2
         upper limit
    		 3.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.13

    Secondary: Maximum change from Baseline for supine systolic blood pressure (SBP) at 9 hours post-dose

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    End point title
    		 Maximum change from Baseline for supine systolic blood pressure (SBP) at 9 hours post-dose
    End point description
    Blood pressure (BP) measurement included supine SBP and diastolic BP (DBP). SBP was recorded at screening, prior to dosing, and at 15 min, 45 min, 1.5,2, 4, 6 and 9 h post-dose on Day 21 of the each treatment period. The maximum observed values for SBP from the time of the morning dose on Day 21 to 9 h post-dose were measured and the data are presented as adjusted mean of maximum SBP. Baseline was defined as the derived parameter from the Baseline assessment. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).
    End point type
    Secondary
    End point timeframe
    At Baseline, and pre-dose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [31]
    19 [32]
    20 [33]
    Units: Millimeters of mercury (mmHg)
        arithmetic mean (standard error)
    0.4 ± 1.46
    0.7 ± 1.43
    -1.5 ± 1.39
    Notes
    [31] - PD Parameter Population
    [32] - PD Parameter Population
    [33] - PD Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair HFA v Advair DISKUS
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of treatment ratios
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 5.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.72
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair HFA with Spacer v Advair DISKUS
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of treatment ratios
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 5.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.71
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA with Spacer v Advair HFA
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of treatment ratios
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.79

    Secondary: Minimum change from Baseline of the supine diastolic BP (DBP) at 9 hours post-dose

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    End point title
    		 Minimum change from Baseline of the supine diastolic BP (DBP) at 9 hours post-dose
    End point description
    Blood pressure (BP) measurement included supine SBP and DBP. DBP were recorded at screening, prior to dosing, and at 15 min, 45 min, 1.5,2, 4, 6 and 9 h post-dose on Day 21 of the each treatment period. Baseline was defined as the derived parameter from the Baseline assessment. The minimum observed values from the time of the morning dose on Day 21 to 9 hours post dose were measured and the data are presented as adjusted mean of minimum DBP. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).
    End point type
    Secondary
    End point timeframe
    At Baseline, and pre-dose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [34]
    19 [35]
    20 [36]
    Units: mmHg
        arithmetic mean (standard error)
    -3.3 ± 1.03
    1 ± 1.01
    -1.3 ± 0.98
    Notes
    [34] - PD Parameter Population
    [35] - PD Parameter Population
    [36] - PD Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair DISKUS v Advair HFA
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of treatment ratios
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.7
         upper limit
    		 0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.33
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair DISKUS v Advair HFA with Spacer
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of treatment ratios
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 4.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.31
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA v Advair HFA with Spacer
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of treatment ratios
    Point estimate
    4.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.37

    Secondary: Weighted mean change from Baseline for supine SBP at 9 hours post-dose

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    End point title
    		 Weighted mean change from Baseline for supine SBP at 9 hours post-dose
    End point description
    Blood pressure (BP) measurement included supine SBP and DBP. SBP was recorded at screening, prior to dosing, and at 15 min, 45 min, 1.5,2, 4, 6 and 9 h post-dose on Day 21 of the each treatment period. Weighted mean (WM) was derived by calculating the AUC, and then dividing by the relevant time interval. Baseline was defined as the derived parameter from the Baseline assessment. The data are presented as adjusted mean of WM SBP. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).
    End point type
    Secondary
    End point timeframe
    At Baseline, and pre-dose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [37]
    19 [38]
    20 [39]
    Units: mmHg
        arithmetic mean (standard error)
    0.6 ± 1.37
    1.1 ± 1.34
    -2.2 ± 1.3
    Notes
    [37] - PD Parameter Population
    [38] - PD Parameter Population
    [39] - PD Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair HFA v Advair DISKUS
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of treatment ratios
    Point estimate
    2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 6.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.7
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair DISKUS v Advair HFA with Spacer
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of treatment ratios
    Point estimate
    3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 6.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.68
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA with Spacer v Advair HFA
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of treatment ratios
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 4.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.76

    Secondary: Weighted mean change from Baseline for supine DBP at 9 hours post-dose

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    End point title
    		 Weighted mean change from Baseline for supine DBP at 9 hours post-dose
    End point description
    Blood pressure (BP) measurement included SBP and DBP. DBP was recorded at screening, prior to dosing, and at 15 min, 45 min, 1.5,2, 4, 6 and 9 h post-dose on Day 21 of the each treatment period. Weighted mean (WM) was derived by calculating the AUC, and then dividing by the relevant time interval. Baseline was defined as the derived parameter from the Baseline assessment. The data are presented as adjusted mean of WM DBP. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).
    End point type
    Secondary
    End point timeframe
    At Baseline, and pre-dose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [40]
    19 [41]
    20 [42]
    Units: mmHg
        arithmetic mean (standard error)
    -1.7 ± 0.89
    -0.9 ± 0.87
    -1.7 ± 0.85
    Notes
    [40] - PD Parameter Population
    [41] - PD Parameter Population
    [42] - PD Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair HFA v Advair DISKUS
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of treatment ratios
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 2.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.09
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair DISKUS v Advair HFA with Spacer
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of treatment ratios
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 3.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.09
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA with Spacer v Advair HFA
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of treatment ratios
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 3.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.14

    Secondary: Area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC[last]) for FP

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    End point title
    		 Area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC[last]) for FP
    End point description
    Blood samples were collected to determine the plasma concentrations of FP from pre-dose up to 12 hour post-dose of each treatment period to derive the AUC(0-t). Blood samples for PK analysis of FP were obtained on Day 21 at pre-dose and 30 minutes (min), 1 hour (h), 2,4,8, and12 h post FP dose administration. For 8 and 12 h post dose, two 4 mL blood samples were collected. Pharmacokinetic (PK) Parameter Population was defined as all participants who received treatment during both treatment periods and for whom PK parameters were derived for both periods.
    End point type
    Secondary
    End point timeframe
    At pre-morning dose, 30 min, 1, 2, 4, 8, and 12 h post-dose on Day 21 of Treatments periods 1 and 2
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [43]
    19 [44]
    20 [45]
    Units: Picograms hrs per milliliter (pg.hr/mL)
        geometric mean (confidence interval 95%)
    24.063 (9.624 to 60.165)
    107.381 (45.714 to 252.236)
    137.592 (69.258 to 273.245)
    Notes
    [43] - PK Parameter Population
    [44] - PK Parameter Population
    [45] - PK Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair HFA v Advair DISKUS
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.512
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair HFA v Advair HFA with Spacer
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    4.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.7
         upper limit
    		 10.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.529
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA with Spacer v Advair DISKUS
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 1.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.507

    Secondary: AUC(last) for Salmeterol

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    End point title
    		 AUC(last) for Salmeterol
    End point description
    Blood samples were collected to determine the plasma concentrations of Salmeterol from pre-dose up to 4 hour post-dose of each treatment period to derive the AUC(0-t). Blood samples for PK analysis of salmeterol were obtained on Day 21 at pre-dose and 30 minutes (min), 1 hour (h), 2 h, and 4 h post salmeterol dose administration. One 4 mL sample was also collected at 10 min post dose on Day 21.
    End point type
    Secondary
    End point timeframe
    At pre-morning dose, 10 minutes (min), 30 min, 1, 2, and 4 h post-dose on Day 21 of Treatments periods 1 and 2
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [46]
    19 [47]
    20 [48]
    Units: pg.hr/mL
        geometric mean (confidence interval 95%)
    125.702 (70.339 to 224.639)
    103.417 (53.576 to 199.623)
    110.139 (55.383 to 219.03)
    Notes
    [46] - PK Parameter Population
    [47] - PK Parameter Population
    [48] - PK Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair HFA v Advair DISKUS
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 2.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.437
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair HFA v Advair HFA with Spacer
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.75
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.448
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA with Spacer v Advair DISKUS
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 1.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.431

    Secondary: Maximum observed plasma concentration (Cmax) at steady state for FP

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    End point title
    		 Maximum observed plasma concentration (Cmax) at steady state for FP
    End point description
    Blood samples were collected to determine the plasma concentrations of FP from pre-dose up to 12 hour post-dose of each treatment period to derive the Cmax. Blood samples for PK analysis of FP were obtained on Day 21 at pre-dose and 30 minutes (min), 1 hour (h), 2 h, 4 h, 8 h, 12 h post FP dose administration. For 8 and 12 h post dose, two 4 mL blood samples were collected.
    End point type
    Secondary
    End point timeframe
    At pre-morning dose, 30 min, 1, 2, 4, 8, and 12 h post-dose on Day 21 of Treatments periods 1 and 2
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [49]
    19 [50]
    20 [51]
    Units: Picogram per millimeter (pg/mL)
        geometric mean (confidence interval 95%)
    15.705 (8.493 to 29.043)
    35.048 (20.359 to 60.335)
    54.369 (33.078 to 89.362)
    Notes
    [49] - PK Parameter Population
    [50] - PK Parameter Population
    [51] - PK Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair HFA v Advair DISKUS
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair HFA v Advair HFA with Spacer
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.18
         upper limit
    		 3.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.342
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA with Spacer v Advair DISKUS
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 0.98
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.327

    Secondary: Cmax at steady state for salmeterol

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    End point title
    		 Cmax at steady state for salmeterol
    End point description
    Blood samples were collected to determine the plasma concentrations of Salmeterol from pre-dose up to 4 hour post-dose of each treatment period to derive the Cmax. Blood samples for PK analysis of salmeterol were obtained on Day 21 at pre-dose and 30 minutes (min), 1 hour (h), 2 h, and 4 h post salmeterol dose administration. One 4 mL sample was also collected at 10 min post dose on Day 21.
    End point type
    Secondary
    End point timeframe
    At pre-morning dose, 10 minutes (min), 30 min, 1, 2, and 4 h post-dose on Day 21 of Treatments periods 1 and 2
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [52]
    19 [53]
    20 [54]
    Units: pg/mL
        geometric mean (confidence interval 95%)
    73.932 (51.987 to 105.14)
    121.196 (77.467 to 189.61)
    96.53 (60.422 to 154.215)
    Notes
    [52] - PK Parameter Population
    [53] - PK Parameter Population
    [54] - PK Parameter Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advair HFA v Advair DISKUS
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.291
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Advair HFA v Advair HFA with Spacer
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    1.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 2.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.298
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Advair HFA with Spacer v Advair DISKUS
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of adjusted geometric means
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 2.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.287

    Secondary: Time to occurrence of Cmax (Tmax) at steady state for FP and salmeterol

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    End point title
    		 Time to occurrence of Cmax (Tmax) at steady state for FP and salmeterol
    End point description
    Blood samples were collected to determine the plasma concentrations of FP and salmeterol from pre-dose up to 12 h post-dose of each treatment period to derive tmax. Blood samples of participants were collected for evaluating Tmax. Tmax is a measure of the time required to reach the maximum concentration of the drug. Blood samples for PK analysis were obtained on Day 21 at pre-dose and 30 minutes (min), 1 hour (h), 2 h, 4 h, 8 h, 12 h post FP dose administration. One 4 mL sample was also collected at 10 min post dose on Day 21. For 8 and 12 h post dose, two 4 mL blood samples were collected.
    End point type
    Secondary
    End point timeframe
    At pre-morning dose, 10 minutes (min), 30 min, 1, 2, 4, 8, and 12 h post-dose on Day 21 of Treatments periods 1 and 2
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    18 [55]
    19 [56]
    20 [57]
    Units: Hour (hr)
    median (full range (min-max))
        Fluticasone propionate
    0.74 (0.47 to 2.02)
    0.98 (0 to 8.17)
    0.5 (0 to 1)
        Salmeterol
    0.2 (0.03 to 2.02)
    0.17 (0.08 to 0.22)
    0.175 (0.13 to 1.97)
    Notes
    [55] - PK Parameter Population
    [56] - PK Parameter Population
    [57] - PK Parameter Population
    No statistical analyses for this end point

    Secondary: Number of paritcipants with any adverse event (AE) or serious adverse event (SAE)

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    End point title
    		 Number of paritcipants with any adverse event (AE) or serious adverse event (SAE)
    End point description
    An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any AE with onset after the start dose of the study medication and on or before the follow-up phone call were collected. All Subjects Population was defined as all participants who received at least one study treatment.
    End point type
    Secondary
    End point timeframe
    From the first dose of the study medication until follow-up period (Up to 7 weeks)
    End point values
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Number of subjects analysed
    21 [58]
    19 [59]
    20 [60]
    Units: Participants
        Adverse event
    13
    9
    14
        Serious adverse event
    0
    0
    0
    Notes
    [58] - All Subjects Population
    [59] - All Subjects Population
    [60] - All Subjects Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from start of IP (Session 1) until Week 7 including the follow-up period.
    Adverse event reporting additional description
    On-treatment SAEs and non-serious AEs are reported for all Subjects Population, comprised of all participants who received at least one dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Advair HFA
    Reporting group description
    		 Participants were randomized to one of the 6 possible treatment arms (AB, BA, AC, CA, BC, or CB): two inhalations of ADVAIR HFA 45/21 µg , which was supplied as a HFA-propelled 120-actuation metered dose inhaler (MDI) desgined to deliver 45 µg of fluticasone propionate (FP) and 21 µg of salmeterol twice daily (BID) for 21 days (on outpatient basis except on Day 21) along with either Advair HFA with Aerochamber Plus Spacer or Adavir DISKUS. After this treatment period 1, participants received a repeat dosing of the same sequence for 21 days without any washout period.

    Reporting group title
    Advair HFA with Spacer
    Reporting group description
    		 Participants were randomized to one of the 6 possible treatment arms (AB, BA, AC, CA, BC, or CB): two inhalations of ADVAIR HFA 45/21 µg with Aerochamber Plus Spacer, which was supplied as a metered dose inhaler (MDI) designed to deliver 45 µg of FP and 21 µg of salmeterol twice daily (BID) for 21 days (on outpatient basis except on Day 21) along with either Advair HFA or Adavir DISKUS. After this treatment period 1, participants received a repeat dosing of the same sequence for 21 days without any washout period.

    Reporting group title
    Advair DISKUS
    Reporting group description
    		 Participants were randomized to one of the 6 possible treatment arms (AB, BA, AC, CA, BC or CB): one inhalation of ADVAIR DISKUS 100/50 µg, which was supplied as a 60-dose multi-dose powder inhaler (MPDI) desgined to deliver 100 µg of FP and 50 µg of salmeterol twice daily (BID) for 21 days (on outpatient basis except on Day 21) along with either Advair HFA with Aerochamber Plus Spacer or Adavir HFA. After this treatment period 1, participants received a repeat dosing of the same sequence for 21 days without any washout period.

    Serious adverse events
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Advair HFA Advair HFA with Spacer Advair DISKUS
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 21 (61.90%)
    9 / 19 (47.37%)
    14 / 20 (70.00%)
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 19 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    2
    0
    2
    Chest pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 21 (42.86%)
    3 / 19 (15.79%)
    5 / 20 (25.00%)
         occurrences all number
    23
    4
    9
    Rhinorrhoea
         subjects affected / exposed
    4 / 21 (19.05%)
    3 / 19 (15.79%)
    5 / 20 (25.00%)
         occurrences all number
    7
    3
    9
    Nasal congestion
         subjects affected / exposed
    5 / 21 (23.81%)
    1 / 19 (5.26%)
    2 / 20 (10.00%)
         occurrences all number
    9
    1
    5
    Wheezing
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 19 (5.26%)
    2 / 20 (10.00%)
         occurrences all number
    2
    1
    3
    Dyspnoea
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Asthma
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Pharyngolaryngeal pain
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    4 / 20 (20.00%)
         occurrences all number
    1
    0
    4
    Gastroenteritis viral
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 19 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    2
    0
    2
    Viral infection
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Ear Infection
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Otitis media
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Sep 2006
    The purpose of this amendment was to change the study design to include a third arm to evaluate the systemic exposure and pharmacodynamics of ADVAIR HFA following administration using the Aerochamber plus Spacer. GlaxoSmithKline plans to use the Aerochamber Plus Spacer in a 12-week safety study (SFA 106484). Since systemic exposure of an inhaled drug product can vary gently depending on the mechanism of administration, the FDA recommended an assessment of the difference of systemic exposure with and without a spacer to be included in this clinical pharmacology protocol. This protocol has also been modified to remove inconsistencies in study procedures and to make clarification to the inclusion/exclusion criteria.
    09 Nov 2006
    Based on feedback at a recent investigators meeting, the inclusion criteria regarding minimum weight for eligibility in this study will be amended to facilitate in the 4 to 7 years age range. The protocol states that 1/3 of the subjects must be ≤7 years of age. However, the current weight restriction would make it difficult to reach this enrollment target. Furthermore, this amendment will clarify exclusion criteria regarding inhaled corticosteroid use.

    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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