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    Clinical Trial Results:
    A Randomized, Double-Blind, Double Dummy, Active Comparator, Parallel Group, Multicenter Study to Evaluate the Safety of Once-Daily Fluticasone Furoate/GW642444 Inhalation Powder for 52 Weeks in Adolescent and Adult Subjects with Asthma

    Summary
    EudraCT number
    		 2009-012054-20
    Trial protocol
    		 DE   Outside EU/EEA  
    Global end of trial date
    12 May 2011

    Results information
    Results version number
    		 v2(current)
    This version publication date
    22 Apr 2016
    First version publication date
    09 Feb 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Minor revisions.

    Trial information

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    Trial identification
    Sponsor protocol code
    HZA106839
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000431-PIP01-08
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Jun 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 May 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability of 12 months treatment with two strengths of Fluticasone Furoate/GW642444 Inhalation Powder once-daily in the evening in subjects 12 years of age and older with asthma.
    Protection of trial subjects
    Participants with life-threatening asthma were not enrolled in the study. Withdrawal of the participant from the trial was required if any of the following criteria were met: participant experienced a severe asthma exacerbation; worsening of asthma criteria were met; participant became pregnant; participant had an adverse event that would make continued participation in the study an unacceptable risk (in the judgment of the investigator); abnormal electrocardiogram criteria were met; abnormal Holter monitoring criteria were met; abnormal ophthalmic examination criteria were met; or liver chemistry threshold criteria were met.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Oct 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 123
    Country: Number of subjects enrolled
    Thailand: 178
    Country: Number of subjects enrolled
    United States: 279
    Country: Number of subjects enrolled
    Ukraine: 128
    Worldwide total number of subjects
    708
    EEA total number of subjects
    123
    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)
    102
    Adults (18-64 years)
    566
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were randomized in a 2:2:1 ratio to Fluticasone Furoate/GW642444 Inhalation Powder (two strengths: 200/25 micrograms (µg) once daily and 100/25 µg once daily) and fluticasone propionate 500 µg twice daily, respectively.

    Pre-assignment
    Screening details
    		 Participants meeting all inclusion criteria and none of the exclusion criteria during the screening visit entered a 2-week Run-in Period for completion of Baseline safety evaluations and to obtain Baseline measures of asthma status. At Visit 2, participants were randomized to a 52-week Double-blind Treatment Period.

    Period 1
    Period 1 title
    2-week Run-in Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Current asthma therapy at a fixed dose
    Arm description
    		 Participants were instructed to continue using an approved fixed dose of an inhaled corticosteroid (ICS) with or without an additional controller medication (i.e., long-acting beta-agonist, leukotriene modifier, etc.) for 2 weeks. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication during the Run-in Period.
    Arm type
    		 Unblinded run-in medication

    Investigational medicinal product name
    inhaled corticosteroid with or without additional controller medication
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Respiratory use
    Dosage and administration details
    fixed dose for 2 weeks

    Number of subjects in period 1
    		Current asthma therapy at a fixed dose
    Started
    617
    Completed
    503
    Not completed
    114
         Did Not Meet Continuation Criteria
    97
         Physician decision
    3
         Consent withdrawn by subject
    11
         Lost to follow-up
    2
         Protocol deviation
    1
    Period 2
    Period 2 title
    52-week Double-blind Treatment Period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FF/VI 100/25 µg OD
    Arm description
    		 Participants received Fluticasone Furoate (FF)/Vilanterol (VI) 100/25 micrograms (µg) inhalation powder once daily (OD) in the evening via the Dry Powder Inhaler (DPI), plus a placebo via DISKUS/ACCUHALER twice daily (BID), for 52 weeks. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication during the Treatment Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone furoate/vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Respiratory use
    Dosage and administration details
    100/25 micrograms (µg), once daily in the evening

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Respiratory use
    Dosage and administration details
    Matching placebo, once daily in the evening/twice daily

    Arm title
    		 FF/VI 200/25 µg OD
    Arm description
    		 Participants received FF/VI 200/25 µg inhalation powder OD in the evening via the DPI, plus a placebo via DISKUS/ACCUHALER BID, for 52 weeks. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication during the Treatment Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone furoate/vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Respiratory use
    Dosage and administration details
    200/25 µg, once daily in the evening

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Respiratory use
    Dosage and administration details
    Matching placebo, once daily in the evening/twice daily

    Arm title
    		 FP 500 µg BID
    Arm description
    		 Participants received Fluticasone Propionate (FP) 500 µg BID via DISKUS/ACCUHALER, plus a placebo via the DPI OD in the evening, for 52 weeks. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication during the Treatment Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Respiratory use
    Dosage and administration details
    500 µg, twice daily

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Respiratory use
    Dosage and administration details
    Matching placebo, once daily in the evening/twice daily

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The randomized treatment period is considered to be the baseline period. Subject disposition data are collected for members of the Intent-to-Treat Population, defined as all randomized participants who received at least a single dose of trial medication. Not all participants enrolled in the trial (participants screened and for whom a record exists on the study database) were randomized to treatment.
    Number of subjects in period 2 [2]
    		FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Started
    201
    202
    100
    Completed
    161
    161
    71
    Not completed
    40
    41
    29
         Physician decision
    1
    -
    3
         Consent withdrawn by subject
    10
    7
    9
         Adverse event, non-fatal
    5
    3
    6
         Protocol-defined Stopping Criteria
    14
    16
    4
         Lost to follow-up
    1
    3
    4
         Lack of efficacy
    1
    4
    1
         Protocol deviation
    8
    8
    2
    Notes
    [2] - 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: The randomized treatment period is considered to be the baseline period. Subject disposition data are collected for members of the Intent-to-Treat Population, defined as all randomized participants who received at least a single dose of trial medication. Not all participants enrolled in the trial (participants screened and for whom a record exists on the study database) were randomized to treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FF/VI 100/25 µg OD
    Reporting group description
    		 Participants received Fluticasone Furoate (FF)/Vilanterol (VI) 100/25 micrograms (µg) inhalation powder once daily (OD) in the evening via the Dry Powder Inhaler (DPI), plus a placebo via DISKUS/ACCUHALER twice daily (BID), for 52 weeks. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication during the Treatment Period.

    Reporting group title
    FF/VI 200/25 µg OD
    Reporting group description
    		 Participants received FF/VI 200/25 µg inhalation powder OD in the evening via the DPI, plus a placebo via DISKUS/ACCUHALER BID, for 52 weeks. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication during the Treatment Period.

    Reporting group title
    FP 500 µg BID
    Reporting group description
    		 Participants received Fluticasone Propionate (FP) 500 µg BID via DISKUS/ACCUHALER, plus a placebo via the DPI OD in the evening, for 52 weeks. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication during the Treatment Period.

    Reporting group values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID Total
    Number of subjects
    		 201 202 100 503
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39.7 ( 15.85 ) 38.5 ( 15.64 ) 38.6 ( 15.97 ) -
    Gender categorical
    Units: Subjects
        Female
    		 130 124 62 316
        Male
    		 71 78 38 187
    Race, customized
    Units: Subjects
        African American/African Heritage
    		 15 17 6 38
        Asian - East Asian Heritage
    		 0 0 1 1
        Asian - South East Asian Heritage
    		 50 51 24 125
        Asian - Mixed Race
    		 0 0 1 1
        White - Arabic/North African Heritage
    		 4 1 0 5
        White - White/Caucasian/European Heritage
    		 129 132 68 329
        White - Mixed Race
    		 2 1 0 3
        Mixed Race
    		 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Current asthma therapy at a fixed dose
    Reporting group description
    		 Participants were instructed to continue using an approved fixed dose of an inhaled corticosteroid (ICS) with or without an additional controller medication (i.e., long-acting beta-agonist, leukotriene modifier, etc.) for 2 weeks. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication during the Run-in Period.
    Reporting group title
    FF/VI 100/25 µg OD
    Reporting group description
    		 Participants received Fluticasone Furoate (FF)/Vilanterol (VI) 100/25 micrograms (µg) inhalation powder once daily (OD) in the evening via the Dry Powder Inhaler (DPI), plus a placebo via DISKUS/ACCUHALER twice daily (BID), for 52 weeks. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication during the Treatment Period.

    Reporting group title
    FF/VI 200/25 µg OD
    Reporting group description
    		 Participants received FF/VI 200/25 µg inhalation powder OD in the evening via the DPI, plus a placebo via DISKUS/ACCUHALER BID, for 52 weeks. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication during the Treatment Period.

    Reporting group title
    FP 500 µg BID
    Reporting group description
    		 Participants received Fluticasone Propionate (FP) 500 µg BID via DISKUS/ACCUHALER, plus a placebo via the DPI OD in the evening, for 52 weeks. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication during the Treatment Period.

    Primary: Number of participants with any adverse event (AE) or serious adverse event (SAE) during the Treatment Period

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    End point title
    		 Number of participants with any adverse event (AE) or serious adverse event (SAE) during the Treatment Period [1]
    End point description
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations. Refer to the General Adverse AE/SAE module for a complete list of AEs and SAEs.
    End point type
    Primary
    End point timeframe
    From the start of study medication until Visit 11 (Week 52)/Early Withdrawal
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [2]
    202 [3]
    100 [4]
    Units: participants
        Any AE
    139
    134
    73
        Any SAE
    3
    1
    7
    Notes
    [2] - ITT Population: participants randomized to treatment who received >=1 dose of study medication
    [3] - ITT Population: participants randomized to treatment who received >=1 dose of study medication
    [4] - ITT Population: participants randomized to treatment who received >=1 dose of study medication
    No statistical analyses for this end point

    Primary: Number of participants with severe asthma exacerbations during the Treatment Period

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    End point title
    		 Number of participants with severe asthma exacerbations during the Treatment Period [5]
    End point description
    A severe asthma exacerbation is defined as the deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. Courses of corticosteroids separated by 1 week or more were treated as separate severe exacerbations.
    End point type
    Primary
    End point timeframe
    From the start of study medication until Visit 11 (Week 52)/Early Withdrawal
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [6]
    202 [7]
    100 [8]
    Units: participants
    3
    6
    3
    Notes
    [6] - Intent-to-Treat (ITT) Population
    [7] - Intent-to-Treat (ITT) Population
    [8] - Intent-to-Treat (ITT) Population
    No statistical analyses for this end point

    Primary: Change from Baseline in albumin and total protein at Week 12, Week 28, and Week 52/Early Withdrawal

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    End point title
    		 Change from Baseline in albumin and total protein at Week 12, Week 28, and Week 52/Early Withdrawal [9]
    End point description
    Blood samples were collected for the measurement of albumin and total protein values at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 12, Week 28, and Week 52/Early Withdrawal
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [10]
    202 [11]
    100 [12]
    Units: Grams per liter (G/L)
    arithmetic mean (standard deviation)
        Albumin, Week 12, n=172, 182, 87
    0.1 ( 2.69 )
    0.2 ( 2.87 )
    -0.5 ( 2.64 )
        Albumin, Week 28, n=180, 176, 79
    -0.2 ( 2.68 )
    -0.3 ( 2.79 )
    -0.4 ( 2.76 )
        Albumin, Week 52, n=157, 159, 67
    -0.1 ( 2.81 )
    -0.8 ( 2.72 )
    -0.5 ( 2.54 )
        Total protein, Week 12, n=172, 182, 87
    -0.6 ( 4.13 )
    -0.1 ( 4.5 )
    -0.6 ( 3.96 )
        Total protein, Week 28, n=180, 176, 79
    -1.1 ( 3.9 )
    -1 ( 4.47 )
    -0.5 ( 4.33 )
        Total protein, Week 52, n=157, 159, 67
    -0.7 ( 4.53 )
    -1.4 ( 4.6 )
    -1 ( 4.38 )
    Notes
    [10] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [11] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [12] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Change from Baseline in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), and gamma glutamyltransferase (GGT) at Week 12, Week 28, and Week 52/Early Withdrawal

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    End point title
    		 Change from Baseline in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), and gamma glutamyltransferase (GGT) at Week 12, Week 28, and Week 52/Early Withdrawal [13]
    End point description
    Blood samples were collected for the measurement of ALP, ALT, AST, CK, and GGT values at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 12, Week 28, and Week 52/Early Withdrawal
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [14]
    202 [15]
    100 [16]
    Units: International units per liter (IU/L)
    arithmetic mean (standard deviation)
        ALP, Week 12, n=158, 165, 84
    -3 ( 18.76 )
    -2.6 ( 29.65 )
    -4.7 ( 24.47 )
        ALP, Week 28, n=180, 176, 79
    -1 ( 32.68 )
    -5.8 ( 30.56 )
    -5.7 ( 24.33 )
        ALP, Week 52, n=157, 157, 67
    -4 ( 30.67 )
    -7.2 ( 34.65 )
    -9.3 ( 27.54 )
        ALT, Week 12, n=172, 182, 87
    -1 ( 10.43 )
    -0.2 ( 13.51 )
    -0.3 ( 12.03 )
        ALT, Week 28, n=180, 176, 79
    -1.6 ( 10.08 )
    -0.1 ( 10.59 )
    0.4 ( 11.96 )
        ALT, Week 52, n=157, 159, 67
    -1.8 ( 12.4 )
    -1.3 ( 11.13 )
    -0.1 ( 9.78 )
        AST, Week 12, n=171, 181, 87
    -0.9 ( 8.07 )
    -0.3 ( 12.05 )
    0.3 ( 8.69 )
        AST, Week 28, n=179, 176, 79
    -1.4 ( 8.42 )
    -0.9 ( 11.6 )
    1.3 ( 10.65 )
        AST, Week 52, n=156, 158, 67
    -1.8 ( 8.78 )
    -1.9 ( 11.21 )
    -0.2 ( 9.22 )
        CK, Week 12, n=172, 181, 87
    10.8 ( 92.06 )
    -11.5 ( 254.71 )
    -18.3 ( 223.59 )
        CK, Week 28, n=180, 176, 79
    2 ( 68.72 )
    -9.9 ( 247.61 )
    15.3 ( 441.68 )
        CK, Week 52, n=157, 159, 67
    -0.7 ( 69.12 )
    -16.8 ( 266.48 )
    -27.7 ( 274.14 )
        GGT, Week 12, n=172, 182, 87
    0.9 ( 12.9 )
    -0.1 ( 18.23 )
    -1.7 ( 12.12 )
        GGT, Week 28, n=180, 176, 79
    3.3 ( 33.79 )
    -0.6 ( 17.63 )
    -0.2 ( 11.85 )
        GGT, Week 52, n=157, 159, 67
    2.7 ( 40.34 )
    -2.7 ( 15.99 )
    -0.5 ( 13.3 )
    Notes
    [14] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [15] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [16] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Change from Baseline in direct bilirubin, indirect bilirubin, total bilirubin, and creatinine at Week 12, Week 28, and Week 52/Early Withdrawal

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    End point title
    		 Change from Baseline in direct bilirubin, indirect bilirubin, total bilirubin, and creatinine at Week 12, Week 28, and Week 52/Early Withdrawal [17]
    End point description
    Blood samples were collected for the measurement of direct bilirubin, indirect bilirubin, total bilirubin, and creatinine values at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 12, Week 28, and Week 52/Early Withdrawal
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [18]
    202 [19]
    100 [20]
    Units: Micromoles per liter (µmol/L)
    arithmetic mean (standard deviation)
        Direct bilirubin, Week 12, n=172, 182, 87
    -0.3 ( 0.99 )
    -0.3 ( 0.98 )
    -0.2 ( 0.93 )
        Direct bilirubin, Week 28, n=180, 176, 79
    -0.3 ( 0.97 )
    -0.2 ( 1.01 )
    -0.1 ( 0.94 )
        Direct bilirubin, Week 52, n=157, 159, 67
    -0.4 ( 0.99 )
    -0.4 ( 1 )
    -0.2 ( 0.9 )
        Indirect bilirubin, Week 12, n=172, 182, 87
    -1.4 ( 3.11 )
    -0.8 ( 2.86 )
    -0.6 ( 3.04 )
        Indirect bilirubin, Week 28, n=180, 175, 79
    -1.3 ( 3.09 )
    -0.9 ( 2.87 )
    -0.4 ( 3.14 )
        Indirect bilirubin, Week 52, n=157, 159, 67
    -2 ( 3.08 )
    -1.6 ( 2.51 )
    -0.8 ( 2.68 )
        Total bilirubin, Week 12, n=172, 182, 87
    -1.7 ( 3.62 )
    -1.1 ( 3.46 )
    -0.8 ( 3.44 )
        Total bilirubin, Week 28, n=180, 175, 79
    -1.6 ( 3.61 )
    -1.2 ( 3.55 )
    -0.5 ( 3.46 )
        Total bilirubin, Week 52, n=157, 159, 67
    -2.4 ( 3.58 )
    -2 ( 2.93 )
    -1 ( 3.14 )
        Creatinine, Week 12, n=172, 181, 87
    3 ( 10.214 )
    3.18 ( 7.983 )
    3.99 ( 8.056 )
        Creatinine, Week 28, n=180, 176, 79
    7.03 ( 19.264 )
    5.1 ( 10.316 )
    17.43 ( 92.175 )
        Creatinine, Week 52, n=157, 159, 67
    2.74 ( 9.45 )
    3.14 ( 11.31 )
    3.32 ( 9.982 )
    Notes
    [18] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [19] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [20] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Change from Baseline in chloride, carbon dioxide content/bicarbonate, glucose, potassium, sodium, and urea/blood urea nitrogen (BUN) at Week 12, Week 28, and Week 52/Early Withdrawal

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    End point title
    		 Change from Baseline in chloride, carbon dioxide content/bicarbonate, glucose, potassium, sodium, and urea/blood urea nitrogen (BUN) at Week 12, Week 28, and Week 52/Early Withdrawal [21]
    End point description
    Blood samples were collected for the measurement of chloride, carbon dioxide (CO2) content/bicarbonate, glucose, potassium, sodium, and urea/BUN values at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 12, Week 28, and Week 52/Early Withdrawal
    Notes
    [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [22]
    202 [23]
    100 [24]
    Units: Millimoles per liter (mmol/L)
    arithmetic mean (standard deviation)
        Chloride, Week 12, n=172, 182, 87
    -0.7 ( 3.43 )
    -0.4 ( 3.5 )
    0.1 ( 2.28 )
        Chloride, Week 28, n=180, 176, 79
    -0.1 ( 2.5 )
    0.2 ( 2.73 )
    -0.1 ( 2.54 )
        Chloride, Week 52, n=157, 159, 67
    -0.5 ( 2.51 )
    0 ( 2.67 )
    -0.3 ( 2.31 )
        CO2 content/bicarbonate, Week 12, n=171, 181, 87
    -0.7 ( 3.13 )
    -0.8 ( 2.91 )
    -0.2 ( 2.72 )
        CO2 content/bicarbonate, Week 28, n=179, 176, 79
    0.3 ( 2.9 )
    0.1 ( 2.61 )
    0.9 ( 2.6 )
        CO2 content/bicarbonate, Week 52, n=156, 158, 67
    -0.1 ( 2.53 )
    0.1 ( 2.51 )
    0.5 ( 2.55 )
        Glucose, Week 12, n=172, 181, 87
    0.33 ( 1.873 )
    0.17 ( 2.085 )
    0.1 ( 1.233 )
        Glucose, Week 28, n=180, 175, 79
    0.21 ( 1.547 )
    0.16 ( 1.556 )
    0.02 ( 1.442 )
        Glucose, Week 52, n=157, 159, 67
    0.45 ( 1.839 )
    0.11 ( 1.426 )
    -0.2 ( 1.191 )
        Potassium, Week 12, n=157, 165, 84
    -0.09 ( 0.572 )
    0 ( 0.721 )
    -0.03 ( 0.606 )
        Potassium, Week 28, n=179, 176, 79
    -0.12 ( 0.467 )
    -0.15 ( 0.449 )
    0.02 ( 0.617 )
        Potassium, Week 52, n=156, 156, 67
    -0.18 ( 0.461 )
    -0.12 ( 0.535 )
    -0.1 ( 0.446 )
        Sodium, Week 12, n=172, 182, 87
    -0.1 ( 2.47 )
    0.2 ( 2.61 )
    0 ( 2.24 )
        Sodium, Week 28, n=180, 176, 79
    0 ( 2.46 )
    0.2 ( 2.65 )
    0.3 ( 2.74 )
        Sodium, Week 52, n=157, 159, 67
    -0.2 ( 2.57 )
    0.1 ( 2.52 )
    0 ( 2.8 )
        Urea/BUN, Week 12, n=172, 182, 87
    0.24 ( 1.299 )
    0.36 ( 1.237 )
    0.02 ( 1.757 )
        Urea/BUN, Week 28, n=180, 176, 79
    0.16 ( 1.46 )
    0.14 ( 1.124 )
    0.41 ( 2.676 )
        Urea/BUN, Week 52, n=157, 159, 67
    0.15 ( 1.244 )
    0.13 ( 1.479 )
    -0.04 ( 1.9 )
    Notes
    [22] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [23] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [24] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Change from Baseline in the percentage of basophils, eosinophils, hematocrit, lymphocytes, monocytes, and segmented neutrophils in the blood at Week 12, Week 28, and Week 52/Early Withdrawal

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    End point title
    		 Change from Baseline in the percentage of basophils, eosinophils, hematocrit, lymphocytes, monocytes, and segmented neutrophils in the blood at Week 12, Week 28, and Week 52/Early Withdrawal [25]
    End point description
    Blood samples were collected for the measurement of the percentage of basophils, eosinophils, hematocrit, lymphocytes, monocytes, and segmented neutrophils in the blood at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 12, Week 28, and Week 52/Early Withdrawal
    Notes
    [25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [26]
    202 [27]
    100 [28]
    Units: percentage
    arithmetic mean (standard deviation)
        Basophils, Week 12, n=171, 170, 86
    -0.01 ( 0.33 )
    -0.06 ( 0.331 )
    -0.08 ( 0.32 )
        Basophils, Week 28, n=169, 169, 77
    -0.01 ( 0.319 )
    0 ( 0.338 )
    -0.06 ( 0.31 )
        Basophils, Week 52, n=155, 155, 71
    0.02 ( 0.314 )
    -0.03 ( 0.279 )
    -0.07 ( 0.319 )
        Eosinophils, Week 12, n=171, 170, 86
    -0.35 ( 4.048 )
    -0.88 ( 3.825 )
    -1.23 ( 3.391 )
        Eosinophils, Week 28, n=169, 169, 77
    -0.97 ( 3.991 )
    -1.34 ( 3.774 )
    -1.63 ( 3.574 )
        Eosinophils, Week 52, n=155, 155, 71
    -0.84 ( 4.096 )
    -0.9 ( 3.946 )
    -1.19 ( 3.611 )
        Lymphocytes, Week 12, n=171, 170, 86
    -0.57 ( 9.28 )
    -0.91 ( 8.414 )
    -1.72 ( 8.449 )
        Lymphocytes, Week 28, n=169, 169, 77
    -1.11 ( 8.816 )
    -1.31 ( 10.2 )
    -1.66 ( 11.054 )
        Lymphocytes, Week 52, n=155, 155, 71
    1.34 ( 9.389 )
    -0.03 ( 10.137 )
    -0.97 ( 8.532 )
        Monocytes, Week 12, n=171, 170, 86
    -0.6 ( 2.692 )
    -0.47 ( 2.5 )
    -0.86 ( 3.147 )
        Monocytes, Week 28, n=169, 169, 77
    -0.66 ( 2.594 )
    -0.53 ( 2.706 )
    -0.84 ( 3.063 )
        Monocytes, Week 52, n=155, 155, 71
    -0.19 ( 2.439 )
    0.31 ( 2.598 )
    -0.3 ( 2.337 )
        Segmented neutrophils, Week 12, n=171, 170, 86
    1.54 ( 10.883 )
    2.32 ( 9.635 )
    3.89 ( 11.397 )
        Segmented neutrophils, Week 28, n=169, 169, 77
    2.71 ( 10.221 )
    3.18 ( 12.008 )
    4.19 ( 13.745 )
        Segmented neutrophils, Week 52, n=155, 155, 71
    -0.33 ( 10.687 )
    0.66 ( 11.768 )
    2.54 ( 10.112 )
    Notes
    [26] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [27] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [28] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Change from Baseline in eosinophil count, total absolute neutrophil count (ANC), platelet count, and white blood cell (WBC) count at Week 12, Week 28, and Week 52/Early Withdrawal

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    End point title
    		 Change from Baseline in eosinophil count, total absolute neutrophil count (ANC), platelet count, and white blood cell (WBC) count at Week 12, Week 28, and Week 52/Early Withdrawal [29]
    End point description
    Blood samples were collected to determine the eosinophil count, total ANC, platelet count, and WBC count at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 12, Week 28, and Week 52/Early Withdrawal
    Notes
    [29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [30]
    202 [31]
    100 [32]
    Units: 10^9 cells per liter (GI/L)
    arithmetic mean (standard deviation)
        Eosinophil count, Week 12, n=171, 170, 86
    -0.01 ( 0.3226 )
    -0.057 ( 0.3841 )
    -0.073 ( 0.222 )
        Eosinophil count, Week 28, n=169, 169, 77
    -0.039 ( 0.331 )
    -0.083 ( 0.3698 )
    -0.083 ( 0.2363 )
        Eosinophil count, Week 52, n=155, 155, 71
    -0.023 ( 0.3273 )
    -0.037 ( 0.3171 )
    -0.044 ( 0.2539 )
        Total ANC, Week 12, n=171, 170, 86
    0.392 ( 1.6161 )
    0.469 ( 1.6904 )
    0.493 ( 1.7488 )
        Total ANC, Week 28, n=169, 169, 77
    0.632 ( 1.5922 )
    0.679 ( 2.0157 )
    0.75 ( 2.013 )
        Total ANC, Week 52, n=136, 136, 60
    0.524 ( 1.4589 )
    0.612 ( 1.91 )
    0.748 ( 1.7946 )
        Platelet count, Week 12, n=167, 159, 78
    -1.3 ( 39.44 )
    1.5 ( 68.1 )
    1.5 ( 43.26 )
        Platelet count, Week 28, n=164, 165, 74
    1 ( 44.49 )
    3.5 ( 35.06 )
    12.4 ( 43.59 )
        Platelet count, Week 52, n=147, 151, 68
    1.8 ( 43.8 )
    4.6 ( 38.49 )
    16.4 ( 50.99 )
        WBC count, Week 12, n=173, 170, 86
    0.51 ( 1.744 )
    0.5 ( 2.007 )
    0.39 ( 1.906 )
        WBC count, Week 28, n=170, 169, 77
    0.74 ( 1.758 )
    0.74 ( 2.103 )
    0.79 ( 2.028 )
        WBC count, Week 52, n=156, 156, 71
    0.91 ( 1.639 )
    0.83 ( 2.046 )
    1.01 ( 1.909 )
    Notes
    [30] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [31] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [32] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Change from Baseline in hematocrit at Week 12, Week 28, and Week 52/Early Withdrawal

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    End point title
    		 Change from Baseline in hematocrit at Week 12, Week 28, and Week 52/Early Withdrawal [33]
    End point description
    Blood samples were collected for the measurement of hematocrit values at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 12, Week 28, and Week 52/Early Withdrawal
    Notes
    [33] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [34]
    202 [35]
    100 [36]
    Units: Proportion of 1.0
    arithmetic mean (standard deviation)
        Week 12, n=176, 172, 86
    -0.0073 ( 0.02307 )
    -0.0013 ( 0.02654 )
    -0.0025 ( 0.02318 )
        Week 28, n=172, 170, 77
    -0.0017 ( 0.02213 )
    -0.0005 ( 0.02464 )
    -0.0028 ( 0.02168 )
        Week 52, n=157, 159, 72
    -0.0027 ( 0.02906 )
    -0.0021 ( 0.02467 )
    -0.0045 ( 0.02495 )
    Notes
    [34] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [35] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [36] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Number of participants with the indicated shift from Baseline to high, normal or no change, and low post-Baseline values for urinary cortisol excretion

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    End point title
    		 Number of participants with the indicated shift from Baseline to high, normal or no change, and low post-Baseline values for urinary cortisol excretion [37]
    End point description
    A 24-hour urine sample was collected for the measurement of 24-hour urinary cortisol excretion (UCE) at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. Any visit post-baseline (AVPB) value was derived using laboratory assessments performed at scheduled, unscheduled, and Early Withdrawal visits. Participants who had a shift from Baseline in their post-Baseline UCE values relative to the normal range, are presented in the "To high and To low" categories. Participants whose post-Baseline UCE values were unchanged (e.g., High to High) or whose value became normal, are presented in the "To normal or no change" category. The normal range for UCE is defined as: 11 to 138 nanomoles per 24 hours (nmol/24 hr) for participants >=18 years of age, 8.3 to 151.7 nmol/24 hr for participants 14 to 17 years of age, and 2.8 to 124.2 nmol/24 hr for participants 12 and 13 years of age.
    End point type
    Primary
    End point timeframe
    Baseline; Week 12, Week 28, and Week 52/Early Withdrawal
    Notes
    [37] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [38]
    202 [39]
    100 [40]
    Units: participants
        Week 12: To high, n=139, 140, 78
    6
    7
    2
        Week 12: To normal or no change, n=139, 140, 78
    131
    128
    67
        Week 12: To low, n=139, 140, 78
    2
    5
    9
        Week 28: To high, n=135, 131, 59
    8
    8
    3
        Week 28: To normal or no change, n=135, 131, 59
    123
    120
    47
        Week 28: To low, n=135, 131, 59
    4
    3
    9
        Week 52: To high, n=134, 140, 65
    10
    7
    4
        Week 52: To normal or no change , n=134, 140, 65
    119
    131
    57
        Week 52: To low, n=134, 140, 65
    5
    2
    4
        AVBP: To high, n=156, 156, 83
    25
    21
    8
        AVBP: To normal or no change, n=156, 156, 83
    119
    126
    58
        AVBP: To low, n=156, 156, 83
    12
    9
    17
    Notes
    [38] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [39] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [40] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Ratio of 24-hour urinary cortisol excretion at Week 12 to Baseline

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    End point title
    		 Ratio of 24-hour urinary cortisol excretion at Week 12 to Baseline
    End point description
    A 24-hour urine sample was collected, and the least square geometric mean (LSGM) for 24-hour urinary cortisol excretion (UCE) was calculated at Baseline and at Week 12. The ratio of the Week 12 LSGM to the Baseline LSGM was calculated as the value at Week 12 divided by the value at Baseline. Analysis was performed using analysis of covariance (ANCOVA) with covariates of region, sex, age, treatment, and the log of the Baseline values. Members of the Urinary cortisol (UC) Population, defined as participants in the ITT Population whose urine samples did not have confounding factors that affected the interpretation of results, were analyzed. These participants were determined prior to breaking the blind. Only those participants available at the specified time point were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    129 [41]
    129 [42]
    71 [43]
    Units: Ratio of LSGM of UCE to Baseline
        number (not applicable)
    1.03
    0.93
    0.61
    Notes
    [41] - UC Population
    [42] - UC Population
    [43] - UC Population
    Statistical analysis title
    		 Statistical Analysis #1
    Comparison groups
    FF/VI 100/25 µg OD v FP 500 µg BID
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Ratio of LSGM to Baseline
    Point estimate
    1.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.34
         upper limit
    		 2.08
    Statistical analysis title
    		 Statistical Analysis #2
    Comparison groups
    FF/VI 200/25 µg OD v FP 500 µg BID
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Ratio of LSGM to Baseline
    Point estimate
    1.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.22
         upper limit
    		 1.89

    Primary: Ratio of 24-hour urinary cortisol excretion at Week 28 to Baseline

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    End point title
    		 Ratio of 24-hour urinary cortisol excretion at Week 28 to Baseline
    End point description
    A 24-hour urine sample was collected, and the LSGM for 24-hour UCE was calculated at Baseline and at Week 28. The ratio of the Week 28 LSGM to the Baseline LSGM was calculated as the value at Week 28 divided by the value at Baseline. Analysis was performed using ANCOVA with covariates of region, sex, age, treatment, and the log of the Baseline values.
    End point type
    Primary
    End point timeframe
    Baseline and Week 28
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    128 [44]
    121 [45]
    56 [46]
    Units: Ratio of LSGM of UCE to Baseline
        number (not applicable)
    1.05
    0.91
    0.64
    Notes
    [44] - UC Population. Only those participants available at the specified time point were analyzed.
    [45] - UC Population. Only those participants available at the specified time point were analyzed.
    [46] - UC Population. Only those participants available at the specified time point were analyzed.
    Statistical analysis title
    		 Statistical Analysis #1
    Comparison groups
    FF/VI 100/25 µg OD v FP 500 µg BID
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Ratio of LSGM to Baseline
    Point estimate
    1.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.29
         upper limit
    		 2.13
    Statistical analysis title
    		 Statistical Analysis #2
    Comparison groups
    FF/VI 200/25 µg OD v FP 500 µg BID
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 ANCOVA
    Parameter type
    		 Ratio of LSGM to Baseline
    Point estimate
    1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.11
         upper limit
    		 1.84

    Primary: Ratio of 24-hour urinary cortisol excretion at Week 52 to Baseline

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    End point title
    		 Ratio of 24-hour urinary cortisol excretion at Week 52 to Baseline
    End point description
    A 24-hour urine sample was collected, and the LSGM for 24-hour UCE was calculated at Baseline and at Week 52. The ratio of the Week 52 LSGM to the Baseline LSGM was calculated as the value at Week 52 divided by the value at Baseline. Analysis was performed using ANCOVA with covariates of region, sex, age, treatment, and the log of the Baseline values.
    End point type
    Primary
    End point timeframe
    Baseline and Week 52
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    125 [47]
    127 [48]
    60 [49]
    Units: Ratio of LSGM of UCE to Baseline
        number (not applicable)
    1
    1.04
    0.95
    Notes
    [47] - UC Population. Only those participants available at the specified time point were analyzed.
    [48] - UC Population. Only those participants available at the specified time point were analyzed.
    [49] - UC Population. Only those participants available at the specified time point were analyzed.
    Statistical analysis title
    		 Statistical Analysis #1
    Comparison groups
    FF/VI 100/25 µg OD v FP 500 µg BID
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.674
    Method
    		 ANCOVA
    Parameter type
    		 Ratio of LSGM to Baseline
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.33
    Statistical analysis title
    		 Statistical Analysis #2
    Comparison groups
    FF/VI 200/25 µg OD v FP 500 µg BID
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.444
    Method
    		 ANCOVA
    Parameter type
    		 Ratio of LSGM to Baseline
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.38

    Primary: Number of participants with evidence of oral candidiasis at any time post-Baseline

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    End point title
    		 Number of participants with evidence of oral candidiasis at any time post-Baseline [50]
    End point description
    A detailed oropharyngeal examination was done at all clinic visits for visual/clinical evidence of oral candidiasis over the entire Treatment Period (worst case any time post-Baseline). For participants with visual/clinical evidence of candidiasis during the Treatment Phase of the study, a culture swab was taken and analyzed for infection.
    End point type
    Primary
    End point timeframe
    From Baseline until Visit 11/Early Withdrawal (52 weeks)
    Notes
    [50] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    199 [51]
    200 [52]
    100 [53]
    Units: participants
        Evidence of oral candidiasis
    15
    14
    5
        Positive culture swab
    13
    11
    3
        Negative culture swab
    1
    2
    2
        No swab result available
    1
    1
    0
    Notes
    [51] - ITT Population. Only those participants available at the specified time points were analyzed.
    [52] - ITT Population. Only those participants available at the specified time points were analyzed.
    [53] - ITT Population. Only those participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Maximum change from Baseline in systolic blood pressure (SBP) and minimum change from Baseline in diastolic blood pressure (DBP)

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    End point title
    		 Maximum change from Baseline in systolic blood pressure (SBP) and minimum change from Baseline in diastolic blood pressure (DBP) [54]
    End point description
    SBP and DBP were measured at the following scheduled time points: Screening, Day 1, Week 2, Week 4, Week 8, Week 12, Week 20, Week 28, Week 36, Week 44, and Week 52/Early Withdrawal. Baseline is defined as the Visit 1 (screening) value. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. Maximum and minimum change from Baseline for any post-Baseline visit was derived using all scheduled, unscheduled, and Early Withdrawal visits.
    End point type
    Primary
    End point timeframe
    From Baseline until Visit 11/Early Withdrawal (52 weeks)
    Notes
    [54] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [55]
    202 [56]
    100 [57]
    Units: Millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        Maximum post-Baseline change in SBP
    10.2 ( 11.05 )
    10 ( 10.17 )
    11.3 ( 11.09 )
        Minimum post-Baseline change in DBP
    -8.9 ( 7.7 )
    -9 ( 8.44 )
    -8 ( 7.76 )
    Notes
    [55] - ITT Population
    [56] - ITT Population
    [57] - ITT Population
    No statistical analyses for this end point

    Primary: Maximum change from Baseline in pulse rate

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    End point title
    		 Maximum change from Baseline in pulse rate [58]
    End point description
    Pulse rate was measured at the following scheduled time points: Screening, Day 1, Week 2, Week 4, Week 8, Week 12, Week 20,Week 28, Week 36, Week 44, and Week 52/Early Withdrawal. Baseline is defined as the Visit 1 (screening) value. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. Maximum change from Baseline for any post-Baseline visit was derived using all scheduled, unscheduled, and Early Withdrawal visits.
    End point type
    Primary
    End point timeframe
    From Baseline until Visit 11/Early Withdrawal (52 weeks)
    Notes
    [58] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [59]
    202 [60]
    100 [61]
    Units: Beats per minute
        arithmetic mean (standard deviation)
    10.5 ( 9.3 )
    10 ( 10.05 )
    7.5 ( 8.29 )
    Notes
    [59] - ITT Population
    [60] - ITT Population
    [61] - ITT Population
    No statistical analyses for this end point

    Primary: Number of participants with the indicated change from Baseline in Lens Opacities Classification System, Version III (LOCS III) Posterior Subcapsular Opacity (P) at Week 28 and Week 52

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    End point title
    		 Number of participants with the indicated change from Baseline in Lens Opacities Classification System, Version III (LOCS III) Posterior Subcapsular Opacity (P) at Week 28 and Week 52 [62]
    End point description
    P is defined as the opacification at the back of the lens adjacent to the capsule (or bag) in which the lens sits. An event of P is defined as an increase of >=0.3 from Baseline in LOCS III grade for P in either eye at any time post-Baseline. Per LOC III, P ranges from 0.1 (clear or colorless) to 5.9 (very opaque). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 28, and Week 52
    Notes
    [62] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [63]
    202 [64]
    100 [65]
    Units: participants
        Left eye, <0.3, Week 28, n=179, 177, 80
    174
    175
    79
        Left eye, >=0.3 and <0.5, Week 28, n=179, 177, 80
    5
    2
    1
        Left eye, >=0.5, Week 28, n=179, 177, 80
    0
    0
    0
        Right eye, <0.3, Week 28, n=179, 177, 80
    175
    175
    80
        Right eye, >=0.3 and <0.5, Week 28, n=179, 177, 80
    4
    2
    0
        Right eye, >=0.5, Week 28, n=179, 177, 80
    0
    0
    0
        Left eye, <0.3, Week 52, n=167, 166, 72
    163
    164
    72
        Left eye, >=0.3 and <0.5, Week 52, n=167, 166, 72
    2
    1
    0
        Left eye, >=0.5, Week 52, n=167, 166, 72
    2
    1
    0
        Right eye, <0.3, Week 52, n=167, 166, 72
    163
    164
    72
        Right eye, >=0.3 and <0.5, Week 52, n=167, 166, 72
    3
    1
    0
        Right eye, >=0.5, Week 52, n=167, 166, 72
    1
    1
    0
    Notes
    [63] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [64] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [65] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Change from Baseline in hemoglobin at Week 12, Week 28, and Week 52/Early Withdrawal

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    End point title
    		 Change from Baseline in hemoglobin at Week 12, Week 28, and Week 52/Early Withdrawal [66]
    End point description
    Blood samples were collected for the measurement of hemoglobin values at the following scheduled time points: Baseline, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the most recent recorded value at Screening or prior to Day 1. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 12, Week 28, and Week 52/Early Withdrawal
    Notes
    [66] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [67]
    202 [68]
    100 [69]
    Units: Grams per liter (g/L)
    arithmetic mean (standard deviation)
        Week 12, n=176, 172, 86
    -3.4 ( 7.48 )
    -1.8 ( 8.25 )
    -2 ( 7.67 )
        Week 28, n=172, 170, 77
    -2.1 ( 7.64 )
    -2.2 ( 8.11 )
    -2.4 ( 7.72 )
        Week 52, n=157, 159, 72
    -2.6 ( 10.26 )
    -2.9 ( 7.47 )
    -3 ( 8.77 )
    Notes
    [67] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [68] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [69] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Number of participants with the indicated change from Baseline in Intraocular Pressure (IOP) at Week 28 and Week 52

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    End point title
    		 Number of participants with the indicated change from Baseline in Intraocular Pressure (IOP) at Week 28 and Week 52 [70]
    End point description
    Intraocular pressure (IOP) is the fluid pressure inside the eye. IOP was measured twice for each eye at Baseline, Week 28, and Week 52 using Goldmann Applanation tonometry. The second IOP reading was used for analysis. The number of participants with a change from Baseline in IOP of <0 mmHg, >=0 to <4 mmHg, >=4 to <7 mmHg, >=7 to <11 mmHg, and >=11 mmHg are presented. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 28 and Week 52
    Notes
    [70] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [71]
    202 [72]
    100 [73]
    Units: participants
        Left eye, <0 mmHg, Week 28, n=179, 177, 80
    71
    78
    32
        Left eye, >=0 to <4 mmHg, Week 28, n=179, 177, 80
    101
    92
    46
        Left eye, >=4 to <7 mmHg, Week 28, n=179, 177, 80
    7
    6
    2
        Left eye, >=7 to <11 mmHg, Week 28, n=179, 177, 80
    0
    1
    0
        Left eye, >=11 mmHg, Week 28, n=179, 177, 80
    0
    0
    0
        Right eye, <0 mmHg, Week 28, n=179, 177, 80
    73
    61
    38
        Right eye, >=0 to <4 mmHg, Week 28, n=179, 177, 80
    101
    110
    38
        Right eye, >=4 to <7 mmHg, Week 28, n=179, 177, 80
    5
    5
    4
        Right eye, >=7 to <11 mmHg,Week 28, n=179, 177, 80
    0
    1
    0
        Right eye, >=11 mmHg, Week 28, n=179, 177, 80
    0
    0
    0
        Left eye, <0 mmHg, Week 52, n=167, 166, 72
    66
    69
    33
        Left eye, >=0 to <4 mmHg, Week 52, n=167, 166, 72
    88
    83
    36
        Left eye, >=4 to <7 mmHg, Week 52, n=167, 166, 72
    11
    14
    3
        Left eye, >=7 to <11 mmHg, Week 52, n=167, 166, 72
    2
    0
    0
        Left eye, >=11 mmHg, Week 52, n=167, 166, 72
    0
    0
    0
        Right eye, <0 mmHg, Week 52, n=167, 166, 72
    63
    61
    32
        Right eye, >=0 to <4 mmHg, Week 52, n=167, 166, 72
    94
    93
    40
        Right eye, >=4 to <7 mmHg, Week 52, n=167, 166, 72
    10
    12
    0
        Right eye, >=7 to <11 mmHg, Week 52, n=167,166, 72
    0
    0
    0
        Right eye, >=11 mmHg, Week 52, n=167, 166, 72
    0
    0
    0
    Notes
    [71] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [72] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [73] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Change from Baseline in horizontal cup-to-disc ratio at Week 28 and Week 52

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    End point title
    		 Change from Baseline in horizontal cup-to-disc ratio at Week 28 and Week 52 [74]
    End point description
    Funduscopic examination was performed at Baseline, Week 28, and Week 52 to measure the horizontal cup-to-disc ratio of both eyes. The horizontal cup-to-disc ratio is the ratio of the horizontal diameter of the physiological cup to that of the horizontal diameter of the optic disc. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 28 and Week 52
    Notes
    [74] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [75]
    202 [76]
    100 [77]
    Units: ratio
    arithmetic mean (standard deviation)
        Left eye, Week 28, n=179, 177, 80
    0.5 ( 4.79 )
    -0.2 ( 5.11 )
    0.5 ( 4.87 )
        Right eye, Week 28, n=179, 177, 80
    0.2 ( 4.17 )
    -0.2 ( 6.49 )
    0.5 ( 5.1 )
        Left eye, Week 52, n=167, 166, 72
    0.4 ( 5.86 )
    0.2 ( 4.89 )
    0.3 ( 4.77 )
        Right eye, Week 52, n=167, 166, 72
    0.1 ( 4.63 )
    0.2 ( 5.57 )
    0 ( 5.26 )
    Notes
    [75] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [76] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [77] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Number of participants with the indicated change from Baseline in Lens Opacities Classification System, Version III (LOCS III) Cortical Opacity (C) at Week 28 and Week 52

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    End point title
    		 Number of participants with the indicated change from Baseline in Lens Opacities Classification System, Version III (LOCS III) Cortical Opacity (C) at Week 28 and Week 52 [78]
    End point description
    C is defined as the opacification of the cortex (outer layer) of the lens. Per LOC III, C ranges from 0.1 (clear or colorless) to 5.9 (very opaque). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 28 and Week 52
    Notes
    [78] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [79]
    202 [80]
    100 [81]
    Units: participants
        Left eye, <0.3, Week 28, n=179, 177, 80
    167
    166
    75
        Left eye, >=0.3 and <0.5, Week 28, n=179, 177, 80
    6
    5
    4
        Left eye, >=0.5, Week 28, n=179, 177, 80
    6
    6
    1
        Right eye, <0.3, Week 28, n=179, 177, 80
    169
    172
    75
        Right eye, >=0.3 and <0.5, Week 28, n=179, 177, 80
    5
    1
    4
        Right eye, >=0.5, Week 28, n=179, 177, 80
    5
    4
    1
        Left eye, <0.3, Week 52, n=167, 166, 72
    154
    156
    66
        Left eye, >=0.3 and <0.5, Week 52, n=167, 166, 72
    7
    4
    3
        Left eye, >=0.5, Week 52, n=167, 166, 72
    6
    6
    3
        Right eye, <0.3, Week 52, n=167, 166, 72
    151
    158
    69
        Right eye, >=0.3 and <0.5, Week 52, n=167, 166, 72
    11
    2
    2
        Right eye, >=0.5, Week 52, n=167, 166, 72
    5
    6
    1
    Notes
    [79] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [80] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [81] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Change from Baseline in Lens Opacities Classification System, Version III (LOCS III) Nuclear Color (NC) at Week 28 and Week 52

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    End point title
    		 Change from Baseline in Lens Opacities Classification System, Version III (LOCS III) Nuclear Color (NC) at Week 28 and Week 52 [82]
    End point description
    NC is the color of the nucleus (central layer) of the lens. Per LOC III, NC ranges from 0.1 (clear or colorless) to 6.9 (very opaque or brunescent). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 28 and Week 52
    Notes
    [82] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [83]
    202 [84]
    100 [85]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 28, Left eye, n=179, 177, 80
    0.01 ( 0.282 )
    0 ( 0.284 )
    -0.02 ( 0.299 )
        Week 28, Right eye, n=179, 177, 80
    0.01 ( 0.292 )
    0.01 ( 0.292 )
    -0.02 ( 0.294 )
        Week 52, Left eye, n=167, 166, 72
    0.02 ( 0.281 )
    -0.02 ( 0.357 )
    0 ( 0.34 )
        Week 52, Right eye, n=167, 166, 72
    0.02 ( 0.304 )
    0 ( 0.339 )
    0.01 ( 0.336 )
    Notes
    [83] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [84] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [85] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Change from Baseline in Lens Opacities Classification System, Version III (LOCS III) Nuclear Opalescence (NO) at Week 28 and Week 52

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    End point title
    		 Change from Baseline in Lens Opacities Classification System, Version III (LOCS III) Nuclear Opalescence (NO) at Week 28 and Week 52 [86]
    End point description
    NO is the opalescence of the nucleus (central layer) of the lens. Per LOC III, NO ranges from 0.1 (clear or colorless) to 6.9 (very opaque or brunescent). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 28 and Week 52
    Notes
    [86] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [87]
    202 [88]
    100 [89]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 28, Left eye, n=179, 177, 80
    0.02 ( 0.236 )
    0.03 ( 0.316 )
    -0.02 ( 0.27 )
        Week 28, Right eye, n=179, 177, 80
    0.01 ( 0.256 )
    0.03 ( 0.303 )
    -0.03 ( 0.272 )
        Week 52, Left eye, n=167, 166, 72
    0.01 ( 0.33 )
    0.03 ( 0.303 )
    0.01 ( 0.369 )
        Week 52, Right eye, n=167, 166, 72
    0 ( 0.351 )
    0.04 ( 0.282 )
    0.02 ( 0.371 )
    Notes
    [87] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [88] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [89] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Change from Baseline in the Logarithm of the Minimum Angle of Resolution (LogMAR) visual acuity at Week 28 and Week 52

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    End point title
    		 Change from Baseline in the Logarithm of the Minimum Angle of Resolution (LogMAR) visual acuity at Week 28 and Week 52 [90]
    End point description
    Visual acuity is defined as the acuteness or clearness of vision. The minimum angle of resolution (MAR) is the angle a viewed object subtends at the eye, usually stated in degrees/minutes of arc. Visual acuity was measured using Early Treatment Diabetic Retinopathy Study (ETDRS) charts in decimal numbers. The LogMAR scale is used to express the visual acuity in a linear scale as the logarithm to base 10 of the MAR. A lower score indicates better visual acuity; visual acuity decreases with an increasing score. Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 28 and Week 52
    Notes
    [90] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [91]
    202 [92]
    100 [93]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 28, Left eye, n=179, 176, 80
    -0.008 ( 0.0723 )
    -0.01 ( 0.0706 )
    -0.004 ( 0.0685 )
        Week 28, Right eye, n=179, 176, 80
    -0.003 ( 0.0739 )
    -0.001 ( 0.0699 )
    -0.008 ( 0.0584 )
        Week 52, Left eye, n=167, 165, 72
    -0.011 ( 0.0747 )
    -0.012 ( 0.0739 )
    -0.007 ( 0.0638 )
        Week 52, Right eye, n=167, 165, 72
    -0.008 ( 0.0928 )
    0.003 ( 0.0755 )
    -0.012 ( 0.0776 )
    Notes
    [91] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [92] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [93] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Maximum change from Baseline in the QT interval using Bazett’s correction (QTcB) and QT interval using Fridericia’s correction (QTcF)

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    End point title
    		 Maximum change from Baseline in the QT interval using Bazett’s correction (QTcB) and QT interval using Fridericia’s correction (QTcF) [94]
    End point description
    The QT interval is an electrocardiogram (ECG) parameter that represents the electrical depolarization and repolarization of the left and right ventricles of the heart. The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the ECG. Corrected QT (QTc) is the QT interval corrected for heart rate by using Bazett's formula (QTcB) and Fridericia's formula (QTcF). 12-lead ECG measurements were perfomed at the following scheduled time points: Baseline; Week 2, Week 12, Week 28, and Week 52/Early Withdrawal. The Baseline value is defined as the value taken pre-dose at screening. The maximum post-Baseline value was derived using all scheduled, unscheduled, and Early Withdrawal ECG assessments. Maximum change from Baseline was calculated as the maximum post-Baseline value minus the value at Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 2, Week 12, Week 28, and Week 52/Early Withdrawal
    Notes
    [94] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    199 [95]
    198 [96]
    100 [97]
    Units: Milliseconds (msec)
    arithmetic mean (standard deviation)
        QTcB
    19 ( 17.33 )
    16.4 ( 19.49 )
    13.2 ( 16.57 )
        QTcF
    12.8 ( 14.51 )
    11.6 ( 15.6 )
    11.4 ( 12.81 )
    Notes
    [95] - ITT Population. Only those participants available at the specified time points were analyzed.
    [96] - ITT Population. Only those participants available at the specified time points were analyzed.
    [97] - ITT Population. Only those participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Mean 24 hour Holter heart rate for participants with at least 16 hours of recorded data

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    End point title
    		 Mean 24 hour Holter heart rate for participants with at least 16 hours of recorded data [98]
    End point description
    Twenty-four hour Holter monitors were obtained using a 12-lead Holter monitor. The Holter monitor is worn by the participant for 24 hours, and the monitor continuously records the heart’s rhythm while the monitor is worn. At the end of the 24 hour period, the data from the monitor are downloaded and transmitted to the centralized vendor for analysis and interpretation by a licensed cardiologist.
    End point type
    Primary
    End point timeframe
    0-24 hours at Screening, Day 1, Week 28, and Week 52
    Notes
    [98] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [99]
    202 [100]
    100 [101]
    Units: beats per minute
    arithmetic mean (standard deviation)
        Screening, n=111, 116, 49
    79 ( 8.23 )
    79.1 ( 9.55 )
    79.8 ( 8.75 )
        Day 1, n=104, 113, 47
    78.6 ( 7.89 )
    78.7 ( 9.45 )
    77.4 ( 7.66 )
        Week 28, n=95, 90, 39
    77.8 ( 8.9 )
    77.5 ( 9.01 )
    74.9 ( 8.54 )
        Week 52, n=88, 82, 37
    78.8 ( 8.72 )
    78 ( 10.15 )
    74.8 ( 8.62 )
    Notes
    [99] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [100] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [101] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Primary: Maximum 24 hour Holter heart rate for participants with at least 16 hours of recorded data

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    End point title
    		 Maximum 24 hour Holter heart rate for participants with at least 16 hours of recorded data [102]
    End point description
    Twenty-four hour Holter monitors were obtained using a 12-lead Holter monitor. Holter monitor data were transmitted to a centralized vendor for analysis and interpretation by a licensed cardiologist.
    End point type
    Primary
    End point timeframe
    0-24 hours at Screening, Day 1, Week 28, and Week 52
    Notes
    [102] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was conducted for this end point.
    End point values
    		 FF/VI 100/25 µg OD FF/VI 200/25 µg OD FP 500 µg BID
    Number of subjects analysed
    201 [103]
    202 [104]
    100 [105]
    Units: beats per minute
    arithmetic mean (standard deviation)
        Screening, n=111, 116, 49
    132.6 ( 17.18 )
    132.1 ( 17.85 )
    133 ( 16.17 )
        Day 1, n=104, 113, 47
    131.2 ( 18.28 )
    130.8 ( 19.5 )
    129.2 ( 18.77 )
        Week 28, n=95, 90, 39
    127.5 ( 17.93 )
    127.4 ( 16.62 )
    123.5 ( 14.93 )
        Week 52, n=88, 82, 37
    126.9 ( 18.16 )
    128.1 ( 16.63 )
    122.8 ( 13.89 )
    Notes
    [103] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [104] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    [105] - ITT Population. Only participants available at the specified time points were analyzed (n=X, X, X).
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication until Follow-up (up to 52 weeks of treatment).
    Adverse event reporting additional description
    SAEs and non-serious AEs were collected in the Intent-to-Treat (ITT) Population, comprised of all participants randomized to treatment who received at least one dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    FF/VI 100/25 µg OD
    Reporting group description
    		 Participants received Fluticasone Furoate (FF)/Vilanterol (VI) 100/25 micrograms (µg) inhalation powder once daily (OD) in the evening via the Dry Powder Inhaler (DPI), plus a placebo via DISKUS/ACCUHALER twice daily (BID), for 52 weeks. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication during the Treatment Period.

    Reporting group title
    FP 500 µg BID
    Reporting group description
    		 Participants received Fluticasone Propionate (FP) 500 µg BID via DISKUS/ACCUHALER, plus a placebo via the DPI OD in the evening, for 52 weeks. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication during the Treatment Period.

    Reporting group title
    FF/VI 200/25 µg OD
    Reporting group description
    		 Participants received FF/VI 200/25 µg inhalation powder OD in the evening via the DPI, plus a placebo via DISKUS/ACCUHALER BID, for 52 weeks. Participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication during the Treatment Period.

    Serious adverse events
    		 FF/VI 100/25 µg OD FP 500 µg BID FF/VI 200/25 µg OD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 201 (1.49%)
    7 / 100 (7.00%)
    1 / 202 (0.50%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 100 (1.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 100 (1.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 100 (1.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 100 (1.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 201 (0.50%)
    2 / 100 (2.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 100 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Dengue fever
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 100 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 100 (1.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 100 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 FF/VI 100/25 µg OD FP 500 µg BID FF/VI 200/25 µg OD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    108 / 201 (53.73%)
    71 / 100 (71.00%)
    105 / 202 (51.98%)
    Cardiac disorders
    Extrasystoles
         subjects affected / exposed
    4 / 201 (1.99%)
    3 / 100 (3.00%)
    15 / 202 (7.43%)
         occurrences all number
    5
    3
    19
    Nervous system disorders
    Tension headache
         subjects affected / exposed
    1 / 201 (0.50%)
    3 / 100 (3.00%)
    0 / 202 (0.00%)
         occurrences all number
    1
    4
    0
    Headache
         subjects affected / exposed
    39 / 201 (19.40%)
    23 / 100 (23.00%)
    35 / 202 (17.33%)
         occurrences all number
    87
    54
    81
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    8 / 201 (3.98%)
    6 / 100 (6.00%)
    13 / 202 (6.44%)
         occurrences all number
    8
    6
    14
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 201 (0.00%)
    3 / 100 (3.00%)
    1 / 202 (0.50%)
         occurrences all number
    0
    3
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 201 (3.48%)
    2 / 100 (2.00%)
    6 / 202 (2.97%)
         occurrences all number
    8
    2
    7
    Abdominal pain upper
         subjects affected / exposed
    8 / 201 (3.98%)
    1 / 100 (1.00%)
    11 / 202 (5.45%)
         occurrences all number
    10
    4
    20
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic
         subjects affected / exposed
    7 / 201 (3.48%)
    2 / 100 (2.00%)
    4 / 202 (1.98%)
         occurrences all number
    9
    3
    5
    Dysphonia
         subjects affected / exposed
    8 / 201 (3.98%)
    3 / 100 (3.00%)
    6 / 202 (2.97%)
         occurrences all number
    9
    4
    7
    Oropharyngeal pain
         subjects affected / exposed
    7 / 201 (3.48%)
    11 / 100 (11.00%)
    12 / 202 (5.94%)
         occurrences all number
    8
    13
    13
    Cough
         subjects affected / exposed
    9 / 201 (4.48%)
    13 / 100 (13.00%)
    11 / 202 (5.45%)
         occurrences all number
    11
    19
    12
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    4 / 201 (1.99%)
    3 / 100 (3.00%)
    2 / 202 (0.99%)
         occurrences all number
    4
    3
    4
    Back pain
         subjects affected / exposed
    8 / 201 (3.98%)
    3 / 100 (3.00%)
    13 / 202 (6.44%)
         occurrences all number
    8
    3
    20
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    6 / 201 (2.99%)
    7 / 100 (7.00%)
    5 / 202 (2.48%)
         occurrences all number
    6
    7
    7
    Sinusitis
         subjects affected / exposed
    9 / 201 (4.48%)
    5 / 100 (5.00%)
    4 / 202 (1.98%)
         occurrences all number
    9
    5
    5
    Bronchitis
         subjects affected / exposed
    7 / 201 (3.48%)
    5 / 100 (5.00%)
    9 / 202 (4.46%)
         occurrences all number
    7
    7
    11
    Oral candidiasis
         subjects affected / exposed
    12 / 201 (5.97%)
    2 / 100 (2.00%)
    11 / 202 (5.45%)
         occurrences all number
    25
    4
    15
    Nasopharyngitis
         subjects affected / exposed
    25 / 201 (12.44%)
    10 / 100 (10.00%)
    19 / 202 (9.41%)
         occurrences all number
    31
    17
    37
    Upper respiratory tract infection
         subjects affected / exposed
    34 / 201 (16.92%)
    18 / 100 (18.00%)
    30 / 202 (14.85%)
         occurrences all number
    48
    24
    56

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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