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    Clinical Trial Results:
    A randomized, double-blind, repeat dose, two period crossover study to evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of inhaled fluticasone furoate/vilanterol 100/25 mcg in children aged 5 to 11 years with persistent asthma

    Summary
    EudraCT number
    		 2012-000754-55
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    29 Jun 2012

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

    Trial information

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    Trial identification
    Sponsor protocol code
    HZA112777
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    30 Jul 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jun 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of inhaled FF/VI 100/25mcg administered once daily in the morning for 14 days via a novel dry powder inhaler in subjects aged 5 to 11 years
    Protection of trial subjects
    A parent was required to stay with the subjects for the long days in the clinic. As much as possible children in the same age group were scheduled for visits on the same day. Games and movies were provided for diversion during the long clinic days. Effort was made to have the same staff members work with the children to help reduce anxiety. Topical anesthetics were used at injection site to reduce discomfort from blood collections. An indwelling catheter was inserted for serial blood draws, to prevent the pain and distress associated with repeated needlesticks.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Oct 2011
    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: 26
    Worldwide total number of subjects
    26
    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)
    26
    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
    		 Participants were enrolled into one of two cohorts based upon age; the younger cohort was enrolled after a review of the safety/pharmacokinetic data of at least six participants from the older cohort. Each participant was assigned to treatment randomly; assignment was not to be influenced by whether participants were in Cohort 1 or Cohort 2.

    Pre-assignment
    Screening details
    		 A Baseline assessment was carried out on Day 1 of the first treatment period. Participants were then randomized to one of the two possible treatments fluticasone furoate [FF] 100 µg/Vilanterol [VI] 25 µg.or FF 100 µg, followed by a cross over after a washout period of at least 7 days.

    Period 1
    Period 1 title
    Treatment Period (TP) 1 (Overall)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FF 100 µg/VI 25 µg in TP 1 and FF 100 µg in TP 2
    Arm description
    		 Participants received fluticasone furoate (FF) 100 micrograms (µg)/Vilanterol (VI) 25 µg in Treatment Period 1 and FF 100 µg in Treatment Period 2. The first 14-day treatment period was followed by a washout period of at least 7 days. Inhaled FF 100 µg/VI 25 µg and FF 100 µg were administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone furoate singularly
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF 100µg once daily x 14 days; 7 day wash out; crossover

    Investigational medicinal product name
    Fluticasone furoate and Vilanterol combined
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF/VI 100/25µg once daily x 14 days; 7 day wash out; crossover

    Arm title
    		 FF 100 µg in TP 1 and FF 100 µg/VI 25 µg in TP 2
    Arm description
    		 Participants received FF 100 µg in Treatment Period 1 and FF 100 µg/VI 25 µg in Treatment Period 2. The first 14-day treatment period was followed by a washout period of at least 7 days. Inhaled FF 100 µg/VI 25 µg and FF 100 µg were administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone furoate singularly
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF 100µg once daily x 14 days; 7 day wash out; crossover

    Investigational medicinal product name
    Fluticasone furoate and Vilanterol combined
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF/VI 100/25µg once daily x 14 days; 7 day wash out; crossover

    Number of subjects in period 1
    		FF 100 µg/VI 25 µg in TP 1 and FF 100 µg in TP 2 FF 100 µg in TP 1 and FF 100 µg/VI 25 µg in TP 2
    Started
    13
    13
    Completed
    12
    12
    Not completed
    1
    1
         Met Protocol-defined Stopping Criteria
    -
    1
         Protocol deviation
    1
    -
    Period 2
    Period 2 title
    Washout Period
    Is this the baseline period?
    		 No
    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 100 µg/VI 25 µg in TP 1 and FF 100 µg in TP 2
    Arm description
    		 Participants received fluticasone furoate (FF) 100 micrograms (µg)/Vilanterol (VI) 25 µg in Treatment Period 1 and FF 100 µg in Treatment Period 2. The first 14-day treatment period was followed by a washout period of at least 7 days. Inhaled FF 100 µg/VI 25 µg and FF 100 µg were administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone furoate singularly
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF 100µg once daily x 14 days; 7 day wash out; crossover

    Investigational medicinal product name
    Fluticasone furoate and Vilanterol combined
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF/VI 100/25µg once daily x 14 days; 7 day wash out; crossover

    Arm title
    		 FF 100 µg in TP 1 and FF 100 µg/VI 25 µg in TP 2
    Arm description
    		 Participants received FF 100 µg in Treatment Period 1 and FF 100 µg/VI 25 µg in Treatment Period 2. The first 14-day treatment period was followed by a washout period of at least 7 days. Inhaled FF 100 µg/VI 25 µg and FF 100 µg were administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone furoate singularly
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF 100µg once daily x 14 days; 7 day wash out; crossover

    Investigational medicinal product name
    Fluticasone furoate and Vilanterol combined
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF/VI 100/25µg once daily x 14 days; 7 day wash out; crossover

    Number of subjects in period 2
    		FF 100 µg/VI 25 µg in TP 1 and FF 100 µg in TP 2 FF 100 µg in TP 1 and FF 100 µg/VI 25 µg in TP 2
    Started
    12
    12
    Completed
    12
    12
    Period 3
    Period 3 title
    Treatment Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FF 100 µg/VI 25 µg in TP 1 and FF 100 µg in TP 2
    Arm description
    		 Participants received fluticasone furoate (FF) 100 micrograms (µg)/Vilanterol (VI) 25 µg in Treatment Period 1 and FF 100 µg in Treatment Period 2. The first 14-day treatment period was followed by a washout period of at least 7 days. Inhaled FF 100 µg/VI 25 µg and FF 100 µg were administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone furoate singularly
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF 100µg once daily x 14 days; 7 day wash out; crossover

    Investigational medicinal product name
    Fluticasone furoate and Vilanterol combined
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF/VI 100/25µg once daily x 14 days; 7 day wash out; crossover

    Arm title
    		 FF 100 µg in TP 1 and FF 100 µg/VI 25 µg in TP 2
    Arm description
    		 Participants received FF 100 µg in Treatment Period 1 and FF 100 µg/VI 25 µg in Treatment Period 2. The first 14-day treatment period was followed by a washout period of at least 7 days. Inhaled FF 100 µg/VI 25 µg and FF 100 µg were administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone furoate singularly
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF 100µg once daily x 14 days; 7 day wash out; crossover

    Investigational medicinal product name
    Fluticasone furoate and Vilanterol combined
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF/VI 100/25µg once daily x 14 days; 7 day wash out; crossover

    Number of subjects in period 3
    		FF 100 µg/VI 25 µg in TP 1 and FF 100 µg in TP 2 FF 100 µg in TP 1 and FF 100 µg/VI 25 µg in TP 2
    Started
    12
    12
    Completed
    12
    11
    Not completed
    0
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period (TP) 1 (Overall)
    Reporting group description
    		 All participants who received FF 100 µg/VI 25 µg in Treatment Period 1 and FF 100 µg in Treatment Period 2 or FF 100 µg in Treatment Period 1 and FF 100 µg/VI 25 µg in Treatment Period 2. The first 14-day treatment period was followed by a washout period of at least 7 days. Inhaled FF 100 µg/VI 25 µg and FF 100 µg were administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler.

    Reporting group values
    		 Treatment Period (TP) 1 (Overall) Total
    Number of subjects
    		 26 26
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.1 ( 1.97 ) -
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 15 15
    Race
    Units: Subjects
        African American/African Heritage
    		 3 3
        White - Arabic/North African Heritage
    		 1 1
        White - White/Caucasian/European Heritage
    		 21 21
        African American/African Heritage & White
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    FF 100 µg/VI 25 µg in TP 1 and FF 100 µg in TP 2
    Reporting group description
    		 Participants received fluticasone furoate (FF) 100 micrograms (µg)/Vilanterol (VI) 25 µg in Treatment Period 1 and FF 100 µg in Treatment Period 2. The first 14-day treatment period was followed by a washout period of at least 7 days. Inhaled FF 100 µg/VI 25 µg and FF 100 µg were administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler.

    Reporting group title
    FF 100 µg in TP 1 and FF 100 µg/VI 25 µg in TP 2
    Reporting group description
    		 Participants received FF 100 µg in Treatment Period 1 and FF 100 µg/VI 25 µg in Treatment Period 2. The first 14-day treatment period was followed by a washout period of at least 7 days. Inhaled FF 100 µg/VI 25 µg and FF 100 µg were administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler.
    Reporting group title
    FF 100 µg/VI 25 µg in TP 1 and FF 100 µg in TP 2
    Reporting group description
    		 Participants received fluticasone furoate (FF) 100 micrograms (µg)/Vilanterol (VI) 25 µg in Treatment Period 1 and FF 100 µg in Treatment Period 2. The first 14-day treatment period was followed by a washout period of at least 7 days. Inhaled FF 100 µg/VI 25 µg and FF 100 µg were administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler.

    Reporting group title
    FF 100 µg in TP 1 and FF 100 µg/VI 25 µg in TP 2
    Reporting group description
    		 Participants received FF 100 µg in Treatment Period 1 and FF 100 µg/VI 25 µg in Treatment Period 2. The first 14-day treatment period was followed by a washout period of at least 7 days. Inhaled FF 100 µg/VI 25 µg and FF 100 µg were administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler.
    Reporting group title
    FF 100 µg/VI 25 µg in TP 1 and FF 100 µg in TP 2
    Reporting group description
    		 Participants received fluticasone furoate (FF) 100 micrograms (µg)/Vilanterol (VI) 25 µg in Treatment Period 1 and FF 100 µg in Treatment Period 2. The first 14-day treatment period was followed by a washout period of at least 7 days. Inhaled FF 100 µg/VI 25 µg and FF 100 µg were administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler.

    Reporting group title
    FF 100 µg in TP 1 and FF 100 µg/VI 25 µg in TP 2
    Reporting group description
    		 Participants received FF 100 µg in Treatment Period 1 and FF 100 µg/VI 25 µg in Treatment Period 2. The first 14-day treatment period was followed by a washout period of at least 7 days. Inhaled FF 100 µg/VI 25 µg and FF 100 µg were administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler.

    Subject analysis set title
    FF 100 µg/VI 25 µg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received FF 100 µg/VI 25 µg in one of the two 14-day treatment periods. FF 100 µg/VI 25 µg was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.

    Subject analysis set title
    FF 100 µg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received FF 100 µg in one of the two 14-day treatment periods. FF 100 µg was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.

    Subject analysis set title
    FF 100 µg/VI 25 µg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received FF 100 µg/VI 25 µg in one of the two 14-day treatment periods. FF 100 µg/VI 25 µg was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.

    Subject analysis set title
    FF 100 µg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received FF 100 µg in one of the two 14-day treatment periods. FF 100 µg was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.

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

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    End point title
    		 Number of participants with any adverse event (AE) or any 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 Week 11 (Visit 9)/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 performed for this primary endpoint; thus, no data are available.
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [2]
    25 [3]
    Units: Participants
        Any AE
    4
    1
        Any SAE
    0
    0
    Notes
    [2] - All Subjects Population: all participants who received at least one dose of study medication
    [3] - All Subjects Population: all participants who received at least one dose of study medication
    No statistical analyses for this end point

    Primary: Basophil, eosinophil, lymphocyte, monocyte, total neutrophil, platelet, and white blood cell count values at Day 14 of the respective treatment period

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    End point title
    		 Basophil, eosinophil, lymphocyte, monocyte, total neutrophil, platelet, and white blood cell count values at Day 14 of the respective treatment period [4]
    End point description
    Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelets, and white blood cell (WBC) count at Day 14 of the respective treatment period.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    Notes
    [4] - 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 performed for this primary endpoint; thus, no data are available.
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [5]
    25 [6]
    Units: 10^9 cells per liter (GI/L)
    arithmetic mean (standard deviation)
        Basophils, n=21, 23
    0.025 ( 0.0175 )
    0.025 ( 0.0153 )
        Eosinophils, n=21, 23
    0.296 ( 0.3395 )
    0.293 ( 0.3957 )
        Lymphocytes, n=21, 23
    2.062 ( 0.8462 )
    2.339 ( 0.7391 )
        Monocytes, n=21, 23
    0.244 ( 0.1188 )
    0.222 ( 0.1375 )
        Total neutrophils, n=21, 23
    3.805 ( 2.409 )
    3.106 ( 1.3526 )
        Platelets, n=21, 23
    270.5 ( 92.27 )
    299 ( 73.66 )
        WBC count, n=21, 23
    6.43 ( 2.889 )
    5.98 ( 1.897 )
    Notes
    [5] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [6] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Hemoglobin and mean corpuscle hemoglobin concentration (MCHC) values at Day 14 of the respective treatment period

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    End point title
    		 Hemoglobin and mean corpuscle hemoglobin concentration (MCHC) values at Day 14 of the respective treatment period [7]
    End point description
    Blood samples were collected for the measurement of hemoglobin and MCHC at Day 14 of the respective treatment period.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    Notes
    [7] - 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 performed for this primary endpoint; thus, no data are available.
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [8]
    25 [9]
    Units: Grams per liter (g/L)
    arithmetic mean (standard deviation)
        Hemoglobin, n=21, 23
    125.9 ( 13.49 )
    128 ( 6.52 )
        MCHC, n=21, 23
    330.3 ( 5.83 )
    330.8 ( 7.88 )
    Notes
    [8] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [9] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Reticulocyte and Red Blood Cell (RBC) values at Day 14 of the respective treatment period

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    End point title
    		 Reticulocyte and Red Blood Cell (RBC) values at Day 14 of the respective treatment period [10]
    End point description
    Blood samples were collected for the measurement of reticulocytes and RBCs at Day 14 of the respective treatment period.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    Notes
    [10] - 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 performed for this primary endpoint; thus, no data are available.
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [11]
    25 [12]
    Units: 10^12 cells per liter (TI/L)
    arithmetic mean (standard deviation)
        Reticulocytes, n=21, 23
    0.0722 ( 0.037473 )
    0.07323 ( 0.032203 )
        RBCs, n=21, 23
    4.33 ( 0.467 )
    4.38 ( 0.199 )
    Notes
    [11] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [12] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Hematocrit values at Day 14 of the respective treatment period

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    End point title
    		 Hematocrit values at Day 14 of the respective treatment period [13]
    End point description
    Blood samples were collected for the measurement of hematocrit at Day 14 of the respective treatment period. Hematocrit is a measure of the percentage of the volume of the whole blood that is composed of red blood cells, as determined by separation of red blood cells from the plasma (usually by centrifugation).
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    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 performed for this primary endpoint; thus, no data are available.
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    21 [14]
    23 [15]
    Units: proportion of 1
        arithmetic mean (standard deviation)
    0.3816 ( 0.04199 )
    0.3866 ( 0.0216 )
    Notes
    [14] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [15] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Mean Corpuscle Volume (MCV) value at Day 14 of the respective treatment period

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    End point title
    		 Mean Corpuscle Volume (MCV) value at Day 14 of the respective treatment period [16]
    End point description
    Blood samples were collected for the measurement of MCV at Day 14 of the respective treatment period.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    Notes
    [16] - 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 performed for this primary endpoint; thus, no data are available.
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    21 [17]
    23 [18]
    Units: 10^15 femtoliters (fL) per cell
        arithmetic mean (standard deviation)
    87.9 ( 2.61 )
    88.6 ( 3.37 )
    Notes
    [17] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [18] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Mean Corpuscle Hemoglobin (MCH) values at Day 14 of the respective treatment period

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    End point title
    		 Mean Corpuscle Hemoglobin (MCH) values at Day 14 of the respective treatment period [19]
    End point description
    Blood samples were collected for the measurement of MCH at Day 14 of the respective treatment period.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    Notes
    [19] - 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 performed for this primary endpoint; thus, no data are available.
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    21 [20]
    23 [21]
    Units: 10^12 picograms (pg) per cell
        arithmetic mean (standard deviation)
    29.03 ( 0.941 )
    29.25 ( 1.116 )
    Notes
    [20] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [21] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Alanine amino transferase (ALT), alkaline phosphatase (ALP), aspartate amino transferase (AST), and gamma glutamyl transferase (GGT) values at Day 14 of the respective treatment period

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    End point title
    		 Alanine amino transferase (ALT), alkaline phosphatase (ALP), aspartate amino transferase (AST), and gamma glutamyl transferase (GGT) values at Day 14 of the respective treatment period [22]
    End point description
    Blood samples were collected for the measurement of ALT, ALP, AST, and GGT at Day 14 of the respective treatment period.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    Notes
    [22] - 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 performed for this primary endpoint; thus, no data are available.
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [23]
    25 [24]
    Units: International units per liter (IU/L)
    arithmetic mean (standard deviation)
        ALT, n=22, 24
    16.9 ( 14.63 )
    17.7 ( 14.88 )
        ALP, n=22, 24
    278.4 ( 110.01 )
    272.6 ( 119.48 )
        AST, n=22, 24
    28.2 ( 8.38 )
    29 ( 7.51 )
        GGT, n=22, 24
    14.6 ( 7.74 )
    16.1 ( 10.36 )
    Notes
    [23] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [24] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Albumin and total protein values at Day 14 of the respective treatment period

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    End point title
    		 Albumin and total protein values at Day 14 of the respective treatment period [25]
    End point description
    Blood samples were collected for the measurement of albumin and total protein at Day 14 of the respective treatment period.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    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 performed for this primary endpoint; thus, no data are available.
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [26]
    25 [27]
    Units: Grams per liter
    arithmetic mean (standard deviation)
        Albumin, n=22, 24
    45.5 ( 1.97 )
    45.6 ( 2.2 )
        Total protein, n=22, 24
    70.4 ( 2.99 )
    70.4 ( 3.12 )
    Notes
    [26] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [27] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Calcium, chloride, carbon dioxide (CO2) content/bicarbonate, glucose, potassium, sodium, and urea/blood urea nitrogen (BUN) values at Day 14 of the respective treatment period

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    End point title
    		 Calcium, chloride, carbon dioxide (CO2) content/bicarbonate, glucose, potassium, sodium, and urea/blood urea nitrogen (BUN) values at Day 14 of the respective treatment period [28]
    End point description
    Blood samples were collected for the measurement of calcium, chloride, carbon dioxide content/bicarbonate (CO2/BI), glucose, potassium, sodium, and urea/BUN at Day 14 of the respective treatment period.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    Notes
    [28] - 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 performed for this primary endpoint; thus, no data are available.
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [29]
    25 [30]
    Units: Millimoles per liter (mmol/L)
    arithmetic mean (standard deviation)
        Calcium, n=22, 24
    2.416 ( 0.0591 )
    2.415 ( 0.0749 )
        Chloride, n=22, 24
    103.3 ( 1.75 )
    103.8 ( 1.79 )
        CO2 content/bicarbonate, n=22, 24
    19 ( 1.85 )
    19.1 ( 2.05 )
        Glucose, n=22, 24
    4.5 ( 0.689 )
    4.53 ( 0.523 )
        Potassium, n=22, 24
    4.24 ( 0.184 )
    4.27 ( 0.265 )
        Sodium, n=22, 24
    138.6 ( 1.84 )
    139 ( 1.85 )
        Urea/BUN, n=22, 24
    4.52 ( 1.006 )
    4.52 ( 1.108 )
    Notes
    [29] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [30] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Total bilirubin, direct bilirubin, creatinine, and uric acid values at Day 14 of the respective treatment period

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    End point title
    		 Total bilirubin, direct bilirubin, creatinine, and uric acid values at Day 14 of the respective treatment period [31]
    End point description
    Blood samples were collected for the measurement of total bilirubin, direct bilirubin, creatinine, and uric acid at Day 14 of the respective treatment period.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    Notes
    [31] - 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 performed for this primary endpoint; thus, no data are available.
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [32]
    25 [33]
    Units: Micromoles per liter (µmol/L)
    arithmetic mean (standard deviation)
        Total bilirubin, n=22, 24
    6.1 ( 1.44 )
    5.9 ( 1.72 )
        Direct bilirubin, n=22, 24
    1.7 ( 0.7 )
    1.9 ( 0.41 )
        Creatinine, n=22, 24
    36 ( 7.617 )
    37.09 ( 6.225 )
        Uric acid, n=22, 24
    231.8 ( 64.85 )
    233.8 ( 54.04 )
    Notes
    [32] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [33] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Peak expiratory flow on Day 1 and Day 14 of the respective treatment period

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    End point title
    		 Peak expiratory flow on Day 1 and Day 14 of the respective treatment period [34]
    End point description
    Peak Expiratory Flow (PEF) is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF is calculated as the maximum of three readings taken at each timepoint for each participant. Baseline is defined as the maximum pre-dose measurement at Day 1 for each period.
    End point type
    Primary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 63)
    Notes
    [34] - 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 performed for this primary endpoint; thus, no data are available.
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [35]
    25 [36]
    Units: liters/minute
    arithmetic mean (standard deviation)
        Day 1, Baseline, n=25, 25
    219 ( 53.27 )
    223.6 ( 56.91 )
        Day 1, 10 minutes post-dose, n=25, 25
    218.8 ( 53.02 )
    223 ( 55.15 )
        Day 1, 20 minutes post-dose, n=25, 25
    222.4 ( 53.5 )
    228.2 ( 56.73 )
        Day 1, 1 hour post-dose, n=25, 25
    223.2 ( 54.23 )
    227.2 ( 54.07 )
        Day 1, 2 hours post-dose, n=25, 25
    227 ( 55.94 )
    228.6 ( 54.17 )
        Day 14, Pre-dose, n=23, 24
    224.8 ( 52.86 )
    215 ( 50.71 )
        Day 14, 20 minutes post-dose, n=23, 24
    227.2 ( 52.18 )
    218.1 ( 52.12 )
        Day 14, 2 hours post-dose, n=23, 24
    235.7 ( 53.16 )
    225.8 ( 48.78 )
        Day 14, 12 hours post-dose, n=23, 24
    238.9 ( 55.84 )
    230.4 ( 52.54 )
    Notes
    [35] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [36] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Day 1 and Day 14 of the respective treatment period

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    End point title
    		 Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Day 1 and Day 14 of the respective treatment period [37]
    End point description
    SBP and DBP were measured at Day 1 and Day 14 of the respective treatment period. Baseline is defined as the pre-dose measurement at Day 1. Change from Baseline was calculated as the Day 14 value minus the Baseline value.
    End point type
    Primary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 63)
    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 performed for this primary endpoint; thus, no data are available.
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [38]
    25 [39]
    Units: Millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        Day 1 SBP, Baseline, n=25, 25
    97.2 ( 5.41 )
    99.9 ( 6.71 )
        Day 1 SBP, 20 minutes, n=25, 25
    -0.1 ( 2.98 )
    -0.1 ( 4.66 )
        Day 1 SBP, 1 hour, n=25, 25
    0.5 ( 2.87 )
    0.4 ( 3.7 )
        Day 1 SBP, 2 hours, n=25, 25
    0.9 ( 3.05 )
    1.3 ( 2.95 )
        Day 14 SBP, Pre-dose, n=23, 24
    1.3 ( 4.32 )
    -1.2 ( 6.92 )
        Day 14 SBP, 20 minutes, n=23, 24
    1.3 ( 4.61 )
    -1.2 ( 6.03 )
        Day 14 SBP, 1 hour, n=23, 24
    1 ( 4.42 )
    -0.8 ( 6.36 )
        Day 14 SBP, 2 hours, n=23, 24
    1.7 ( 4.17 )
    -0.8 ( 6.34 )
        Day 14 SBP, 4 hours, n=23, 24
    2.1 ( 4.22 )
    0.1 ( 6.47 )
        Day 14 SBP, 8 hours, n=23, 24
    2 ( 4.33 )
    -0.4 ( 7.17 )
        Day 1 DBP, Baseline, n=25, 25
    62.3 ( 3.54 )
    63.6 ( 3.86 )
        Day 1 DBP, 20 minutes, n=25, 25
    0.3 ( 2.81 )
    -0.3 ( 3.76 )
        Day 1 DBP, 1 hour, n=25, 25
    1 ( 3.17 )
    0.8 ( 3.11 )
        Day 1 DBP, 2 hours, n=25, 25
    0.9 ( 3.42 )
    1 ( 3.38 )
        Day 14 DBP, Pre-dose, n=23, 24
    0.6 ( 3.54 )
    0.2 ( 3.29 )
        Day 14 DBP, 20 minutes, n=23, 24
    0.1 ( 3.69 )
    0.1 ( 2.62 )
        Day 14 DBP, 1 hour, n=23, 24
    0.4 ( 4.18 )
    0 ( 2.3 )
        Day 14 DBP, 2 hours, n=23, 24
    1.3 ( 3.75 )
    0.4 ( 3.19 )
        Day 14 DBP, 4 hours, n=23, 24
    1.1 ( 4.17 )
    1.1 ( 3.35 )
        Day 14 DBP, 8 hours, n=23, 24
    1.4 ( 3.27 )
    -0.2 ( 3.02 )
    Notes
    [38] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [39] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Change from Baseline in heart rate at Day1 and Day 14 of the respective treatment period

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    End point title
    		 Change from Baseline in heart rate at Day1 and Day 14 of the respective treatment period
    End point description
    Heart rate (HR) was measured at Day 1 and Day 14 of the respective treatment period. hr=hour. Baseline is defined as the pre-dose measurement at Day 1. Change from Baseline was calculated as the Day 14 value minus the Baseline value. Treatment, period, day (1 and 14), participant Baseline, period Baseline, and treatment*day interaction were fitted as fixed effects, and participant was fitted as a random effect.
    End point type
    Primary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [40]
    25 [41]
    Units: Beats per minute
    least squares mean (standard error)
        Day 1, n=25, 25
    84.4 ( 1.63 )
    88.6 ( 1.63 )
        Day 14, n=23, 24
    89.4 ( 1.71 )
    85.7 ( 1.67 )
    Notes
    [40] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [41] - All Subjects Population: Only participants available at the specified time points were analyzed.
    Statistical analysis title
    		 Analysis 1
    Comparison groups
    FF 100 µg v FF 100 µg/VI 25 µg
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [42]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.8
         upper limit
    		 0.4
    Notes
    [42] - Day 1 HR. The estimated value represents the treatment difference: FF/VI 100/25 µg minus FF 100 µg.
    Statistical analysis title
    		 Analysis 2
    Comparison groups
    FF 100 µg/VI 25 µg v FF 100 µg
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [43]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 8.5
    Notes
    [43] - Day 14 HR. The estimated value represents the treatment difference: FF/VI 100/25 µg minus FF 100 µg.

    Primary: Maximum QTcF at Day 1 and Day 14 of the respective treatment period

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    End point title
    		 Maximum QTcF at Day 1 and Day 14 of the respective treatment period
    End point description
    QTcF is the QT domain corrected for heart rate by Fridericia’s formula. Treatment, period, day (1 and 14), participant Baseline, period Baseline, and treatment*day interaction were fitted as fixed effects, and participant was fitted as a random effect.
    End point type
    Primary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [44]
    25 [45]
    Units: milliseconds
    least squares mean (standard error)
        Day 1 QTcF, n=25, 25
    403.3 ( 1.98 )
    402.2 ( 1.98 )
        Day 14 QTcF, n=23, 24
    404 ( 2.06 )
    404.2 ( 2.02 )
    Notes
    [44] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [45] - All Subjects Population: Only participants available at the specified time points were analyzed.
    Statistical analysis title
    		 Analysis 1
    Comparison groups
    FF 100 µg v FF 100 µg/VI 25 µg
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [46]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 6.7
    Notes
    [46] - Day 1 QTcF. The estimated value represents the treatment difference: FF/VI 100/25 µg minus FF 100 µg.
    Statistical analysis title
    		 Analysis 2
    Comparison groups
    FF 100 µg/VI 25 µg v FF 100 µg
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [47]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 5.5
    Notes
    [47] - Day 14 QTcF. The estimated value represents the treatment difference: FF/VI 100/25 µg minus FF 100 µg.

    Secondary: AUC(0-t) and AUC(0-4) of FF on Day 14 of the respective treatment period

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    End point title
    		 AUC(0-t) and AUC(0-4) of FF on Day 14 of the respective treatment period
    End point description
    Area under the concentration-time (AUC) curve from time zero (pre-dose) to the last time AUC(0-t) and from time zero to 4 hours AUC(0-4) of quantifiable concentration of FF on Day 14 of the respective treatment period was measured. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, and 4 hours post-dose. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the PK Population.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    24 [48]
    24 [49]
    Units: picograms*hour per milliliter (pg*hr/mL)
    geometric mean (confidence interval 95%)
        AUC(0-t), n=23, 24
    38.895 (21.63 to 69.941)
    32.88 (18.268 to 59.179)
        AUC(0-4), n=17, 15
    86.14 (70.03 to 105.96)
    83.83 (71.49 to 98.3)
    Notes
    [48] - FF PK Population:all participants in the All Subjects Pop for whom a FF PK sample was analyzed
    [49] - FF PK Population:all participants in the All Subjects Pop for whom a FF PK sample was analyzed
    No statistical analyses for this end point

    Secondary: Cmax of FF on Day 14 of the respective treatment period

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    End point title
    		 Cmax of FF on Day 14 of the respective treatment period
    End point description
    Cmax is defined as the maximum observed concentration of FF on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, and 4 hours post-dose.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    23 [50]
    24 [51]
    Units: picograms per milliliter (pg/mL)
        geometric mean (confidence interval 95%)
    20.73 (15.16 to 28.36)
    21.16 (14.91 to 30.02)
    Notes
    [50] - FF PK Population: Only participants available at the specified time points were analyzed.
    [51] - FF PK Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: tmax and tlast of FF on Day 14 of the respective treatment period

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    End point title
    		 tmax and tlast of FF on Day 14 of the respective treatment period
    End point description
    tmax is defined as the time to reach the observed maximum concentration, and tlast is defined as the time of the last observed quantifiable concentration on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, and 4 hours post-dose.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    24 [52]
    24 [53]
    Units: hours
    median (full range (min-max))
        tmax, n=20, 19
    0.965 (0 to 2.07)
    0.5 (0 to 3.95)
        tlast, n=20, 19
    4.03 (0.52 to 4.13)
    4.02 (1.03 to 4.05)
    Notes
    [52] - FF PK Population: Only participants available at the specified time points were analyzed.
    [53] - FF PK Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: AUC(0-t) and AUC(0-4) of VI on Day 14 of the respective treatment period

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    End point title
    		 AUC(0-t) and AUC(0-4) of VI on Day 14 of the respective treatment period
    End point description
    Area under the concentration-time (AUC) curve from time zero (pre-dose) to the last time AUC(0-t) and from time zero to 4 hours AUC(0-4) of quantifiable concentration of VI on Day 14 of the respective treatment period was measured. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, and 4 hours post-dose. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the VI PK Population.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg
    Number of subjects analysed
    23 [54]
    Units: picograms*hour per milliliter (pg*hr/mL)
    geometric mean (confidence interval 95%)
        AUC(0-t), n=23
    44.297 (26.996 to 72.688)
        AUC(0-4), n=11
    119.19 (102.41 to 138.73)
    Notes
    [54] - VI PK Population:all participants in the All Subjects Pop for whom a VI PK sample was analyzed
    No statistical analyses for this end point

    Secondary: Cmax of VI on Day 14 of the respective treatment period

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    End point title
    		 Cmax of VI on Day 14 of the respective treatment period
    End point description
    Cmax is defined as the maximum observed concentration of VI on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, and 4 hours post-dose.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg
    Number of subjects analysed
    23 [55]
    Units: picograms per milliliter (pg/mL)
        geometric mean (confidence interval 95%)
    44.21 (27.65 to 70.7)
    Notes
    [55] - VI PK Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: tmax and tlast of VI on Day 1 of the respective treatment period

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    End point title
    		 tmax and tlast of VI on Day 1 of the respective treatment period
    End point description
    tmax is defined as the time to reach the observed maximum VI concentration, and tlast is defined as the time of the last observed quantifiable VI concentration on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, and 4 hours post-dose.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg
    Number of subjects analysed
    23 [56]
    Units: hours
    median (full range (min-max))
        tmax, n=21
    0.17 (0 to 2.08)
        tlast, n=21
    3.87 (0.5 to 4.13)
    Notes
    [56] - VI PK Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Blood glucose and potassium values on Day 14 of the respective treatment period

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    End point title
    		 Blood glucose and potassium values on Day 14 of the respective treatment period
    End point description
    Blood glucose and potassium values were measured on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, and 4 hours post-dose. Weighted means were derived using the linear trapezoidal rule. Actual relative times were used for the calculation except where actual times were missing. If any actual times were missing, planned relative time were used for these observations. Treatment and period were fitted as fixed effects and participant was fitted as a random effect.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [57]
    25 [58]
    Units: Millimoles per liter (mmol/L)
    least squares mean (confidence interval 95%)
        Glucose, n=22, 24
    5.578 (5.275 to 5.881)
    5.074 (4.781 to 5.367)
        Potassium, n=21, 23
    4.059 (3.969 to 4.15)
    4.148 (4.062 to 4.234)
    Notes
    [57] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [58] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Serum cortisol (SC) weighted mean (0–12 hours) on Day 14 of the respective treatment period

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    End point title
    		 Serum cortisol (SC) weighted mean (0–12 hours) on Day 14 of the respective treatment period
    End point description
    SC weighted mean was determined for each participant over the time period of 0–12 hours on Day 14 of the respective treatment period. SC weighted mean was derived by dividing the area under the concentration-time curve (AUC; defined as thearea under the concentration-time curve from time zero up to 24 hours) by the sample collection time interval. The sample collection time interval is defined as the difference between the time of the last cortisol sample and the time of the first cortisol sample. Samples were collected at the following time points: 0 (first blood draw/pre-dose); 2, 4, 8, and 12 hours (relative to the "0" time point). Weighted means were derived using the linear trapezoidal rule. Actual relative times were used for the calculation except where actual times were missing. If any actual times were missing, planned relative time were used for these observations. Treatment and period were fitted as fixed effects and participant was fitted as a random effect.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    23 [59]
    23 [60]
    Units: nanomoles per Liter
        geometric mean (confidence interval 95%)
    193.77 (168.42 to 222.93)
    192.5 (167.32 to 221.48)
    Notes
    [59] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [60] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Average oropharyngeal cross-sectional area on Day 1 and Day 14 of the respective treatment period

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    End point title
    		 Average oropharyngeal cross-sectional area on Day 1 and Day 14 of the respective treatment period
    End point description
    During the pharyngometry assessment, participants inhaled through a wavetube, which had a mouthpiece with the same dimensions as the mouthpiece on the dry powder inhaler used for the study. This technique was used to measure the size of the throat and mouth (oropharynx) in the form of pharyngograms. Pharyngometry data were recorded for each day (Day 1 and Day 14 of the respective treatment period) using the mean of four measurements (pharyngograms), and the average oropharyngeal cross-sectional area was calculated.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [61]
    25 [62]
    Units: centimeters squared (cm^2)
    arithmetic mean (standard deviation)
        Day 1, n=23, 23
    4.13 ( 2.01 )
    3.85 ( 2.043 )
        Day 14, n=23, 23
    3.76 ( 2.195 )
    3.7 ( 2.279 )
    Notes
    [61] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [62] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Distance of assessment on Day 1 and Day 14 of the respective treatment period

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    End point title
    		 Distance of assessment on Day 1 and Day 14 of the respective treatment period
    End point description
    During the pharyngometry assessment, participants inhaled through a wavetube, which had a mouthpiece with the same dimensions as the mouthpiece on the dry powder inhaler used for this study. This technique was used to measure the size of the throat and mouth (oropharynx) in the form of pharyngograms. Distance of assessment is defined as the distance (length measured in centimeters [cm]) estimated to be from the lips to the larynx. Pharyngometry data were recorded for each day (Days 1 and 14 of the respective treatment period) using the mean of four measurements (pharyngograms), and the average oropharyngeal cross-sectional area was calculated.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [63]
    25 [64]
    Units: centimeters (cm)
    arithmetic mean (standard deviation)
        Day 1, n=23, 23
    19.2 ( 1.097 )
    19.24 ( 0.959 )
        Day 14, n=23, 23
    19.26 ( 0.717 )
    19.1 ( 1.003 )
    Notes
    [63] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [64] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Oropharyngeal volume on Day 1 and Day 14 of the respective treatment period

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    End point title
    		 Oropharyngeal volume on Day 1 and Day 14 of the respective treatment period
    End point description
    During the pharyngometry assessment, participants inhaled through a wavetube, which had a mouthpiece with the same dimensions as the mouthpiece on the dry powder inhaler used for this study. This technique was used to measure the size of the throat and mouth (oropharynx) in the form of pharyngograms. Oropharyngeal volume is defined as the volume (cm^3) of the mouth and throat estimated to be from the lips to the larynx. Pharyngometry data were recorded for each day (Days 1 and 14 of the respective treatment period) using the mean of four measurements (pharyngograms), and the average oropharyngeal cross-sectional area was calculated.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [65]
    25 [66]
    Units: Liters per minute (L/min)
    arithmetic mean (standard deviation)
        Day 1, n=23, 23
    79.49 ( 43.398 )
    75.54 ( 44.195 )
        Day 14, n=23, 23
    72.35 ( 42.437 )
    71.47 ( 45.841 )
    Notes
    [65] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [66] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Average flow rate and Peak Inspiratory Flow Rate (PIFR) on Day 1 and Day 14 of the respective treatment period

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    End point title
    		 Average flow rate and Peak Inspiratory Flow Rate (PIFR) on Day 1 and Day 14 of the respective treatment period
    End point description
    During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Average flow rate is defined as the average inspiratory flow rate (Liters [L]/min) across the inhalation profile when inhaling across the resistance of the inhaler. PIFR is defined as the Peak Inspiratory Flow Rate (L/min) of the inhalation profile when inhaling across the resistance of the inhaler.The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was used for each day (Days 1 and 14 of the respective treatment period), and the average flow rate and PIFR were determined.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [67]
    25 [68]
    Units: Liters per minute (L/min)
    arithmetic mean (standard deviation)
        Day 1, Average flow rate, n=23, 23
    41.11 ( 11.294 )
    42.72 ( 11.593 )
        Day 14, Average flow rate, n=23, 23
    42.29 ( 10.895 )
    41.36 ( 10.354 )
        Day 1, PIFR, n=23, 23
    65.85 ( 16.649 )
    67.6 ( 16.097 )
        Day 14, PIFR, n=23, 23
    67.36 ( 16.432 )
    64.79 ( 15.886 )
    Notes
    [67] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [68] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Inhalation time on Days 1 and 14 of of the respective treatment period

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    End point title
    		 Inhalation time on Days 1 and 14 of of the respective treatment period
    End point description
    During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Inhalation time is defined as the duration of the inhalation(s) when inhaling across the resistance of the inhaler. The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was used for each day (Days 1 and 14 of the respective treatment period), and the inhalation time was determined.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [69]
    25 [70]
    Units: Seconds (sec)
    arithmetic mean (standard deviation)
        Day 1, n=23, 23
    0.97 ( 0.35 )
    0.83 ( 0.385 )
        Day 14, n=23, 23
    0.96 ( 0.314 )
    0.91 ( 0.347 )
    Notes
    [69] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [70] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Inhaled volume on Days 1 and 14 of the respective treatment period

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    End point title
    		 Inhaled volume on Days 1 and 14 of the respective treatment period
    End point description
    During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Inhaled volume is defined as the volume of air (Liters) inhaled during the inhalation across the resistance of the inhaler. The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was used for each day (Days 1 and 14 of the respective treatment period), and the inhalaled volume was determined.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [71]
    25 [72]
    Units: Liters
    arithmetic mean (standard deviation)
        Day 1, n=23, 23
    0.69 ( 0.337 )
    0.58 ( 0.285 )
        Day 14, n=23, 23
    0.68 ( 0.308 )
    0.65 ( 0.352 )
    Notes
    [71] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [72] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Peak pressure drop on Days 1 and 14 of the respective treatment period

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    End point title
    		 Peak pressure drop on Days 1 and 14 of the respective treatment period
    End point description
    During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Peak pressure drop is defined as the maximum pressure drop (kilopascal [kPa]) achieved during inhalation across the resistance of the inhaler. The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was calculated for each day (Days 1 and 14 of the respective treatment period), and used for subsequent modeling and prediction of dose emission attributes.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [73]
    25 [74]
    Units: Kilopascal (kpa)
    arithmetic mean (standard deviation)
        Day 1, n=23, 23
    3.79 ( 1.706 )
    3.97 ( 1.787 )
        Day 14, n=23, 23
    3.93 ( 1.877 )
    3.67 ( 1.611 )
    Notes
    [73] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [74] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Total emitted dose (TED) on Day 14 of the respective treatment period

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    End point title
    		 Total emitted dose (TED) on Day 14 of the respective treatment period
    End point description
    The total emitted dose (TED) is defined as the mass (micrograms) of the nominal dose that passes beyond the throat. The recorded inhalation profiles of the participants and the mouth-throat (oropharyngeal) models of the sizes that approximated to pharyngometry measurements of the participants were used in conjunction with the electronic Lung (eLung) for in vitro assessment. The eLung is a breathing simulator that replicates the selected inhalation profile with an active inhaler placed at the lips end of the selected ororpharyngeal model. After the dose is emitted from the inhaler, the analysis and assay of throat deposition and material passing beyond the throat was used to derive the nominal, minimum, and maximum predicted total emitted dose. The TED of VI was not assessed in participants receiving only FF; therefore, the values are reported as 0.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [75]
    25 [76]
    Units: micrograms
    arithmetic mean (standard deviation)
        Nominal TED FF, n=23, 23
    87.58 ( 0.305 )
    86.33 ( 1.505 )
        Minimum TED FF, n=23, 23
    87.64 ( 0.33 )
    86.72 ( 1.589 )
        Maximum TED FF, n=23, 23
    87.51 ( 0.289 )
    85.93 ( 1.534 )
        Nominal TED VI, n=23, 0
    20.26 ( 0.162 )
    0 ( 0 )
        Minimum TED VI, n=23, 0
    20.22 ( 0.153 )
    0 ( 0 )
        Maximum TED VI, n=23, 0
    20.29 ( 0.175 )
    0 ( 0 )
    Notes
    [75] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [76] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Ex-throat dose (ETD) and ETD <2 microns on Day 14 of the respective treatment period

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    End point title
    		 Ex-throat dose (ETD) and ETD <2 microns on Day 14 of the respective treatment period
    End point description
    The ex-throat dose (ETD) and the “nominal ETD” is the mass (micrograms) of active investigational material that passes beyond the throat, nominal being the mean. The recorded inhalation profiles of the participants and the mouth-throat (oropharyngeal) models of the sizes that approximated to pharyngometry measurements of the participants were used in conjunction with the electronic Lung (eLung) for in vitro assessment. The eLung is a breathing simulator that replicates the selected inhalation profile with an active inhaler placed at the lips end of the selected ororpharyngeal model. After the dose is emitted from the inhaler, the analysis and assay of throat deposition and material passing beyond the throat was used to derive the nominal, minimum, and maximum predicted ETD and ETD <2 microns. The ETD of VI was not assessed in participants receiving only FF; therefore, the values were entered as 0.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 63)
    End point values
    		 FF 100 µg/VI 25 µg FF 100 µg
    Number of subjects analysed
    25 [77]
    25 [78]
    Units: micrograms
    arithmetic mean (standard deviation)
        Nominal ETD FF, n=23, 23
    24.96 ( 5.801 )
    24.34 ( 8.574 )
        Minimum ETD FF, n=23, 23
    23.38 ( 7.023 )
    22.99 ( 9.12 )
        Maximum ETD FF, n=23, 23
    26.24 ( 4.825 )
    25.48 ( 8.197 )
        ETD <2 microns FF, n=23, 23
    6.66 ( 0.948 )
    5.97 ( 1.382 )
        Minimum ETD <2 microns FF, n=23, 23
    6.45 ( 0.788 )
    5.77 ( 1.319 )
        Maximum ETD <2 microns FF, n=23, 23
    6.92 ( 1.147 )
    6.21 ( 1.476 )
        Nominal ETD VI, n=23, 0
    8.54 ( 0.953 )
    0 ( 0 )
        Minimum ETD VI, n=23, 0
    8.33 ( 0.793 )
    0 ( 0 )
        Maximum ETD VI, n=23, 0
    8.8 ( 1.154 )
    0 ( 0 )
        ETD <2 microns VI, n=23, 0
    4.86 ( 1.162 )
    0 ( 0 )
        Minimum ETD <2 microns VI, n=23, 0
    4.6 ( 0.965 )
    0 ( 0 )
        Maximum ETD <2 microns VI, n=23, 0
    5.18 ( 1.409 )
    0 ( 0 )
    Notes
    [77] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [78] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment AEs
    Adverse event reporting additional description
    Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    FF 100 µg/VI 25 µg
    Reporting group description
    		 Participants received FF 100 µg/VI 25 µg in one of the two 14-day treatment periods. FF 100 µg/VI 25 µg was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.

    Reporting group title
    FF 100 µg
    Reporting group description
    		 Participants received FF 100 µg in one of the two 14-day treatment periods. FF 100 µg was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.

    Serious adverse events
    		 FF 100 µg/VI 25 µg FF 100 µg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 FF 100 µg/VI 25 µg FF 100 µg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 25 (16.00%)
    1 / 25 (4.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis, Viral
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    Pharyngitis, Streptococcal
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1

    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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