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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, two-way crossover 14-day study to invstigate the safety, tolerability,pharmacodynamics and pharmacokinetics of repeat dose inhaled fluticasone furoate 100 mcg in children aged 5-11 years with persistent asthma

    Summary
    EudraCT number
    		 2012-000753-31
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    29 Jan 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Mar 2016
    First version publication date
    25 Feb 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HZA102942
    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
    29 Jan 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jan 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the safety and tolerability following administration of fluticasone furoate 100 μg (via a novel dry powder inhaler) once daily for 14 days in 5–11 year-old subjects.
    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 May 2010
    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: 27
    Worldwide total number of subjects
    27
    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)
    27
    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 treatment sequences (fluticasone furoate [FF] 100 µg followed by placebo; placebo followed by FF 100 µg). Results are reported by intervention, regardless of the age of the participant.

    Period 1
    Period 1 title
    Treatment Period 1 (14 days):Overall
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Subject, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sequence 1: FF 100 µg followed by Placebo
    Arm description
    		 Participants received fluticasone furoate (FF) 100 micrograms (µg) in Treatment Period 1 and matching placebo in Treatment Period 2. Inhaled FF 100 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Arm type
    		 Experimental:Placebo

    Investigational medicinal product name
    Fluticasone furoate; placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF 100ug or Pbo once daily x 14 days; 7 day w/o; crossover

    Arm title
    		 Sequence 2: Placebo followed by FF 100 µg
    Arm description
    		 Participants received placebo in Treatment Period 1 and FF 100 µg in Treatment Period 2. Inhaled FF 100 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Arm type
    		 Experimental:Placebo

    Investigational medicinal product name
    Fluticasone furoate; placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF 100ug or Pbo once daily x 14 days; 7 day w/o; crossover

    Number of subjects in period 1
    		Sequence 1: FF 100 µg followed by Placebo Sequence 2: Placebo followed by FF 100 µg
    Started
    14
    13
    Completed
    12
    12
    Not completed
    2
    1
         Adverse event, non-fatal
    1
    -
         Protocol deviation
    1
    1
    Period 2
    Period 2 title
    Washout Period (>=7 days)
    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
    		 Sequence 1: FF 100 µg followed by Placebo
    Arm description
    		 Participants received fluticasone furoate (FF) 100 micrograms (µg) in Treatment Period 1 and matching placebo in Treatment Period 2. Inhaled FF 100 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Arm type
    		 Experimental:Placebo

    Investigational medicinal product name
    Fluticasone furoate; placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF 100ug or Pbo once daily x 14 days; 7 day w/o; crossover

    Arm title
    		 Sequence 2: Placebo followed by FF 100 µg
    Arm description
    		 Participants received placebo in Treatment Period 1 and FF 100 µg in Treatment Period 2. Inhaled FF 100 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Arm type
    		 Experimental:Placebo

    Investigational medicinal product name
    Fluticasone furoate; placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF 100ug or Pbo once daily x 14 days; 7 day w/o; crossover

    Number of subjects in period 2
    		Sequence 1: FF 100 µg followed by Placebo Sequence 2: Placebo followed by FF 100 µg
    Started
    12
    12
    Completed
    12
    12
    Period 3
    Period 3 title
    Treatment Period 2 (14 days)
    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
    		 Sequence 1: FF 100 µg followed by Placebo
    Arm description
    		 Participants received fluticasone furoate (FF) 100 micrograms (µg) in Treatment Period 1 and matching placebo in Treatment Period 2. Inhaled FF 100 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Arm type
    		 Experimental:Placebo

    Investigational medicinal product name
    Fluticasone furoate; placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF 100ug or Pbo once daily x 14 days; 7 day w/o; crossover

    Arm title
    		 Sequence 2: Placebo followed by FF 100 µg
    Arm description
    		 Participants received placebo in Treatment Period 1 and FF 100 µg in Treatment Period 2. Inhaled FF 100 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Arm type
    		 Experimental:Other

    Investigational medicinal product name
    Fluticasone furoate; placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF 100ug or Pbo once daily x 14 days; 7 day w/o; crossover

    Number of subjects in period 3
    		Sequence 1: FF 100 µg followed by Placebo Sequence 2: Placebo followed by FF 100 µg
    Started
    12
    12
    Completed
    11
    11
    Not completed
    1
    1
         Physician decision
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period 1 (14 days):Overall
    Reporting group description
    		 Participants received either fluticasone furoate (FF) 100 micrograms (µg) or matching placebo in the first of two 14-day treatment periods, followed by the other therapy (the therapy not received in the first treatment period) in the second 14-day treatment period. Inhaled FF 100 µg or matching placebo 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 values
    		 Treatment Period 1 (14 days):Overall Total
    Number of subjects
    		 27 27
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.2 ( 2.08 ) -
    Gender categorical
    Units: Subjects
        Female
    		 13 13
        Male
    		 14 14
    Race
    Units: Subjects
        African American/African Heritage
    		 9 9
        White
    		 16 16
        African American/African Heritage & White
    		 1 1
        Unknown; Child Was Adopted
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Sequence 1: FF 100 µg followed by Placebo
    Reporting group description
    		 Participants received fluticasone furoate (FF) 100 micrograms (µg) in Treatment Period 1 and matching placebo in Treatment Period 2. Inhaled FF 100 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.

    Reporting group title
    Sequence 2: Placebo followed by FF 100 µg
    Reporting group description
    		 Participants received placebo in Treatment Period 1 and FF 100 µg in Treatment Period 2. Inhaled FF 100 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Reporting group title
    Sequence 1: FF 100 µg followed by Placebo
    Reporting group description
    		 Participants received fluticasone furoate (FF) 100 micrograms (µg) in Treatment Period 1 and matching placebo in Treatment Period 2. Inhaled FF 100 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.

    Reporting group title
    Sequence 2: Placebo followed by FF 100 µg
    Reporting group description
    		 Participants received placebo in Treatment Period 1 and FF 100 µg in Treatment Period 2. Inhaled FF 100 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Reporting group title
    Sequence 1: FF 100 µg followed by Placebo
    Reporting group description
    		 Participants received fluticasone furoate (FF) 100 micrograms (µg) in Treatment Period 1 and matching placebo in Treatment Period 2. Inhaled FF 100 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.

    Reporting group title
    Sequence 2: Placebo followed by FF 100 µg
    Reporting group description
    		 Participants received placebo in Treatment Period 1 and FF 100 µg in Treatment Period 2. Inhaled FF 100 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants who received matching placebo in one or both of the two 14-day treatment periods. Matching placebo 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
    All participants who received FF 100 µg in one or both of the 14-day treatment periods. Inhaled 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
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All participants who received FF 100 µg in one or both of the 14-day treatment periods. Inhaled 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 6)/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
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [2]
    26 [3]
    Units: Participants
        Any AE
    4
    8
        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 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 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 respective treatment period.
    End point type
    Primary
    End point timeframe
    Day 14 of respective treatment period (up to Study Day 44)
    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
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [5]
    26 [6]
    Units: 10^9 cells per liter (GI/L)
    arithmetic mean (standard deviation)
        Basophils, n=23, 21
    0.022 ( 0.0153 )
    0.022 ( 0.0154 )
        Eosinophils, n=23, 21
    0.308 ( 0.2204 )
    0.252 ( 0.2182 )
        Lymphocytes, n=23, 21
    2.595 ( 0.7834 )
    2.43 ( 0.6563 )
        Monocytes, n=23, 21
    0.28 ( 0.1669 )
    0.27 ( 0.1204 )
        Total neutrophils, n=23, 21
    2.74 ( 1.2091 )
    3.209 ( 1.3103 )
        Platelets, n=23, 20
    266.4 ( 48.59 )
    263.3 ( 55.9 )
        WBCs, n=23, 21
    5.94 ( 1.696 )
    6.18 ( 1.513 )
    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 44)
    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
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [8]
    26 [9]
    Units: Grams per liter (g/L)
    arithmetic mean (standard deviation)
        Hemoglobin, n=23, 21
    129.1 ( 7.15 )
    129.6 ( 6.5 )
        MCHC, n=23, 21
    336.4 ( 7.66 )
    336.6 ( 7.8 )
    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 reticulocyte 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 44)
    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
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [11]
    26 [12]
    Units: 10^12 cells per liter (TI/L)
    arithmetic mean (standard deviation)
        Reticulocytes, n=23, 21
    0.04952 ( 0.024497 )
    0.04499 ( 0.021309 )
        RBCs, n=23, 21
    4.43 ( 0.277 )
    4.46 ( 0.296 )
    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 44)
    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
    		 Placebo FF 100 µg
    Number of subjects analysed
    23 [14]
    21 [15]
    Units: percentage of red blood cells in blood
        arithmetic mean (standard deviation)
    0.384 ( 0.02621 )
    0.3854 ( 0.02296 )
    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 44)
    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
    		 Placebo FF 100 µg
    Number of subjects analysed
    23 [17]
    21 [18]
    Units: 10^15 femtoliters (fL) per cell
        arithmetic mean (standard deviation)
    86.8 ( 4.05 )
    86.9 ( 4.4 )
    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 44)
    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
    		 Placebo FF 100 µg
    Number of subjects analysed
    23 [20]
    21 [21]
    Units: 10^12 picograms (pg) per cell
        arithmetic mean (standard deviation)
    29.18 ( 1.279 )
    29.24 ( 1.458 )
    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 44)
    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
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [23]
    26 [24]
    Units: International units per liter (IU/L)
    arithmetic mean (standard deviation)
        ALT, n=22, 20
    12.2 ( 3.06 )
    13 ( 6.04 )
        ALP, n=22, 20
    257.8 ( 59.24 )
    260.7 ( 64.15 )
        AST, n=22, 19
    26.8 ( 4.39 )
    26.1 ( 4.53 )
        GGT, n=22, 20
    14.3 ( 3.58 )
    15.4 ( 4.5 )
    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 44)
    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
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [26]
    26 [27]
    Units: Grams per liter
    arithmetic mean (standard deviation)
        Albumin, n=22, 20
    43 ( 2.26 )
    42.9 ( 1.83 )
        Total protein, n=22, 20
    67.8 ( 2.98 )
    67.8 ( 2.57 )
    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 44)
    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
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [29]
    26 [30]
    Units: Millimoles per liter (mmol/L)
    arithmetic mean (standard deviation)
        Calcium, n=20, 19
    2.371 ( 0.0791 )
    2.366 ( 0.0626 )
        Chloride, n=22, 20
    105.2 ( 1.93 )
    104.7 ( 1.72 )
        CO2 content/bicarbonate, n=20, 19
    17.4 ( 2.04 )
    17.8 ( 1.86 )
        Glucose, n=22, 20
    5.13 ( 0.614 )
    4.86 ( 0.319 )
        Potassium, n=20, 19
    4.24 ( 0.254 )
    4.24 ( 0.289 )
        Sodium, n=22, 20
    138.3 ( 1.55 )
    137.4 ( 1.54 )
        Urea/BUN, n=22, 20
    4.66 ( 0.993 )
    4.83 ( 1.331 )
    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, creatinine, and uric acid values at Day 14 of the respective treatment period

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    End point title
    		 Total 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, 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 44)
    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
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [32]
    26 [33]
    Units: Micromoles per liter (µmol/L)
    arithmetic mean (standard deviation)
        Total bilirubin, n= 22, 20
    5.9 ( 2.27 )
    5.6 ( 1.23 )
        Creatinine, n= 22, 20
    39.89 ( 7.775 )
    40.62 ( 8.421 )
        Uric acid, n= 22, 20
    237.7 ( 65.46 )
    234.5 ( 70.97 )
    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 X)
    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
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [35]
    25 [36]
    Units: liters/minute
    arithmetic mean (standard deviation)
        Day 1, Baseline, n=25, 25
    242.3 ( 77.68 )
    238.4 ( 64.98 )
        Day 1, 15 minutes post-dose, n=25, 25
    242.1 ( 78.98 )
    238.2 ( 58.97 )
        Day 1, 30 minutes post-dose, n=25, 25
    249.2 ( 78.07 )
    246 ( 62.65 )
        Day 1, 1 hour post-dose, n=25, 25
    247.7 ( 72.54 )
    247 ( 64.75 )
        Day 1, 2 hours post-dose, n=25, 25
    252.3 ( 89.08 )
    252.6 ( 61.77 )
        Day 14, Pre-dose, n=24, 23
    242 ( 73.6 )
    240.6 ( 83.88 )
        Day 14, 30 minutes post-dose, n=23, 23
    246.1 ( 81.17 )
    238.8 ( 88.78 )
        Day 14, 1 hours post-dose, n=23, 23
    247 ( 77.95 )
    237.6 ( 78.66 )
        Day 14, 2 hours post-dose, n=23, 23
    249.5 ( 74.09 )
    242.3 ( 72.02 )
        Day 14, 4 hours post-dose, n=23, 23
    250.6 ( 82.43 )
    246.2 ( 70.43 )
        Day 14, 7 hours post-dose, n=23, 23
    246.3 ( 79.07 )
    232.1 ( 59.82 )
        Day 14, 12 hours post-dose, n=23, 23
    241.9 ( 75.8 )
    245.6 ( 76.68 )
    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: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Baseline and Day 14 of the respective treatment period

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    End point title
    		 Systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Baseline and Day 14 of the respective treatment period [37]
    End point description
    SBP and DBP were measured at Baseline and Day 14 of the respective treatment period. Baseline is defined as the pre-dose measurement at Day 1 for each period.
    End point type
    Primary
    End point timeframe
    Baseline and Day 14 of the respective treatment period (up to Study Day 44)
    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
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [38]
    26 [39]
    Units: Millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        Day 1 SBP, Predose, n=25, 26
    103.1 ( 9.29 )
    102.9 ( 9.68 )
        Day 1 SBP, 30 minutes, n=25, 26
    101.2 ( 8.57 )
    103.8 ( 10.44 )
        Day 1 SBP, 1 hour, n=25, 26
    102.7 ( 11.11 )
    105.2 ( 11.19 )
        Day 1 SBP, 2 hours, n=25, 26
    102.9 ( 9.98 )
    103.9 ( 9.04 )
        Day 14 SBP, Predose, n=24, 23
    101.8 ( 8.04 )
    102.1 ( 9.92 )
        Day 14 SBP, 1 hour, n=23, 23
    102.6 ( 9.14 )
    103.1 ( 8.04 )
        Day 14 SBP, 4 hours, n=23, 23
    102 ( 9.07 )
    102.7 ( 9.43 )
        Day 14 SBP, 7 hours, n=23, 23
    103.4 ( 9.34 )
    103.9 ( 9.88 )
        Day 14 SBP, 12 hours, n=23, 23
    103.2 ( 7.42 )
    106.3 ( 10.61 )
        Day 1 DBP, Predose, n=25, 26
    62 ( 9.71 )
    61.7 ( 7.66 )
        Day 1 DBP, 30 minutes, n=25, 26
    63 ( 9.09 )
    62.6 ( 6.39 )
        Day 1 DBP, 1 hour, n=25, 26
    61.4 ( 8.69 )
    62.3 ( 8.73 )
        Day 1 DBP, 2 hours, n=25, 26
    63 ( 8.34 )
    61.2 ( 8.39 )
        Day 14 DBP, Predose, n=24, 23
    61.3 ( 6.91 )
    61.4 ( 6.81 )
        Day 14 DBP, 1 hour, n=23, 23
    63.9 ( 10.14 )
    62.7 ( 6.88 )
        Day 14 DBP, 4 hours, n=23, 23
    60.4 ( 8.81 )
    60.5 ( 6.73 )
        Day 14 DBP, 7 hours, n=23, 23
    61.8 ( 9.27 )
    62.3 ( 8.23 )
        Day 14 DBP, 12 hours, n=23, 23
    62 ( 8.1 )
    63.9 ( 8.68 )
    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: Heart rate at Baseline and Day 14 of the respective treatment period

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    End point title
    		 Heart rate at Baseline and Day 14 of the respective treatment period [40]
    End point description
    Heart rate (HR) was measured at Baseline and Day 14 of the respective treatment period. Baseline is defined as the pre-dose measurement at Day 1 for each period.
    End point type
    Primary
    End point timeframe
    Baseline and Day 14 of the respective treatment period (up to Study Day 44)
    Notes
    [40] - 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
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [41]
    26 [42]
    Units: Beats per minute
    arithmetic mean (standard deviation)
        Day 1, Baseline, n=25, 26
    78.7 ( 13.18 )
    75.9 ( 11.48 )
        Day 1, 30 minutes, n=25, 26
    78.5 ( 13.99 )
    75.5 ( 10.9 )
        Day 1, 1 hour, n=25, 26
    78.6 ( 12.62 )
    77.6 ( 11.49 )
        Day 1, 2 hours, n=25, 26
    80.6 ( 13.3 )
    79.6 ( 11.78 )
        Day 14, Predose, n=24, 23
    76.8 ( 13.52 )
    74.5 ( 10.6 )
        Day 14, 1 hour, n=23, 23
    80.3 ( 14.76 )
    76.2 ( 8.6 )
        Day 14, 4 hours, n=23, 23
    78.2 ( 10.46 )
    77.7 ( 9.77 )
        Day 14, 7 hours, n=23, 23
    83.1 ( 14.65 )
    81.2 ( 12.13 )
        Day 14, 12 hours, n=23, 23
    83.6 ( 11.7 )
    81.1 ( 10.71 )
    Notes
    [41] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [42] - 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 the indicated electrocardiographic (ECG) parameters at the indicated time points on Day 14 of the respective treatment period

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    End point title
    		 Change from Baseline in the indicated electrocardiographic (ECG) parameters at the indicated time points on Day 14 of the respective treatment period [43]
    End point description
    PR, QRS, QT, QTcB, QTcF, and RR were measured at Baseline and Day 14 of the respective treatment period. Baseline is defined as the pre-dose measurement at Day 1 for each period. Change from Baseline was calculated as the value at Day 14 minus the Baseline value. QTcB is the QT duration corrected for heart rate by Bazett’s formula. QTcF is the QT duration corrected for heart rate by Fridericia’s formula.
    End point type
    Primary
    End point timeframe
    Baseline and Day 14 of the respective treatment period (up to Study Day 44)
    Notes
    [43] - 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
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [44]
    26 [45]
    Units: milliseconds (msec)
    arithmetic mean (standard deviation)
        Day 1 PR Interval, 30 minutes, n=25, 26
    6.4 ( 6.37 )
    7.5 ( 7.54 )
        Day 1 PR Interval, 1 hour, n=25, 26
    7.3 ( 6.68 )
    8.4 ( 7.17 )
        Day 1 PR Interval, 2 hours, n=25, 26
    8 ( 8.61 )
    9.5 ( 10.48 )
        Day 14 PR Interval, Predose, n=24, 23
    7.8 ( 6.76 )
    9.6 ( 9.82 )
        Day 14 PR Interval, 1 hour, n=23, 23
    8.7 ( 6.74 )
    8.3 ( 6.03 )
        Day 14 PR Interval, 4 hours, n=23, 23
    6.4 ( 3.7 )
    8.9 ( 6.86 )
        Day 14 PR Interval, 7 hour, n=23, 23
    8.3 ( 6.56 )
    10.2 ( 10.09 )
        Day 14 PR Interval, 12 hours, n=22, 23
    7.2 ( 7.5 )
    9.7 ( 6.54 )
        Day 1 QRS Interval, 30 minutes, n=25, 26
    4.6 ( 3.46 )
    5.2 ( 4.7 )
        Day 1 QRS Interval, 1 hour, n=25, 26
    4.1 ( 2.84 )
    4.4 ( 3.86 )
        Day 1 QRS Interval, 2 hours, n=25, 26
    4 ( 2.64 )
    4.5 ( 3.61 )
        Day 14 QRS Interval, Predose, n=24, 23
    4.2 ( 3.71 )
    4.7 ( 4.29 )
        Day 14 QRS Interval, 1 hour, n=23, 23
    5.7 ( 3.54 )
    5.3 ( 4.71 )
        Day 14 QRS Interval, 4 hours, n=23, 23
    5.6 ( 3.85 )
    4.9 ( 3.93 )
        Day 14 QRS Interval, 7 hours, n=23, 23
    6.1 ( 5.25 )
    4.3 ( 4.22 )
        Day 14 QRS Interval, 12 hours, n=23, 23
    5 ( 4.7 )
    4.8 ( 4.02 )
        Day 1 QT Interval, 30 minutes, n=25, 26
    9.8 ( 8.14 )
    10.5 ( 9.57 )
        Day 1 QT Interval, 1 hour, n=25, 26
    13.1 ( 11.04 )
    12.7 ( 11.53 )
        Day 1 QT Interval, 2 hours, n=25, 26
    17.5 ( 13.88 )
    15.5 ( 13.83 )
        Day 14 QT Interval, Predose, n=24, 23
    12.5 ( 9.81 )
    15.5 ( 13.34 )
        Day 14 QT Interval, 1 hour, n=23, 23
    11.4 ( 6.45 )
    15.9 ( 11.11 )
        Day 14 QT Interval, 4 hours, n=23, 23
    13.3 ( 9.65 )
    16.7 ( 12.52 )
        Day 14 QT Interval, 7 hours, n=23, 23
    14.7 ( 10.94 )
    15.3 ( 11.93 )
        Day 14 QT Interval, 12 hours, n=23, 23
    14.7 ( 10.42 )
    24.8 ( 14.93 )
        Day 1 QTcB Interval, 30 minutes, n=25, 26
    15.4 ( 14.44 )
    14.2 ( 11.64 )
        Day 1 QTcB Interval, 1 hour, n=25, 26
    17.3 ( 13.46 )
    17.7 ( 13.18 )
        Day 1 QTcB Interval, 2 hours, n=25, 26
    13.6 ( 11.07 )
    18.2 ( 17.54 )
        Day 14 QTcB Interval, Predose, n=24, 23
    20.7 ( 15.54 )
    17.9 ( 14.92 )
        Day 14 QTcB Interval, 1 hour, n=23, 23
    16.6 ( 9.43 )
    16.2 ( 9.71 )
        Day 14 QTcB Interval, 4 hours, n=23, 23
    14.7 ( 9.13 )
    16.8 ( 9.23 )
        Day 14 QTcB Interval, 7 hours, n=23, 23
    14.5 ( 10.14 )
    19.6 ( 12.03 )
        Day 14 QTcB Interval, 12 hours, n=23, 23
    13.8 ( 10.7 )
    18.5 ( 15.7 )
        Day 1 QTcF Interval, 30 minutes, n=25, 26
    10.8 ( 9.31 )
    11.8 ( 9.3 )
        Day 1 QTcF Interval, 1 hour, n=25, 26
    11.6 ( 9.57 )
    12.6 ( 10 )
        Day 1 QTcF Interval, 2 hours, n=25, 26
    10.4 ( 8.36 )
    15.4 ( 12.88 )
        Day 14 QTcF Interval, Predose, n=24, 23
    14.2 ( 9.92 )
    12.6 ( 10.99 )
        Day 14 QTcF Interval, 1 hour, n=23, 23
    9.3 ( 6.09 )
    11.4 ( 9.56 )
        Day 14 QTcF Interval, 4 hours, n=23, 23
    7.8 ( 6.97 )
    15.7 ( 7.41 )
        Day 14 QTcF Interval, 7 hours, n=23, 23
    9.3 ( 7.77 )
    15 ( 9.51 )
        Day 14 QTcF Interval, 12 hours, n=23, 23
    8.8 ( 5.84 )
    15.8 ( 11.61 )
        Day 1 RR Interval, 30 minutes, n=25, 26
    70.4 ( 66.47 )
    54.2 ( 44.61 )
        Day 1 RR Interval, 1 hour, n=25, 26
    93.5 ( 64.97 )
    90.7 ( 52.94 )
        Day 1 RR Interval, 2 hours, n=25, 26
    102 ( 61.66 )
    80.4 ( 71.51 )
        Day 14 RR Interval, Predose, n=24, 23
    106 ( 73.2 )
    103.5 ( 78.48 )
        Day 14 RR Interval, 1 hour, n=23, 23
    92.5 ( 64.45 )
    87.7 ( 63.3 )
        Day 14 RR Interval, 4 hours, n=23, 23
    92.1 ( 65.93 )
    63.6 ( 47.14 )
        Day 14 RR Interval, 7 hours, n=23, 23
    89.6 ( 63.06 )
    74.5 ( 78.18 )
        Day 14 RR Interval, 12 hours, n=23, 23
    94.4 ( 73.45 )
    110.3 ( 101.24 )
    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.
    No statistical analyses for this end point

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

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    End point title
    		 AUC(0-t) on Day 14 of the respective treatment period
    End point description
    Area under the concentration-time (AUC(0-t)) curve from time zero (pre-dose) to the last time of quantifiable concentration of FF on Day 14 of the respective treatment period was measured. Samples were collected at the following times: pre-dose; 30 minutes, 1, 2, 4, 7, and 12 hours post-dose on Day 14 of the respective treatment period. Due to non-quantifiable values, it was not possible to derive AUC(0-12).
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period
    End point values
    		 FF 100 µg
    Number of subjects analysed
    23 [46]
    Units: picograms*hour per milliliter (pg*hr/mL)
        geometric mean (confidence interval 95%)
    91.29 (63.24 to 131.78)
    Notes
    [46] - Pharmacokinetic (PK) Pop: all participants in the All Subjects Pop for whom a PK sample was analyzed
    No statistical analyses for this end point

    Secondary: Cmax on Day 14 of the respective treatment period

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    End point title
    		 Cmax on Day 14 of the respective treatment period
    End point description
    Cmax is defined as the maximum observed concentration on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 30 minutes, 1, 2, 4, 7, and 12 hours post-dose on Day 14 of the respective treatment period.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period
    End point values
    		 FF 100 µg
    Number of subjects analysed
    23 [47]
    Units: picograms per milliliter (pg/mL)
        geometric mean (confidence interval 95%)
    24.68 (20.24 to 30.1)
    Notes
    [47] - Pharmacokinetic (PK) Pop: all participants in the All Subjects Pop for whom a PK sample was analyzed
    No statistical analyses for this end point

    Secondary: tmax and t at Day 14 of the respective treatment period

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    End point title
    		 tmax and t at Day 14 of the respective treatment period
    End point description
    tmax is defined as the time to reach the observed maximum concentration, and t 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; 30 minutes, 1, 2, 4, 7, and 12 hours post-dose on Day 14 of the respective treatment period.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period
    End point values
    		 FF 100 µg
    Number of subjects analysed
    22 [48]
    Units: hours
    arithmetic mean (standard deviation)
        tmax
    0.863 ( 0.7926 )
        time (t)
    6.953 ( 4.0875 )
    Notes
    [48] - Pharmacokinetic (PK) Pop: all participants in the All Subjects Pop for whom a PK sample was analyzed
    No statistical analyses for this end point

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

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    End point title
    		 Serum cortisol weighted mean (0–12 hours) on Day 14 of the respective treatment period
    End point description
    Serum cortisol weighted mean was determined for each participant over the time period 0-12 hours on Day 14 of the respective treatmentperiod. Samples were collected at the following times: pre-dose; 30 minutes, 1, 2, 4, 7, and 12 hours post-dose on Day 14 of the respective treatment period.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period
    End point values
    		 Placebo FF 100 µg
    Number of subjects analysed
    22 [49]
    23 [50]
    Units: nanomoles per Liter
        geometric mean (confidence interval 95%)
    178.76 (157.43 to 202.97)
    150.41 (132.91 to 170.22)
    Notes
    [49] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [50] - 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 Days 1 and 14 of the respective treatment period

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    End point title
    		 Average oropharyngeal cross-sectional area on Days 1 and 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. Pharyngometry data were recorded for each day (Days 1 and 14 of the resepctive 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
    Days 1 and 14 of the respective treatment period
    End point values
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [51]
    26 [52]
    Units: centimeters squared (cm^2)
    arithmetic mean (standard deviation)
        Day 1, n=14, 18
    4.06 ( 1.875 )
    4.24 ( 1.677 )
        Day 14, n= 12, 12
    5.49 ( 1.586 )
    4.58 ( 1.497 )
    Notes
    [51] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [52] - 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 Days 1 and 14 of the respective treatment period

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    End point title
    		 Distance of assessment on Days 1 and 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
    Days 1 and 14 of the respective treatment period
    End point values
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [53]
    26 [54]
    Units: centimeters (cm)
    arithmetic mean (standard deviation)
        Day 1, n=14, 18
    18.63 ( 1.736 )
    18.69 ( 1.432 )
        Day 14, n= 12, 12
    19.37 ( 1.823 )
    18.61 ( 1.942 )
    Notes
    [53] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [54] - All Subjects Population: Only participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Oropharyngeal Volume on Days 1 and 14 of the respective treatment period

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    End point title
    		 Oropharyngeal Volume on Days 1 and 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
    Days 1 and 14 of the respective treatment period
    End point values
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [55]
    26 [56]
    Units: cubic centimeters (cm^3)
    arithmetic mean (standard deviation)
        Day 1, n=14, 18
    74.19 ( 32.402 )
    78.86 ( 31.092 )
        Day 14, n= 12, 12
    106.31 ( 33.188 )
    86.22 ( 34.363 )
    Notes
    [55] - All Subjects Population: Only participants available at the specified time points were analyzed.
    [56] - 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 Days 1 and 14 of the respective treatment period

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    End point title
    		 Average flow rate and Peak Inspiratory Flow Rate (PIFR) 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. 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
    End point values
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [57]
    26 [58]
    Units: Liters per minute (L/min)
    arithmetic mean (standard deviation)
        Day 1 Average flow rate, n=21, 20
    35.38 ( 11.441 )
    34.65 ( 10.84 )
        Day 14 Average flow rate, n=21, 22
    36.25 ( 11.243 )
    36.17 ( 12.772 )
        Day 1 PIFR, n=21, 20
    51.83 ( 17.286 )
    52.9 ( 16.028 )
        Day 14 PIFR, n=21, 22
    55.7 ( 16.589 )
    54.76 ( 17.986 )
    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: Inhalation time on Days 1 and 14 of the respective treatment period

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    End point title
    		 Inhalation time 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. 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
    End point values
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [59]
    26 [60]
    Units: Seconds
    arithmetic mean (standard deviation)
        Day 1, n=21, 20
    1.71 ( 0.534 )
    1.93 ( 0.861 )
        Day 14, n= 21, 22
    1.6 ( 0.802 )
    1.61 ( 0.858 )
    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: 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
    End point values
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [61]
    26 [62]
    Units: Liters
    arithmetic mean (standard deviation)
        Day 1, n=21, 20
    0.99 ( 0.461 )
    1.07 ( 0.48 )
        Day 14, n= 21, 22
    1 ( 0.58 )
    0.95 ( 0.541 )
    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: 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 resepctive treatment period
    End point values
    		 Placebo FF 100 µg
    Number of subjects analysed
    25 [63]
    26 [64]
    Units: Kilopascal (kpa)
    arithmetic mean (standard deviation)
        Day 1, n=21, 20
    2.44 ( 1.63 )
    2.53 ( 1.56 )
        Day 14, n= 21, 22
    2.78 ( 1.543 )
    2.74 ( 1.609 )
    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: Total emitted dose (TED) on Days 1 and 14 of the respective treatment period

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    End point title
    		 Total emitted dose (TED) on Days 1 and 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.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period
    End point values
    		 FF 100 µg
    Number of subjects analysed
    26 [65]
    Units: micrograms
    arithmetic mean (standard deviation)
        Day 1, Nominal TED, n=0, 20
    85.35 ( 1.576 )
        Day 14, Nominal TED, n=0, 22
    85.57 ( 1.857 )
        Day 1, Minimum TED, n=0, 20
    84.84 ( 1.617 )
        Day 14, Minimum TED, n=0, 22
    85.17 ( 1.905 )
        Day 1, Maximum TED, n=0, 20
    85.86 ( 1.639 )
        Day 14, Maximum TED, n=0, 22
    85.97 ( 1.861 )
    Notes
    [65] - 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 Days 1 and 14 of the respective treatment period

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    End point title
    		 Ex-throat dose (ETD) and ETD <2 microns on Days 1 and 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.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period
    End point values
    		 FF 100 µg
    Number of subjects analysed
    26 [66]
    Units: micrograms
    arithmetic mean (standard deviation)
        Day 1, Nominal ETD, n=0, 17
    29.37 ( 2.874 )
        Day 14, Nominal ETD, n=0, 12
    29.83 ( 2.528 )
        Day 1, Minimum ETD, n=0, 17
    28.47 ( 3.241 )
        Day 14, Minimum ETD, n=0, 12
    29.35 ( 2.664 )
        Day 1, Maximum ETD, n=0, 17
    30.26 ( 2.598 )
        Day 14, Maximum ETD, n=0, 12
    30.26 ( 2.472 )
        Day 1, ETD <2 microns, n=0, 17
    5.13 ( 0.498 )
        Day 14, ETD <2 microns, n=0, 12
    5.07 ( 0.455 )
        Day 1, Minimum ETD <2 microns, n=0, 17
    4.96 ( 0.459 )
        Day 14, Minimum ETD <2 microns, n=0, 12
    4.99 ( 0.448 )
        Day 1, Maximum ETD <2 microns, n=0, 17
    5.3 ( 0.559 )
        Day 14, Maximum ETD <2 microns, n=0, 12
    5.17 ( 0.476 )
    Notes
    [66] - 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
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 All participants who received matching placebo in one or both of the two 14-day treatment periods. Matching placebo was administered once daily in the morning (Day 1 to Day 14) via the Novel Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.

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

    Serious adverse events
    		 Placebo FF 100 µg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 26 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo FF 100 µg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 25 (16.00%)
    8 / 26 (30.77%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    Product taste abnormal
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    Toothache
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Acute tonsillitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Otitis externa
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Tooth abscess
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         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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