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    Clinical Trial Results:
    A SINGLE-DOSE, OPEN-LABEL, 2-WAY CROSS-OVER, CLINICAL PHARMACOLOGY STUDY OF CHF 1535 50/6 HFA pMDI (FIXED COMBINATION OF BECLOMETHASONE DIPROPIONATE 50µg PLUS FORMOTEROL FUMARATE 6 µg ) USING THE AEROCHAMBER PLUS™ SPACER DEVICE VERSUS THE FREE COMBINATION OF BECLOMETHASONE HFA pMDI AND FORMOTEROL HFA pMDI AVAILABLE ON THE MARKET USING THE AEROCHAMBER PLUS™ SPACER DEVICE IN ASTHMATIC CHILDREN

    Summary
    EudraCT number
    		 2009-010434-22
    Trial protocol
    		 DK  
    Global end of trial date
    07 Dec 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jul 2016
    First version publication date
    09 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-0902-PR-0013
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01848769
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici SpA
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy, 43122
    Public contact
    Chiesi Clinical Trials, ClinicalTrials_info@chiesi.com, Chiesi Farmaceutici SpA, ClinicalTrials_info@chiesi.com
    Scientific contact
    Chiesi Clinical Trials, ClinicalTrials_info@chiesi.com, Chiesi Farmaceutici SpA, ClinicalTrials_info@chiesi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000548-PIP01-09
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Feb 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Dec 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective(s). To evaluate, in children, the systemic exposure to B17MP (active metabolite of BDP) as AUC0-t , after inhalation of CHF 1535 pMDI 50/6 with AeroChamber Plus spacer device in comparison with an already approved free combination of BDP pMDI and formoterol pMDI with AeroChamber Plus spacer device.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practices (GCP) guidelines and local law requirements. Other than routine care, no specific measures for protection of trial subjects were implemented.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Sep 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 26
    Worldwide total number of subjects
    26
    EEA total number of subjects
    26
    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
    		 -

    Pre-assignment
    Screening details
    		 A total of 27 patients were screened. Twenty six (26) were randomised. Three patients did not receive any treatment and therefore the safety population consisted of 23 patients.

    Period 1
    Period 1 title
    Overall trial by sequence (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    As this was an open study, blinding procedures were not applicable.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Sequence T--R
    Arm description
    		 Test treatment (fixed combination): CHF 1535 HFA pMDI (fixed combination of BDP 50 μg + Formoterol 6 μg) using AeroChamber PlusTM spacer device, 4 puffs. Total dose: BDP 200 μg and formoterol 24 μg Reference treatment (free combination): BDP HFA pMDI (Aerobec® 50 μg, Teva) plus Formoterol HFA pMDI (Atimos 6 μg) using AeroChamber PlusTM spacer device, 2+2 puffs respectively and this sequence will be repeated 2 times. Total dose: BDP 200 μg and formoterol 24 μg.
    Arm type
    		 experimental - active comparator

    Investigational medicinal product name
    CHF 1535 pMDI - BDP pMDI + FF pMDI
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    The study included a screening visit, followed by a wash out period (from 7 days to 3 weeks), first treatment visits followed by a wash out period (from 7 days to 3 weeks) and a second treatment visit followed by a follow-up visit within 7 days. Test treatment: Product: Aerobec® Dose: Beclomethasone dipropionate 50 μg.Total dose 200 μg (4 puffs) Administration: Inhalation Duration of Treatment: single dose Reference treatment: Product: Atimos® Dose: Formoterol fumarate 6 μg. Total dose 24 μg (4 puffs), Administration: Inhalation Duration of Treatment: single dose

    Arm title
    		 Sequence R--T
    Arm description
    		 Reference treatment (free combination): BDP HFA pMDI (Aerobec® 50 μg, Teva) plus Formoterol HFA pMDI (Atimos 6 μg) using AeroChamber PlusTM spacer device, 2+2 puffs respectively and this sequence will be repeated 2 times. Total dose: BDP 200 μg and formoterol 24 μg. Test treatment (fixed combination): CHF 1535 HFA pMDI (fixed combination of BDP 50 μg + Formoterol 6 μg) using AeroChamber PlusTM spacer device, 4 puffs. Total dose: BDP 200 μg and formoterol 24 μg
    Arm type
    		 Active comparator - Experimental

    Investigational medicinal product name
    BDP pMDI + FF pMDI - CHF 1535 pMDI
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    The study included a screening visit, followed by a wash out period (from 7 days to 3 weeks), first treatment visits followed by a wash out period (from 7 days to 3 weeks) and a second treatment visit followed by a follow-up visit within 7 days. Reference treatment: Product: Atimos® Dose: Formoterol fumarate 6 μg. Total dose 24 μg (4 puffs), Administration: Inhalation Duration of Treatment: single dose Test treatment: Product: Aerobec® Dose: Beclomethasone dipropionate 50 μg.Total dose 200 μg (4 puffs) Administration: Inhalation Duration of Treatment: single dose

    Number of subjects in period 1
    		Sequence T--R Sequence R--T
    Started
    11
    12
    Completed
    11
    11
    Not completed
    0
    1
         Technical problem with blood sampling
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Overall trial by sequence
    Reporting group description
    		 -

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Twenty-six patients were randomised; 3 patients did not receive any treatment and, therefore, the safety population consisted of 23 patients. Baseline characteristics are reported for those 23 patients.
    Reporting group values
    		 Overall trial by sequence Total
    Number of subjects
    		 23 23
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 10 (7.6 to 11.9) -
    Gender categorical
    Units: Subjects
        Female
    		 5 5
        Male
    		 18 18
    Subject analysis sets

    Subject analysis set title
    Test treatment - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who used at least one dose of study medication.

    Subject analysis set title
    Reference treatment - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who used at least one dose of study

    Subject analysis set title
    Test treatment - PK
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic population: subpopulation of the safety population without any major protocol deviation that could affect the PK.

    Subject analysis set title
    Reference treatment - PK
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subpopulation of the safety population without any major protocol deviation that could affect the PK.

    Subject analysis sets values
    		 Test treatment - Safety Reference treatment - Safety Test treatment - PK Reference treatment - PK
    Number of subjects
    22
    23
    20
    20
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
    5
    5
    5
    5
        Male
    17
    18
    15
    15

    End points

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    End points reporting groups
    Reporting group title
    Sequence T--R
    Reporting group description
    		 Test treatment (fixed combination): CHF 1535 HFA pMDI (fixed combination of BDP 50 μg + Formoterol 6 μg) using AeroChamber PlusTM spacer device, 4 puffs. Total dose: BDP 200 μg and formoterol 24 μg Reference treatment (free combination): BDP HFA pMDI (Aerobec® 50 μg, Teva) plus Formoterol HFA pMDI (Atimos 6 μg) using AeroChamber PlusTM spacer device, 2+2 puffs respectively and this sequence will be repeated 2 times. Total dose: BDP 200 μg and formoterol 24 μg.

    Reporting group title
    Sequence R--T
    Reporting group description
    		 Reference treatment (free combination): BDP HFA pMDI (Aerobec® 50 μg, Teva) plus Formoterol HFA pMDI (Atimos 6 μg) using AeroChamber PlusTM spacer device, 2+2 puffs respectively and this sequence will be repeated 2 times. Total dose: BDP 200 μg and formoterol 24 μg. Test treatment (fixed combination): CHF 1535 HFA pMDI (fixed combination of BDP 50 μg + Formoterol 6 μg) using AeroChamber PlusTM spacer device, 4 puffs. Total dose: BDP 200 μg and formoterol 24 μg

    Subject analysis set title
    Test treatment - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who used at least one dose of study medication.

    Subject analysis set title
    Reference treatment - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who used at least one dose of study

    Subject analysis set title
    Test treatment - PK
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic population: subpopulation of the safety population without any major protocol deviation that could affect the PK.

    Subject analysis set title
    Reference treatment - PK
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subpopulation of the safety population without any major protocol deviation that could affect the PK.

    Primary: AUC0-t of B17MP (active metabolite of beclomethasone dipropionate)

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    End point title
    		 AUC0-t of B17MP (active metabolite of beclomethasone dipropionate)
    End point description
    V1 = screening visit wash out period (7 days to 3 weeks) V2 = treatment period 1 wash out period (7 days to 3 weeks) V3 = treatment period 2 V4 = follow-up visit
    End point type
    Primary
    End point timeframe
    Visit 2 and Visit 3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: hours*pg/mL
        geometric mean (full range (min-max))
    1165 (613.7 to 2145)
    1433 (727.5 to 2307)
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Statistical analysis description
    ANOVA of the log transformed AUC0-t parameter values, where subject nested within sequence is included as a random effect and sequence, period and treatment are included as fixed effects.
    Comparison groups
    Reference treatment - PK v Test treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 adjusted least square mean in ln
    Point estimate
    0.81
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.697
         upper limit
    		 0.948
    Variability estimate
    Standard deviation

    Secondary: AUC0-∞ for B17MP (active metabolite of beclomethasone dipropionate)

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    End point title
    		 AUC0-∞ for B17MP (active metabolite of beclomethasone dipropionate)
    End point description
    V1 = screening visit wash out period (7 days to 3 weeks) V2 = treatment period 1 wash out period (7 days to 3 weeks) V3 = treatment period 2 V4 = follow-up visit
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: hours*pg/mL
        geometric mean (confidence interval 95%)
    1336 (764.2 to 2281)
    1615 (877.6 to 2427)
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Comparison groups
    Test treatment - PK v Reference treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 adjusted least square mean in ln
    Point estimate
    0.83
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.724
         upper limit
    		 0.945

    Secondary: Cmax for B17MP (active metabolite of beclomethasone dipropionate)

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    End point title
    		 Cmax for B17MP (active metabolite of beclomethasone dipropionate)
    End point description
    V1 = screening visit wash out period (7 days to 3 weeks) V2 = treatment period 1 wash out period (7 days to 3 weeks) V3 = treatment period 2 V4 = follow-up visit
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: pg/mL
        geometric mean (confidence interval 95%)
    535.2 (279 to 994)
    656 (382 to 1068)
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Comparison groups
    Reference treatment - PK v Test treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 adjusted least square mean in ln
    Point estimate
    0.82
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.701
         upper limit
    		 0.947

    Secondary: AUC0-0.5h of B17MP (active metabolite of beclomethasone dipropionate)

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    End point title
    		 AUC0-0.5h of B17MP (active metabolite of beclomethasone dipropionate)
    End point description
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: hours*pg/mL
        geometric mean (confidence interval 95%)
    138.5 (72.1 to 256.8)
    170.5 (98.7 to 275.9)
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Comparison groups
    Reference treatment - PK v Test treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 adjusted least square mean in ln
    Point estimate
    0.81
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.697
         upper limit
    		 0.943

    Secondary: Tmax for B17MP (active metabolite of beclomethasone dipropionate)

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    End point title
    		 Tmax for B17MP (active metabolite of beclomethasone dipropionate)
    End point description
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: hours
        median (full range (min-max))
    0.517 (0.517 to 0.533)
    0.517 (0.517 to 0.55)
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Comparison groups
    Test treatment - PK v Reference treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Hodges-Lehmann estimate of shift
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0

    Secondary: T1/2 for B17MP (active metabolite of beclomethasone dipropionate)

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    End point title
    		 T1/2 for B17MP (active metabolite of beclomethasone dipropionate)
    End point description
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: hours
        median (full range (min-max))
    1.714 (1.261 to 2.123)
    1.756 (1.137 to 2.403)
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Comparison groups
    Reference treatment - PK v Test treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Hodges-Lehmann estimate of shift
    Point estimate
    0.044
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.068
         upper limit
    		 0.196

    Secondary: AUC0-t of formoterol

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    End point title
    		 AUC0-t of formoterol
    End point description
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: hours*pg/mL
        geometric mean (confidence interval 95%)
    65 (31.8 to 105)
    66.3 (36 to 95.2)
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Comparison groups
    Test treatment - PK v Reference treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 adjusted least square mean in ln
    Point estimate
    0.97
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.1

    Secondary: AUC0-∞ for formoterol

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    End point title
    		 AUC0-∞ for formoterol
    End point description
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: hours*pg/mL
        geometric mean (full range (min-max))
    85.4 (44 to 141)
    87.4 (46 to 143.9)
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Comparison groups
    Reference treatment - PK v Test treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 adjusted least square mean in ln
    Point estimate
    0.97
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.12

    Secondary: AUC0-0.5h for formoterol

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    End point title
    		 AUC0-0.5h for formoterol
    End point description
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: hours*pg/mL
        geometric mean (full range (min-max))
    4.5 (1.8 to 7.3)
    4.9 (3.4 to 8.6)
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Comparison groups
    Test treatment - PK v Reference treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 adjusted least square mean in ln
    Point estimate
    0.91
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.06

    Secondary: Cmax for formoterol

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    End point title
    		 Cmax for formoterol
    End point description
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: pg/mL
        geometric mean (full range (min-max))
    17.8 (6.9 to 28.4)
    19 (13.1 to 33.1)
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Comparison groups
    Test treatment - PK v Reference treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 adjusted least square mean in ln
    Point estimate
    0.92
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.08

    Secondary: Tmax for formoterol

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    End point title
    		 Tmax for formoterol
    End point description
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: hours
        arithmetic mean (standard deviation)
    0.592 ( 0.183 )
    0.545 ( 0.115 )
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Comparison groups
    Test treatment - PK v Reference treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Hodges-Lehmann estimate of shift
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0

    Secondary: T1/2 for formoterol

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    End point title
    		 T1/2 for formoterol
    End point description
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: hours
        arithmetic mean (standard deviation)
    3.526 ( 0.718 )
    3.44 ( 0.591 )
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Comparison groups
    Test treatment - PK v Reference treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Hodges-Lehmann estimate of shift
    Point estimate
    -0.046
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.371
         upper limit
    		 0.325

    Secondary: Serum potassium, AUC0-8h

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    End point title
    		 Serum potassium, AUC0-8h
    End point description
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: mEq/L*hours
        arithmetic mean (standard deviation)
    31.1 ( 1.9 )
    30.7 ( 2.2 )
    No statistical analyses for this end point

    Secondary: Serum potassium, Cmin

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    End point title
    		 Serum potassium, Cmin
    End point description
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: mEq/L
        arithmetic mean (standard deviation)
    3.7 ( 0.3 )
    3.7 ( 0.2 )
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Comparison groups
    Reference treatment - PK v Test treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 adjusted least square mean in ln
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 1.03

    Secondary: Serum potassium, Tmin

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    End point title
    		 Serum potassium, Tmin
    End point description
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: hours
        arithmetic mean (standard deviation)
    3.4 ( 2.1 )
    3.3 ( 2 )
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Comparison groups
    Test treatment - PK v Reference treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.7963
    Method
    		 Friedman's test
    Confidence interval

    Secondary: Urinary glucose excretion

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    End point title
    		 Urinary glucose excretion
    End point description
    Number of patients who present glucose in the urine
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: number of subject
    2
    0
    No statistical analyses for this end point

    Secondary: Cortisol urinary excretion 0-8h

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    End point title
    		 Cortisol urinary excretion 0-8h
    End point description
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: mcg
        arithmetic mean (standard deviation)
    14.6 ( 9.3 )
    13.4 ( 8.4 )
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Comparison groups
    Test treatment - PK v Reference treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 adjusted least square mean in ln
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.69

    Secondary: Cortisol/creatinine ratio

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    End point title
    		 Cortisol/creatinine ratio
    End point description
    Cortisol urinary excretion 0-8h normalised for creatinine excretion 0-8h
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - PK Reference treatment - PK
    Number of subjects analysed
    20
    20
    Units: mcg/g
        arithmetic mean (standard deviation)
    61 ( 23.7 )
    60.6 ( 33.5 )
    Statistical analysis title
    		 Comparison between treatments (T vs R)
    Comparison groups
    Test treatment - PK v Reference treatment - PK
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 adjusted least square mean in ln
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.44

    Secondary: Heart rate, AUC(0-8h)/8

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    End point title
    		 Heart rate, AUC(0-8h)/8
    End point description
    End point type
    Secondary
    End point timeframe
    V2 and V3
    End point values
    		 Test treatment - Safety Reference treatment - Safety
    Number of subjects analysed
    22
    23
    Units: bpm
        geometric mean (confidence interval 95%)
    82.5 (76.4 to 89.2)
    81.8 (75.4 to 88.4)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    V1,V2, V3 and V4
    Adverse event reporting additional description
    Adverse events were fully described and coded according to the MedDRA Dictionary (version 12.0). Frequency of subjects presenting with treatment-emergent AEs (TEAEs), IMP-related AEs (ADR) and SAEs was tabulated for each treatment group by system organ class (SOC) and preferred term (PT).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Safety population (N=23)
    Reporting group description
    		 Only one adverse event occurred during the study. In the afternoon 8.5 hours after the second study drug administration (test drug) an 11 year old male reported vertigo with a duration of 3.75 hours (Source EOT list 8 (Appendix 16.4.1)). The condition resolved spontaneously. The event was considered of mild intensity and not related to study drug administration.

    Serious adverse events
    		 Safety population (N=23)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 23 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety population (N=23)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 23 (4.35%)
    Nervous system disorders
    vertigo
    Additional description: Only one adverse event occurred during the study; 8.5 hours after the second drug administration (test drug) an 11 year old male reported vertigo (duration 3.75 h). The condition was mild, not related to study drug, and resolved spontaneously.
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Nov 2009
    - Avoid the blood sampling for potassium and glucose determination. This allowed the use of less sampling tubes to be filled in. In this way, there was more blood to separate plasma for the primary endpoint (pharmacokinetic). This also allowed avoiding the fasting condition for children and thus the reduction of discomfort. - Increase the time deviations permitted for the sampling points, taking into account the objective difficulties in the procedure. - Measure PEF instead of FEV1 for all children, in order to simplify the study process for the children. The PEF values were tested as already described in the protocol. - Avoid the training with Vitalograph AIM: this device was conceived to reduce coordination problems when using pMDIs, but children used spacers, according to the guidelines, to avoid these problems, therefore, this training was not necessary. - Measure heart rate manually: the use of pulseoximeter was a more complex procedure and it would have delayed the PK sampling - Repeatedly breath into the spacer instead of breathing once deeply, taking into account that this was the common practice in children for the use of pMDIs with spacers.
    25 Jan 2010
    - Change of the Principal Investigator. - Issues related to technical aspects and timelines. The present study has been inserted into a Paediatric Investigational Plan (PIP) and is subjected to the revision and approval of the EMEA Paediatric Committee (PDCO). PDCO provided scientific input and: �� agreed to avoid the fasting conditions and noted that fasting is not rigidly necessary to assess plasma potassium (and urinary glucose). Potassium and glucose were very important safety measures that cannot be waived in this kind of study. �� Suggested that the study protocol was to be further amended in order to keep the determination of potassium in plasma and to replace blood glucose by urinary glucose. �� Suggested to use a more precise method to measure the heart rate: the use of pulseoximeter was recommended. �� Suggested that children older than 5 years were able to perform the inhalation manoeuvre with spacers and suggested that one single deep inhalation was preferable than tidal breathing through the spacer device (AeroChamber Plus™).

    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.
    No limitations and caveats are specified to this summary of the results
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