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    Clinical Trial Results:
    A SINGLE-DOSE, OPEN-LABEL, RANDOMIZED, 2-WAY CROSS-OVER, CLINICAL PHARMACOLOGY STUDY OF CHF 1535 50/6 NEXT DPI® (FIXED COMBINATION OF BECLOMETASONE DIPROPIONATE 50 µg PLUS FORMOTEROL FUMARATE 6 µg ) VERSUS THE FREE COMBINATION OF LICENSED BECLOMETASONE DPI AND FORMOTEROL DPI IN ASTHMATIC CHILDREN

    Summary
    EudraCT number
    		 2011-001208-36
    Trial protocol
    		 DK  
    Global end of trial date
    21 Aug 2012

    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-1103-PR-0058
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01468272
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo, 26/A, Parma, Italy, 43122
    Public contact
    Clinical Trial Transparency Manager, Chiesi Farmaceutici S.p.A., clinicalTrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency Manager, Chiesi Farmaceutici S.p.A., 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
    21 Aug 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Aug 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Aug 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary: - To evaluate, in children, the systemic exposure to B17MP (active metabolite of BDP) as AUC0-t , after inhalation of CHF 1535 NEXT DPI® in comparison with a free combination of licensed BDP DPI and formoterol DPI.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (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
    15 Nov 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 27
    Worldwide total number of subjects
    27
    EEA total number of subjects
    27
    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
    		 -

    Pre-assignment
    Screening details
    		 A total of 29 patients were screened. Two patients were screening failures: one patient did not meet the inclusion and exclusion criteria and one patient withdrew his/her consent (see Section 14.1.2). A total of 27 patients were randomised, 6 in the age range 5-8 years and 21 in the age range 9-11 (see Section 14.1.6); 14 patients in the sequenc

    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-label study, no blinding procedure was used.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sequence T-R
    Arm description
    		 Test treatment:CHF 1535 50/6 NEXT DPI®: fixed combination of beclometasone dipropionate 50 μg/unit dose plus formoterol fumarate 6 μg/unit dose, administered via the NEXT DPI® dry powder inhaler. Reference Treatment:Free combination of - Beclometasone dipropionate 100 μg inhalation powder (Clenil® Pulvinal®) - Formoterol fumarate 6 μg inhalation powder (Oxis® Turbohaler®)
    Arm type
    		 experimental - active comparator

    Investigational medicinal product name
    CHF 1535 NEXT DPI - BDP DPI + FF DPI
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test Treatment: CHF 1535 50/6μg NEXT DPI® (total dose: BDP/FF 200/24 μg) - 4 (four) inhalations of CHF 1535 50/6 NEXT DPI® Reference Treatment: BDP 100 μg DPI + FF 6 μg DPI (total dose: BDP 200 μg + FF 24 μg) - 2 (two) inhalations of BDP 100μg DPI - 4 (four) inhalations of FF 6 μg DPI Eligible subjects were randomized to one of the two treatment sequences.

    Arm title
    		 Sequence R-T
    Arm description
    		 Reference Treatment:Free combination of - Beclometasone dipropionate 100 μg inhalation powder (Clenil® Pulvinal®) - Formoterol fumarate 6 μg inhalation powder (Oxis® Turbohaler®) Test treatment:CHF 1535 50/6 NEXT DPI®: fixed combination of beclometasone dipropionate 50 μg/unit dose plus formoterol fumarate 6 μg/unit dose, administered via the NEXT DPI® dry powder inhaler.
    Arm type
    		 active comparator - experimental

    Investigational medicinal product name
    BDP DPI + FF DPI - CHF 1535 NEXT DPI
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test Treatment: CHF 1535 50/6μg NEXT DPI® (total dose: BDP/FF 200/24 μg) - 4 (four) inhalations of CHF 1535 50/6 NEXT DPI® Reference Treatment: BDP 100 μg DPI + FF 6 μg DPI (total dose: BDP 200 μg + FF 24 μg) - 2 (two) inhalations of BDP 100μg DPI - 4 (four) inhalations of FF 6 μg DPI Eligible subjects were randomized to one of the two treatment sequences.

    Number of subjects in period 1
    		Sequence T-R Sequence R-T
    Started
    14
    13
    Completed
    13
    13
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence T-R
    Reporting group description
    		 Test treatment:CHF 1535 50/6 NEXT DPI®: fixed combination of beclometasone dipropionate 50 μg/unit dose plus formoterol fumarate 6 μg/unit dose, administered via the NEXT DPI® dry powder inhaler. Reference Treatment:Free combination of - Beclometasone dipropionate 100 μg inhalation powder (Clenil® Pulvinal®) - Formoterol fumarate 6 μg inhalation powder (Oxis® Turbohaler®)

    Reporting group title
    Sequence R-T
    Reporting group description
    		 Reference Treatment:Free combination of - Beclometasone dipropionate 100 μg inhalation powder (Clenil® Pulvinal®) - Formoterol fumarate 6 μg inhalation powder (Oxis® Turbohaler®) Test treatment:CHF 1535 50/6 NEXT DPI®: fixed combination of beclometasone dipropionate 50 μg/unit dose plus formoterol fumarate 6 μg/unit dose, administered via the NEXT DPI® dry powder inhaler.

    Reporting group values
    		 Sequence T-R Sequence R-T Total
    Number of subjects
    		 14 13 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)
    		 9.6 ± 1.39 9 ± 1.53 -
    Gender categorical
    Units: Subjects
        Female
    		 3 5 8
        Male
    		 11 8 19

    End points

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    End points reporting groups
    Reporting group title
    Sequence T-R
    Reporting group description
    		 Test treatment:CHF 1535 50/6 NEXT DPI®: fixed combination of beclometasone dipropionate 50 μg/unit dose plus formoterol fumarate 6 μg/unit dose, administered via the NEXT DPI® dry powder inhaler. Reference Treatment:Free combination of - Beclometasone dipropionate 100 μg inhalation powder (Clenil® Pulvinal®) - Formoterol fumarate 6 μg inhalation powder (Oxis® Turbohaler®)

    Reporting group title
    Sequence R-T
    Reporting group description
    		 Reference Treatment:Free combination of - Beclometasone dipropionate 100 μg inhalation powder (Clenil® Pulvinal®) - Formoterol fumarate 6 μg inhalation powder (Oxis® Turbohaler®) Test treatment:CHF 1535 50/6 NEXT DPI®: fixed combination of beclometasone dipropionate 50 μg/unit dose plus formoterol fumarate 6 μg/unit dose, administered via the NEXT DPI® dry powder inhaler.

    Subject analysis set title
    CHF 1535 NEXT DPI - Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized subjects who used at least one dose of study medication.

    Subject analysis set title
    BDP DPI + FF DPI - Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized subjects who used at least one dose of study medication.

    Subject analysis set title
    CHF 1535 NEXT DPI - PK/PD population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients from the safety population excluding subjects without any valid PK/PD measurement or with major protocol deviations significantly affecting PK/PD

    Subject analysis set title
    PMI DPI + FF DPI - PK/PD population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients from the safety population excluding subjects without any valid PK/PD measurement or with major protocol deviations significantly affecting PK/PD

    Primary: Plasma AUC0-t for B17MP

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    End point title
    		 Plasma AUC0-t for B17MP
    End point description
    The area under the plasma concentration vs. time curve observed from time 0 up to the last measurable concentration, computed using the linear trapezoidal rule [16]. An 8 hour value was required for derivation of AUC0-t. Eight blood samples were to be collected in the 0-8 h interval after dosing (pre-dose, 15 min, 30 min, 1, 2, 4, 6, and 8 hours post-dose) to determine BDP, its metabolite B17MP and formoterol
    End point type
    Primary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: h*pg/mL
        geometric mean (full range (min-max))
    2099.057 (1105.17 to 2926.97)
    1446.354 (553.86 to 2252.89)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    CHF 1535 NEXT DPI - PK/PD population v PMI DPI + FF DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    1.453
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.31
         upper limit
    		 1.62

    Secondary: Plasma AUC0-t for BDP

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    End point title
    		 Plasma AUC0-t for BDP
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: h*pg/mL
        geometric mean (full range (min-max))
    258.919 (129.13 to 489.13)
    187.13 (85 to 374.85)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    CHF 1535 NEXT DPI - PK/PD population v PMI DPI + FF DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    1.3836
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.19
         upper limit
    		 1.61

    Secondary: Plasma BDP AUC0-inf

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    End point title
    		 Plasma BDP AUC0-inf
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: h*pg/mL
        geometric mean (full range (min-max))
    331.983 (172.44 to 548.66)
    260.101 (130.32 to 441.54)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    PMI DPI + FF DPI - PK/PD population v CHF 1535 NEXT DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    1.2497
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 1.42

    Secondary: Plasma BDP Cmax

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    End point title
    		 Plasma BDP Cmax
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: pg/mL
        geometric mean (full range (min-max))
    585.817 (346 to 1176)
    353.58 (151 to 723)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    CHF 1535 NEXT DPI - PK/PD population v PMI DPI + FF DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    1.6568
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.45
         upper limit
    		 1.89

    Secondary: Plasma BDP t1/2

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    End point title
    		 Plasma BDP t1/2
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: hours
        geometric mean (full range (min-max))
    0.307 (0.21 to 0.8)
    0.413 (0.27 to 0.68)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    CHF 1535 NEXT DPI - PK/PD population v PMI DPI + FF DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    0.6995
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 0.77

    Secondary: Plasma BDP tmax

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    End point title
    		 Plasma BDP tmax
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: hours
        geometric mean (full range (min-max))
    0.256 (0.25 to 0.28)
    0.257 (0.22 to 0.52)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    PMI DPI + FF DPI - PK/PD population v CHF 1535 NEXT DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Hodges-Lehmann estimate of median differ
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0

    Secondary: Plasma formoterol AUC0-t

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    End point title
    		 Plasma formoterol AUC0-t
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: h*pg/mL
        geometric mean (full range (min-max))
    156.55 (89.37 to 284.29)
    106.771 (58.49 to 172.39)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    PMI DPI + FF DPI - PK/PD population v CHF 1535 NEXT DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    1.4662
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.31
         upper limit
    		 1.64

    Secondary: Plasma formoterol AUC0-inf

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    End point title
    		 Plasma formoterol AUC0-inf
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: h*pg/mL
        geometric mean (full range (min-max))
    200.112 (109.01 to 363.61)
    133.779 (65.49 to 227.8)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    PMI DPI + FF DPI - PK/PD population v CHF 1535 NEXT DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    1.4958
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.33
         upper limit
    		 1.68

    Secondary: Plasma formoterol Cmax

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    End point title
    		 Plasma formoterol Cmax
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: pg/mL
        geometric mean (full range (min-max))
    72.098 (44.4 to 112)
    37.724 (26.2 to 53.1)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    CHF 1535 NEXT DPI - PK/PD population v PMI DPI + FF DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    1.9112
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.68
         upper limit
    		 2.17

    Secondary: Plasma formoterol t1/2

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    End point title
    		 Plasma formoterol t1/2
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: hours
        geometric mean (full range (min-max))
    3.511 (2.71 to 5.03)
    3.261 (1.87 to 4.98)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    CHF 1535 NEXT DPI - PK/PD population v PMI DPI + FF DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    1.0768
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.18

    Secondary: Plasma formoterol Tmax

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    End point title
    		 Plasma formoterol Tmax
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: hours
        geometric mean (full range (min-max))
    0.256 (0.25 to 0.28)
    0.286 (0.22 to 0.98)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    CHF 1535 NEXT DPI - PK/PD population v PMI DPI + FF DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Hodges-Lehmann estimate of median differ
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0

    Secondary: Plasma B17MP AUC0-inf

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    End point title
    		 Plasma B17MP AUC0-inf
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: h*pg/mL
        geometric mean (full range (min-max))
    2411.667 (1327.77 to 4095.76)
    1704.533 (730.77 to 2446.76)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    PMI DPI + FF DPI - PK/PD population v CHF 1535 NEXT DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    1.4161
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.29
         upper limit
    		 1.55

    Secondary: Plasma B17MP Cmax

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    End point title
    		 Plasma B17MP Cmax
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: pg/mL
        geometric mean (full range (min-max))
    705.119 (363 to 1298)
    451.857 (199 to 793)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    CHF 1535 NEXT DPI - PK/PD population v PMI DPI + FF DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    1.5605
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 1.74

    Secondary: Plasma B17MP t1/2

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    End point title
    		 Plasma B17MP t1/2
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: hours
        geometric mean (full range (min-max))
    2.49 (1.48 to 4.47)
    2.353 (1.48 to 3.39)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    PMI DPI + FF DPI - PK/PD population v CHF 1535 NEXT DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    1.0587
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 1.15

    Secondary: Plasma B17MP tmax

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    End point title
    		 Plasma B17MP tmax
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: hours
        geometric mean (full range (min-max))
    0.443 (0.25 to 1)
    0.832 (0.28 to 2.02)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    CHF 1535 NEXT DPI - PK/PD population v PMI DPI + FF DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Hodges-Lehmann estimate of median differ
    Point estimate
    0.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.1

    Secondary: Plasma potassium Cmin

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    End point title
    		 Plasma potassium Cmin
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: mEq/L
        geometric mean (full range (min-max))
    3.224 (2.8 to 3.7)
    3.241 (1.4 to 4)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    CHF 1535 NEXT DPI - PK/PD population v PMI DPI + FF DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    0.9947
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.1

    Secondary: Plasma potassium AUC0-t

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    End point title
    		 Plasma potassium AUC0-t
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: h*mEq/L
        geometric mean (full range (min-max))
    28.182 (24.36 to 31.28)
    29.959 (26.42 to 32.71)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    PMI DPI + FF DPI - PK/PD population v CHF 1535 NEXT DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    0.9396
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 0.96

    Secondary: Plasma potassium tmin

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    End point title
    		 Plasma potassium tmin
    End point description
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: hours
        arithmetic mean (standard deviation)
    1.782 ± 1.141
    1.948 ± 1.446
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    PMI DPI + FF DPI - PK/PD population v CHF 1535 NEXT DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Hodges-Lehmann estimate of median differ
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 2

    Secondary: PEF

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    End point title
    		 PEF
    End point description
    PEF was measured pre-dose and 15 min, 30 min, 1 h, 2 h, 4 h, 6 h and 8 h post-dose. Only data at 8 h post-dose are reported here.
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: L/min
        arithmetic mean (standard deviation)
    290 ± 76.07
    271.4 ± 64.26
    No statistical analyses for this end point

    Secondary: Ae/Aecreat

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    End point title
    		 Ae/Aecreat
    End point description
    Ae/Aecreat: 8h urinary excretion of cortisol, normalized for 8h creatinine excretion (Aecreat).
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - Safety population BDP DPI + FF DPI - Safety population
    Number of subjects analysed
    27
    26
    Units: integer
        geometric mean (full range (min-max))
    0.036 (0 to 0.2)
    0.043 (0 to 0.1)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    CHF 1535 NEXT DPI - Safety population v BDP DPI + FF DPI - Safety population
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    0.8549
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.08

    Secondary: Glucose concentration in urine

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    End point title
    		 Glucose concentration in urine
    End point description
    Glucose concentration was evaluated in urine. Urinary glucose reference interval was: 0 - 30 mg/dL. The reference PK/PD population is 25 patients because for one patient (S026) no result for glucose was reported after inhalation of the reference product, hence the patient was excluded for both the test and reference.
    End point type
    Secondary
    End point timeframe
    At Visits 2 and 3
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    25
    25
    Units: n. subjects with urine glucose >30 mg/dL
    10
    3
    No statistical analyses for this end point

    Secondary: Heart rate as AUC0-8h/8h

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    End point title
    		 Heart rate as AUC0-8h/8h
    End point description
    End point type
    Secondary
    End point timeframe
    At each clinic visit from Visit 1 to Visit 4.
    End point values
    		 CHF 1535 NEXT DPI - PK/PD population PMI DPI + FF DPI - PK/PD population
    Number of subjects analysed
    26
    26
    Units: bpm
        geometric mean (full range (min-max))
    101.13 (86.9 to 129.3)
    95.68 (80.8 to 120.4)
    Statistical analysis title
    		 Test treatment vs Reference treatment
    Comparison groups
    CHF 1535 NEXT DPI - PK/PD population v PMI DPI + FF DPI - PK/PD population
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 least square mean ratio
    Point estimate
    1.057
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 1.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At each clinic visit from Visit 1 to Visit 4
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Sequence T-R
    Reporting group description
    		 Test treatment:CHF 1535 50/6 NEXT DPI®: fixed combination of beclometasone dipropionate 50 μg/unit dose plus formoterol fumarate 6 μg/unit dose, administered via the NEXT DPI® dry powder inhaler. Reference Treatment:Free combination of - Beclometasone dipropionate 100 μg inhalation powder (Clenil® Pulvinal®) - Formoterol fumarate 6 μg inhalation powder (Oxis® Turbohaler®)

    Reporting group title
    Sequence R-T
    Reporting group description
    		 Reference Treatment:Free combination of - Beclometasone dipropionate 100 μg inhalation powder (Clenil® Pulvinal®) - Formoterol fumarate 6 μg inhalation powder (Oxis® Turbohaler®) Test treatment:CHF 1535 50/6 NEXT DPI®: fixed combination of beclometasone dipropionate 50 μg/unit dose plus formoterol fumarate 6 μg/unit dose, administered via the NEXT DPI® dry powder inhaler.

    Serious adverse events
    		 Sequence T-R Sequence R-T
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (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: 1%
    Non-serious adverse events
    		 Sequence T-R Sequence R-T
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    Respiratory, thoracic and mediastinal disorders
    Nasopharyngitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         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.
    No limitations or caveat are reported for this trial.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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