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    Clinical Trial Results:
    A phase II, multinational, multicentre, double blind, double dummy, randomised, cross-over, active - and placebo-controlled clinical study to compare the bronchodilator effect of single administration of CHF 1535 pMDI (fixed combination of extrafine beclomethasone dipropionate 50 μg + formoterol fumarate 6 μg/metered dose, total dose 100/12 μg) given with spacer vs. free combination of licensed extrafine beclomethasone dipropionate pMDI given with spacer (total dose 100 μg) plus formoterol pMDI given with spacer (total dose 12 μg) in terms of FEV1 AUC0-12h in asthmatic children

    Summary
    EudraCT number
    		 2011-002060-24
    Trial protocol
    		 PL   Outside EU/EEA  
    Global end of trial date
    26 Feb 2013

    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-0903-PR-0060
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01584492
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici SpA
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy, 43122
    Public contact
    Clinical Trial Transparency Manager, Chiesi Farmaceutici SpA, clinicalTrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency Manager, 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
    26 Feb 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Feb 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Feb 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority in terms of bronchodilator effect of single administration of CHF 1535 50/6 pMDI (fixed combination of extrafine beclomethasone dipropionate 50 µg + formoterol fumarate 6 µg/metered dose, 2 inhalations, total dose 100/12 µg) given with spacer vs. free combination of extrafine beclomethasone dipropionate 50 µg/metered dose pMDI (2 inhalations, total dose 100 µg) given with spacer plus formoterol 6 µg/metered dose pMDI (2 inhalations, total dose 12 µg) given with spacer in terms of FEV1 AUC 0-12 hours corrected by time for the 12 hours study period in asthmatic children
    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
    27 Dec 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Ukraine: 39
    Country: Number of subjects enrolled
    Poland: 20
    Worldwide total number of subjects
    59
    EEA total number of subjects
    20
    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)
    59
    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 81 patients were screened, of whom 59 patients were randomised from eight sites. Twenty-two patients failed screening because they did not meet the inclusion criteria. 1-week ± 3 days run-in period was followed by five single-day randomised treatment periods separated by wash-out periods of 14±7 days.

    Period 1
    Period 1 title
    Overall trial by sequence (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Two matched placebos were provided to achieve a complete double-blind, double-dummy design. The canisters/actuators of CHF 1535 and FF pMDI were identical. The randomisation list was provided to the labelling facility but was not available to patients, investigators, monitors or employees of the centre involved in the management of the trial before unblinding of the data, unless in case of emergency. The Sponsor’s clinical team was also blinded during the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sequence A/B/C/D/E
    Arm description
    		 - Treatment A (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations - Treatment B (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations - Treatment C (Exp): CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment D (Ref): formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment E (Ref): placebo pMDI with spacer, 6 inhalations in the morning at the clinic Drug administration was done in the morning of each visit day at the clinic between 7.00 and 9.00 a.m.. Each patient will have 6 inhalations at each
    Arm type
    		 experimental - active comparator - placebo

    Investigational medicinal product name
    CHF 1535 pMDI - formoterol pMDI + BDP pMDI - placebo pMDI
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate, placebo
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    A 1-week ± 3 days run-in period was followed by five single-day randomized treatment periods separated by wash-out periods of 14±7 days. A safety follow-up phone contact was made 7 ±3 days after the last treatment visit or premature discontinuation, for safety purposes. During the run-in period and during the wash-out periods, patients were treated with BDP pMDI HFA 50 μg extrafine (Ventolair®, Teva), 1 inhalation twice daily (daily dose: BDP 100 μg) administered with AeroChamber Plus™ spacer device.

    Arm title
    		 Sequence B/C/D/E/A
    Arm description
    		 - Treatment B (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations - Treatment C (Exp): CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment D (Ref): formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment E (Ref): placebo pMDI with spacer, 6 inhalations in the morning at the clinic - Treatment A (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations Drug administration was done in the morning of each visit day at the clinic between 7.00 and 9.00 a.m.
    Arm type
    		 experimental - active comparator - placebo

    Investigational medicinal product name
    CHF 1535 pMDI - formoterol pMDI + BDP pMDI - placebo pMDI
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate, placebo
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    A 1-week ± 3 days run-in period was followed by five single-day randomized treatment periods separated by wash-out periods of 14±7 days. A safety follow-up phone contact was made 7 ±3 days after the last treatment visit or premature discontinuation, for safety purposes. During the run-in period and during the wash-out periods, patients were treated with BDP pMDI HFA 50 μg extrafine (Ventolair®, Teva), 1 inhalation twice daily (daily dose: BDP 100 μg) administered with AeroChamber Plus™ spacer device.

    Arm title
    		 Sequence C/D/E/A/B
    Arm description
    		 - Treatment C (Exp): CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment D (Ref): formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment E (Ref): placebo pMDI with spacer, 6 inhalations in the morning at the clinic - Treatment A (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations - Treatment B (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations Drug administration was done in the morning of each visit day at the clinic between 7.00 and 9.00 a.m.
    Arm type
    		 experimental - active comparator - placebo

    Investigational medicinal product name
    CHF 1535 pMDI - formoterol pMDI + BDP pMDI - placebo pMDI
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate, placebo
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    A 1-week ± 3 days run-in period was followed by five single-day randomized treatment periods separated by wash-out periods of 14±7 days. A safety follow-up phone contact was made 7 ±3 days after the last treatment visit or premature discontinuation, for safety purposes. During the run-in period and during the wash-out periods, patients were treated with BDP pMDI HFA 50 μg extrafine (Ventolair®, Teva), 1 inhalation twice daily (daily dose: BDP 100 μg) administered with AeroChamber Plus™ spacer device.

    Arm title
    		 Sequence D/E/A/B/C
    Arm description
    		 - Treatment D (Ref): formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment E (Ref): placebo pMDI with spacer, 6 inhalations in the morning at the clinic - Treatment A (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations - Treatment B (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations - Treatment C (Exp): CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations Drug administration was done in the morning of each visit day at the clinic between 7.00 and 9.00 a.m.
    Arm type
    		 experimental - active comparator - placebo

    Investigational medicinal product name
    CHF 1535 pMDI - formoterol pMDI + BDP pMDI - placebo pMDI
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate, placebo
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    A 1-week ± 3 days run-in period was followed by five single-day randomized treatment periods separated by wash-out periods of 14±7 days. A safety follow-up phone contact was made 7 ±3 days after the last treatment visit or premature discontinuation, for safety purposes. During the run-in period and during the wash-out periods, patients were treated with BDP pMDI HFA 50 μg extrafine (Ventolair®, Teva), 1 inhalation twice daily (daily dose: BDP 100 μg) administered with AeroChamber Plus™ spacer device.

    Arm title
    		 Sequence E/A/B/C/D
    Arm description
    		 - Treatment E (Ref): placebo pMDI with spacer, 6 inhalations in the morning at the clinic - Treatment A (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations - Treatment B (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations - Treatment C (Exp): CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment D (Ref): formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations Drug administration was done in the morning of each visit day at the clinic between 7.00 and 9.00 a.m.
    Arm type
    		 experimental - active comparator - placebo

    Investigational medicinal product name
    CHF 1535 pMDI - formoterol pMDI + BDP pMDI - placebo pMDI
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate, placebo
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    A 1-week ± 3 days run-in period was followed by five single-day randomized treatment periods separated by wash-out periods of 14±7 days. A safety follow-up phone contact was made 7 ±3 days after the last treatment visit or premature discontinuation, for safety purposes. During the run-in period and during the wash-out periods, patients were treated with BDP pMDI HFA 50 μg extrafine (Ventolair®, Teva), 1 inhalation twice daily (daily dose: BDP 100 μg) administered with AeroChamber Plus™ spacer device.

    Number of subjects in period 1
    		Sequence A/B/C/D/E Sequence B/C/D/E/A Sequence C/D/E/A/B Sequence D/E/A/B/C Sequence E/A/B/C/D
    Started
    13
    13
    13
    11
    9
    Completed
    12
    13
    12
    10
    9
    Not completed
    1
    0
    1
    1
    0
         Consent withdrawn by subject
    -
    -
    1
    1
    -
         Adverse event, non-fatal
    1
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence A/B/C/D/E
    Reporting group description
    		 - Treatment A (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations - Treatment B (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations - Treatment C (Exp): CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment D (Ref): formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment E (Ref): placebo pMDI with spacer, 6 inhalations in the morning at the clinic Drug administration was done in the morning of each visit day at the clinic between 7.00 and 9.00 a.m.. Each patient will have 6 inhalations at each

    Reporting group title
    Sequence B/C/D/E/A
    Reporting group description
    		 - Treatment B (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations - Treatment C (Exp): CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment D (Ref): formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment E (Ref): placebo pMDI with spacer, 6 inhalations in the morning at the clinic - Treatment A (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations Drug administration was done in the morning of each visit day at the clinic between 7.00 and 9.00 a.m.

    Reporting group title
    Sequence C/D/E/A/B
    Reporting group description
    		 - Treatment C (Exp): CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment D (Ref): formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment E (Ref): placebo pMDI with spacer, 6 inhalations in the morning at the clinic - Treatment A (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations - Treatment B (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations Drug administration was done in the morning of each visit day at the clinic between 7.00 and 9.00 a.m.

    Reporting group title
    Sequence D/E/A/B/C
    Reporting group description
    		 - Treatment D (Ref): formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment E (Ref): placebo pMDI with spacer, 6 inhalations in the morning at the clinic - Treatment A (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations - Treatment B (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations - Treatment C (Exp): CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations Drug administration was done in the morning of each visit day at the clinic between 7.00 and 9.00 a.m.

    Reporting group title
    Sequence E/A/B/C/D
    Reporting group description
    		 - Treatment E (Ref): placebo pMDI with spacer, 6 inhalations in the morning at the clinic - Treatment A (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations - Treatment B (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations - Treatment C (Exp): CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment D (Ref): formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations Drug administration was done in the morning of each visit day at the clinic between 7.00 and 9.00 a.m.

    Reporting group values
    		 Sequence A/B/C/D/E Sequence B/C/D/E/A Sequence C/D/E/A/B Sequence D/E/A/B/C Sequence E/A/B/C/D Total
    Number of subjects
    		 13 13 13 11 9 59
    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)
    		 8.5 ( 1.9 ) 9.4 ( 1.4 ) 8.6 ( 1.3 ) 8.8 ( 1.7 ) 9 ( 1.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 4 6 4 2 18
        Male
    		 11 9 7 7 7 41

    End points

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    End points reporting groups
    Reporting group title
    Sequence A/B/C/D/E
    Reporting group description
    		 - Treatment A (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations - Treatment B (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations - Treatment C (Exp): CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment D (Ref): formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment E (Ref): placebo pMDI with spacer, 6 inhalations in the morning at the clinic Drug administration was done in the morning of each visit day at the clinic between 7.00 and 9.00 a.m.. Each patient will have 6 inhalations at each

    Reporting group title
    Sequence B/C/D/E/A
    Reporting group description
    		 - Treatment B (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations - Treatment C (Exp): CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment D (Ref): formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment E (Ref): placebo pMDI with spacer, 6 inhalations in the morning at the clinic - Treatment A (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations Drug administration was done in the morning of each visit day at the clinic between 7.00 and 9.00 a.m.

    Reporting group title
    Sequence C/D/E/A/B
    Reporting group description
    		 - Treatment C (Exp): CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment D (Ref): formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment E (Ref): placebo pMDI with spacer, 6 inhalations in the morning at the clinic - Treatment A (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations - Treatment B (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations Drug administration was done in the morning of each visit day at the clinic between 7.00 and 9.00 a.m.

    Reporting group title
    Sequence D/E/A/B/C
    Reporting group description
    		 - Treatment D (Ref): formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment E (Ref): placebo pMDI with spacer, 6 inhalations in the morning at the clinic - Treatment A (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations - Treatment B (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations - Treatment C (Exp): CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations Drug administration was done in the morning of each visit day at the clinic between 7.00 and 9.00 a.m.

    Reporting group title
    Sequence E/A/B/C/D
    Reporting group description
    		 - Treatment E (Ref): placebo pMDI with spacer, 6 inhalations in the morning at the clinic - Treatment A (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations - Treatment B (Exp): CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations - Treatment C (Exp): CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations - Treatment D (Ref): formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations Drug administration was done in the morning of each visit day at the clinic between 7.00 and 9.00 a.m.

    Subject analysis set title
    CHF 1535 50/6 μg - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients who received at least one dose of study medication and with any post-dose efficacy evaluations for a given treatment period.

    Subject analysis set title
    CHF 1535 100/12 μg - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients who will receive at least one dose of study medication and with any post-dose efficacy evaluations for a given treatment period.

    Subject analysis set title
    CHF 1535 200/24 μg - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients who will receive at least one dose of study medication and with any post-dose efficacy evaluations for a given treatment period.

    Subject analysis set title
    BDP 100 μg + FF 12 μg - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients who will receive at least one dose of study medication and with any post-dose efficacy evaluations for a given treatment period.

    Subject analysis set title
    Placebo - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients who will receive at least one dose of study medication and with any post-dose efficacy evaluations for a given treatment period.

    Subject analysis set title
    CHF 1535 50/6 μg - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised patients who took at least one dose of study medication.

    Subject analysis set title
    CHF 1535 100/12 μg - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised patients who took at least one dose of study medication.

    Subject analysis set title
    CHF 1535 200/24 μg - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised patients who took at least one dose of study medication.

    Subject analysis set title
    BDP 100 μg + FF 12 μg - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised patients who took at least one dose of study medication.

    Subject analysis set title
    Placebo - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised patients who took at least one dose of study medication.

    Primary: FEV1 AUC0-12h standardised by time

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    End point title
    		 FEV1 AUC0-12h standardised by time
    End point description
    FEV1 AUC corrected by time measured over 12 hours (10 min pre-dose and 10 min, 30 min, 1, 2, 4, 6, 8, 10, 12 hours postdose) following the morning dose of study medication.
    End point type
    Primary
    End point timeframe
    At each visit from Visit 1 (screening visit, run-in period) to Visit 6 (from Visit 2 to Visit 6: treatment period)
    End point values
    		 CHF 1535 50/6 μg - ITT CHF 1535 100/12 μg - ITT CHF 1535 200/24 μg - ITT BDP 100 μg + FF 12 μg - ITT Placebo - ITT
    Number of subjects analysed
    58
    57
    58
    59
    57
    Units: liters
        arithmetic mean (standard deviation)
    1.789 ( 0.388 )
    1.81 ( 0.405 )
    1.82 ( 0.416 )
    1.821 ( 0.416 )
    1.738 ( 0.365 )
    Statistical analysis title
    		 CHF1535 100/12 μg vs BDP 100 μg + FF 12 μg
    Comparison groups
    CHF 1535 100/12 μg - ITT v BDP 100 μg + FF 12 μg - ITT
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.909
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    -0.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.047
         upper limit
    		 0.042
    Statistical analysis title
    		 CHF 1535 50/6 μg vs placebo
    Comparison groups
    CHF 1535 50/6 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.048
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.045
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.089
    Statistical analysis title
    		 CHF 1535 100/12 μg vs placebo
    Comparison groups
    CHF 1535 100/12 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.076
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.032
         upper limit
    		 0.121
    Statistical analysis title
    		 CHF1535 200/24 μg vs placebo
    Comparison groups
    CHF 1535 200/24 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.086
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.041
         upper limit
    		 0.131
    Statistical analysis title
    		 BDP 100 μg + FF 12 μg vs placebo
    Comparison groups
    Placebo - ITT v BDP 100 μg + FF 12 μg - ITT
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.079
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.034
         upper limit
    		 0.123

    Secondary: Peak FEV1

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    End point title
    		 Peak FEV1
    End point description
    Peak FEV1 is intended as the maximum value of the post-dose measurements during a 12 hour interval
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening visit, run-in period) to Visit 6 (from Visit 2 to Visit 6: treatment period)
    End point values
    		 CHF 1535 50/6 μg - ITT CHF 1535 100/12 μg - ITT CHF 1535 200/24 μg - ITT BDP 100 μg + FF 12 μg - ITT Placebo - ITT
    Number of subjects analysed
    58
    57
    58
    59
    57
    Units: liters
        arithmetic mean (standard deviation)
    1.923 ( 0.4 )
    2 ( 0.427 )
    1.971 ( 0.404 )
    1.961 ( 0.426 )
    1.879 ( 0.371 )
    Statistical analysis title
    		 CHF1535 100/12 μg vs BDP 100 μg + FF 12 μg
    Comparison groups
    CHF 1535 100/12 μg - ITT v BDP 100 μg + FF 12 μg - ITT
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.198
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.034
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.018
         upper limit
    		 0.086
    Statistical analysis title
    		 CHF1535 50/6 μg vs placebo
    Comparison groups
    CHF 1535 50/6 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.037
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.015
         upper limit
    		 0.089
    Statistical analysis title
    		 CHF1535 100/12 μg vs placebo
    Comparison groups
    Placebo - ITT v CHF 1535 100/12 μg - ITT
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.119
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.067
         upper limit
    		 0.171
    Statistical analysis title
    		 CHF1535 200/24 μg vs placebo
    Comparison groups
    Placebo - ITT v CHF 1535 200/24 μg - ITT
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.094
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.042
         upper limit
    		 0.146
    Statistical analysis title
    		 BDP 100 μg + FF 12 μg vs placebo
    Comparison groups
    Placebo - ITT v BDP 100 μg + FF 12 μg - ITT
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.085
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.033
         upper limit
    		 0.137

    Secondary: FEV1 at 12 h post-dose

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    End point title
    		 FEV1 at 12 h post-dose
    End point description
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening visit, run-in period) to Visit 6 (from Visit 2 to Visit 6: treatment period)
    End point values
    		 CHF 1535 50/6 μg - ITT CHF 1535 100/12 μg - ITT CHF 1535 200/24 μg - ITT BDP 100 μg + FF 12 μg - ITT Placebo - ITT
    Number of subjects analysed
    58
    57
    58
    59
    57
    Units: liters
        arithmetic mean (standard deviation)
    1.721 ( 0.423 )
    1.754 ( 0.395 )
    1.799 ( 0.432 )
    1.794 ( 0.424 )
    1.733 ( 0.368 )
    Statistical analysis title
    		 CHF1535 100/12 μg vs BDP 100 μg + FF 12 μg
    Comparison groups
    CHF 1535 100/12 μg - ITT v BDP 100 μg + FF 12 μg - ITT
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.24
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    -0.037
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.098
         upper limit
    		 0.025
    Statistical analysis title
    		 CHF1535 50/6 μg vs placebo
    Comparison groups
    CHF 1535 50/6 μg - ITT v Placebo - ITT
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.76
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    -0.009
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.071
         upper limit
    		 0.052
    Statistical analysis title
    		 CHF1535 100/12 μg vs placebo
    Comparison groups
    Placebo - ITT v CHF 1535 100/12 μg - ITT
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.283
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.033
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.028
         upper limit
    		 0.094
    Statistical analysis title
    		 CHF1535 200/24 μg vs placebo
    Comparison groups
    Placebo - ITT v CHF 1535 200/24 μg - ITT
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.078
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.017
         upper limit
    		 0.139
    Statistical analysis title
    		 BDP 100 μg + FF 12 μg vs placebo
    Comparison groups
    Placebo - ITT v BDP 100 μg + FF 12 μg - ITT
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.025
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.009
         upper limit
    		 0.131

    Secondary: Pre-dose heart rate

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    End point title
    		 Pre-dose heart rate
    End point description
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening visit, run-in period) to Visit 6 (from Visit 2 to Visit 6: treatment period)
    End point values
    		 CHF 1535 50/6 μg - Safety CHF 1535 100/12 μg - Safety CHF 1535 200/24 μg - Safety BDP 100 μg + FF 12 μg - Safety Placebo - Safety
    Number of subjects analysed
    58
    57
    58
    59
    57
    Units: beats/min
        arithmetic mean (standard deviation)
    80.2 ( 13.7 )
    80.3 ( 13.1 )
    80.4 ( 14.2 )
    81.7 ( 12.6 )
    81.5 ( 15.1 )
    No statistical analyses for this end point

    Secondary: Post-dose heart rate

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    End point title
    		 Post-dose heart rate
    End point description
    End point type
    Secondary
    End point timeframe
    30 minutes post-dose at each clinic visit from Visit 2 to Visit 6
    End point values
    		 CHF 1535 50/6 μg - Safety CHF 1535 100/12 μg - Safety CHF 1535 200/24 μg - Safety BDP 100 μg + FF 12 μg - Safety Placebo - Safety
    Number of subjects analysed
    58
    57
    58
    59
    57
    Units: beats/min
        arithmetic mean (standard deviation)
    79 ( 11.9 )
    80.7 ( 12.7 )
    81.6 ( 14.1 )
    80.1 ( 14.1 )
    79.7 ( 13.4 )
    No statistical analyses for this end point

    Secondary: Pre-dose systolic blood pressure

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    End point title
    		 Pre-dose systolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Sitting systolic blood pressure at each visit from Visit 1 (screening visit, run-in period) to Visit 6 (from Visit 2 to Visit 6: treatment period).
    End point values
    		 CHF 1535 50/6 μg - Safety CHF 1535 100/12 μg - Safety CHF 1535 200/24 μg - Safety BDP 100 μg + FF 12 μg - Safety Placebo - Safety
    Number of subjects analysed
    58
    57
    58
    59
    57
    Units: mmHg
        arithmetic mean (standard deviation)
    102.1 ( 6.7 )
    101.4 ( 6.8 )
    101.2 ( 7 )
    101.3 ( 6.7 )
    102 ( 6.4 )
    No statistical analyses for this end point

    Secondary: Post-dose systolic blood pressure

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    End point title
    		 Post-dose systolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    30 minutes post-dose, sitting systolic blood pressure at each visit from Visit 2 to Visit 6 (treatment period).
    End point values
    		 CHF 1535 50/6 μg - Safety CHF 1535 100/12 μg - Safety CHF 1535 200/24 μg - Safety BDP 100 μg + FF 12 μg - Safety Placebo - Safety
    Number of subjects analysed
    58
    57
    58
    59
    57
    Units: mmHg
        arithmetic mean (standard deviation)
    102.2 ( 6.5 )
    101.9 ( 7.2 )
    101.4 ( 7.4 )
    102.2 ( 6.2 )
    102.5 ( 6.5 )
    No statistical analyses for this end point

    Secondary: Pre-dose distolic blood pressure

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    End point title
    		 Pre-dose distolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose, sitting diastolic blood pressure at each visit from Visit 1 (screening visit, run-in) to Visit 6 (from Visit 2 to Visit 6: treatment period).
    End point values
    		 CHF 1535 50/6 μg - Safety CHF 1535 100/12 μg - Safety CHF 1535 200/24 μg - Safety BDP 100 μg + FF 12 μg - Safety Placebo - Safety
    Number of subjects analysed
    58
    57
    58
    59
    57
    Units: mmHg
        arithmetic mean (standard deviation)
    66.2 ( 6.4 )
    65.2 ( 6.6 )
    65.8 ( 6.9 )
    65.9 ( 6.7 )
    66.3 ( 6.2 )
    No statistical analyses for this end point

    Secondary: Post-dose diastolic blood pressure

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    End point title
    		 Post-dose diastolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    30 minutes post-dose, sitting diastolic blood pressure at each visit from Visit 2 to Visit 6 (treatment period).
    End point values
    		 CHF 1535 50/6 μg - Safety CHF 1535 100/12 μg - Safety CHF 1535 200/24 μg - Safety BDP 100 μg + FF 12 μg - Safety Placebo - Safety
    Number of subjects analysed
    58
    57
    58
    59
    57
    Units: mmHg
        arithmetic mean (standard deviation)
    65.7 ( 5.9 )
    66.1 ( 5.8 )
    65.6 ( 6.3 )
    65.9 ( 6.3 )
    66.1 ( 5.8 )
    No statistical analyses for this end point

    Secondary: Pre-dose QTcF

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    End point title
    		 Pre-dose QTcF
    End point description
    End point type
    Secondary
    End point timeframe
    15 minutes pre-dose at each visit from Visit 1 (screening visit, run-in period) to Visit 6 (from Visit 2 to Visit 6: treatment period).
    End point values
    		 CHF 1535 50/6 μg - Safety CHF 1535 100/12 μg - Safety CHF 1535 200/24 μg - Safety BDP 100 μg + FF 12 μg - Safety Placebo - Safety
    Number of subjects analysed
    58
    57
    58
    59
    57
    Units: msec
        arithmetic mean (standard deviation)
    405.4 ( 12.6 )
    400.9 ( 13.6 )
    401.4 ( 14.9 )
    402.4 ( 15.4 )
    402.6 ( 14.4 )
    No statistical analyses for this end point

    Secondary: 30 min post-dose QTcF

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    End point title
    		 30 min post-dose QTcF
    End point description
    End point type
    Secondary
    End point timeframe
    30 minutes post-dose at each visit from Visit 2 to Visit 6 (treatment period).
    End point values
    		 CHF 1535 50/6 μg - Safety CHF 1535 100/12 μg - Safety CHF 1535 200/24 μg - Safety BDP 100 μg + FF 12 μg - Safety Placebo - Safety
    Number of subjects analysed
    58
    57
    58
    59
    57
    Units: msec
        arithmetic mean (standard deviation)
    404.3 ( 14 )
    405.5 ( 13.2 )
    406.4 ( 16.4 )
    402.5 ( 18.1 )
    401.1 ( 15.5 )
    No statistical analyses for this end point

    Secondary: 1 hour post-dose QTcF

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    End point title
    		 1 hour post-dose QTcF
    End point description
    End point type
    Secondary
    End point timeframe
    1 hour post-dose at each visit from Visit 2 to Visit 6 (treatment period).
    End point values
    		 CHF 1535 50/6 μg - Safety CHF 1535 100/12 μg - Safety CHF 1535 200/24 μg - Safety BDP 100 μg + FF 12 μg - Safety Placebo - Safety
    Number of subjects analysed
    58
    57
    58
    59
    57
    Units: msec
        arithmetic mean (standard deviation)
    405.7 ( 12.8 )
    400.7 ( 16.1 )
    406.4 ( 16.3 )
    402.8 ( 14.5 )
    402.2 ( 14.4 )
    No statistical analyses for this end point

    Secondary: 2 hour QTcF

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    End point title
    		 2 hour QTcF
    End point description
    End point type
    Secondary
    End point timeframe
    2 hours post-dose at each visit from Visit 2 to Visit 6 (treatment period).
    End point values
    		 CHF 1535 50/6 μg - Safety CHF 1535 100/12 μg - Safety CHF 1535 200/24 μg - Safety BDP 100 μg + FF 12 μg - Safety Placebo - Safety
    Number of subjects analysed
    58
    57
    58
    59
    57
    Units: msec
        arithmetic mean (standard deviation)
    403.2 ( 13.4 )
    400.8 ( 12.9 )
    405.1 ( 16.7 )
    402.5 ( 13.8 )
    403.1 ( 15.3 )
    No statistical analyses for this end point

    Secondary: 6 hour post-dose QTcF

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    End point title
    		 6 hour post-dose QTcF
    End point description
    End point type
    Secondary
    End point timeframe
    6 hours post-dose at each visit from Visit 2 to Visit 6 (treatment period).
    End point values
    		 CHF 1535 50/6 μg - Safety CHF 1535 100/12 μg - Safety CHF 1535 200/24 μg - Safety BDP 100 μg + FF 12 μg - Safety Placebo - Safety
    Number of subjects analysed
    58
    57
    58
    59
    57
    Units: msec
        arithmetic mean (standard deviation)
    402.5 ( 13.8 )
    402.1 ( 15.9 )
    403.2 ( 14.1 )
    402 ( 15.3 )
    402 ( 15.1 )
    No statistical analyses for this end point

    Secondary: 12 hour post-dose QTcF

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    End point title
    		 12 hour post-dose QTcF
    End point description
    End point type
    Secondary
    End point timeframe
    12 hours post-dose at each visit from Visit 2 to Visit 6 (treatment period).
    End point values
    		 CHF 1535 50/6 μg - Safety CHF 1535 100/12 μg - Safety CHF 1535 200/24 μg - Safety BDP 100 μg + FF 12 μg - Safety Placebo - Safety
    Number of subjects analysed
    58
    57
    58
    59
    57
    Units: mesc
        arithmetic mean (standard deviation)
    399.3 ( 12.6 )
    398.3 ( 13.3 )
    402.5 ( 13.8 )
    398.6 ( 12.3 )
    399.1 ( 15.3 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At each visit from Visit 1 (screening visit, run-in period) to Visit 6 (from Visit 2 to Visit 6: treatment period) to follow-up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Safety population - CHF 1535 50/6 μg
    Reporting group description
    		 CHF 1535 50/6 administered via a pMDI with spacer, 1 inhalation (dose: BDP 50 μg/FF 6 μg) + placebo HFA pMDI with spacer, 5 inhalations.

    Reporting group title
    Safety population - CHF 1535 100/12 μg
    Reporting group description
    		 CHF 1535 50/6 administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg/FF 12 μg) + placebo HFA pMDI with spacer, 4 inhalations

    Reporting group title
    Safety population - CHF 1535 200/24 μg
    Reporting group description
    		 CHF 1535 50/6 (dose: BDP 200 μg/FF 24 μg) administered via a pMDI with spacer, 4 inhalations (dose: BDP 200 μg/FF 24 μg) + placebo HFA pMDI with spacer, 2 inhalations

    Reporting group title
    Safety population - BDP 100 μg + FF 12 μg
    Reporting group description
    		 Formoterol 6 μg HFA administered via a pMDI with spacer, 2 inhalations (dose: FF 12 μg) + extrafine BDP 50 μg, administered via a pMDI with spacer, 2 inhalations (dose: BDP 100 μg) + placebo HFA pMDI with spacer, 2 inhalations

    Reporting group title
    Safety population - Placebo
    Reporting group description
    		 Placebo pMDI with spacer, 6 inhalations in the morning at the clinic

    Serious adverse events
    		 Safety population - CHF 1535 50/6 μg Safety population - CHF 1535 100/12 μg Safety population - CHF 1535 200/24 μg Safety population - BDP 100 μg + FF 12 μg Safety population - Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 57 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Safety population - CHF 1535 50/6 μg Safety population - CHF 1535 100/12 μg Safety population - CHF 1535 200/24 μg Safety population - BDP 100 μg + FF 12 μg Safety population - Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 57 (5.26%)
    4 / 58 (6.90%)
    3 / 59 (5.08%)
    4 / 57 (7.02%)
    Nervous system disorders
    Tremor
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 57 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 57 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Cough
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 57 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Throat irritation
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 57 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    0
    0
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    0
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    2 / 58 (3.45%)
    1 / 59 (1.69%)
    2 / 57 (3.51%)
         occurrences all number
    0
    0
    2
    1
    2
    Respiratory tract infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 57 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jul 2012
    This substantial amendment was introduced: 1. To modify the inclusion criterion n.6 about reversibility test at the screening visit lowering the positive threshold to 12% improvement with 200 μg salbutamol from pre-dose value instead of 15% in this children population under stable inhaled corticosteroid therapy; 2. To increase the time window between the 12-hour spirometry visits, and the relevant tolerance, from 7±3 to 14±7 days, in order to improve the acceptability of the study by patients and their parents, and to better match the availability of study personnel at the sites; 3. To provide also parents/patients with instructions for cleaning of AeroChamber Plus™ spacers in case of delay in attending clinic visits; 4. To decrease the number of participating Countries, keeping the same number of involved investigational sites; 5. To update the planned study start and end; 6. To allow the concomitant treatment with leukotriene antagonists if taken at stable dose in the 4 weeks prior to study entry and to be continued at the same dose throughout all the study period; 7. To correct some typing errors.

    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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