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    Clinical Trial Results:
    A phase III, 12-week, multicentre, multinational, randomised, double-blind, double-dummy, 3 arm-parallel group study to test the efficacy of CHF 1535 50/6 microgram (fixed combination of beclomethasone dipropionate plus formoterol fumarate) versus a free combination of beclomethasone dipropionate 50 microgram plus formoterol fumarate 6 microgram and versus a monotherapy of beclomethasone dipropionate 50 microgram, in partly controlled asthmatic children.

    Summary
    EudraCT number
    		 2009-016757-18
    Trial protocol
    		 DE   FR   HU   SK   ES   BG   IT   Outside EU/EEA  
    Global end of trial date
    28 Sep 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Jul 2016
    First version publication date
    31 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CCD-0807-PR-0024
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01475032
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici SpA
    Sponsor organisation address
    Via Palermo, 26/A, Parma, Italy, 43126
    Public contact
    Chiesi Clinical Trials, Chiesi Farmaceutici SpA, ClinicalTrials_info@chiesi.com
    Scientific contact
    Chiesi Clinical Trials, 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
    28 Sep 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Sep 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Demonstrate that CHF 1535 50/6 μg pMDI (daily dose: BDP 200 μg/FF 24 μg) is superior to the corresponding monotherapy with beclomethasone dipropionate 50 μg pMDI (daily dose: BDP 200 μg) and non-inferior relative to the corresponding free combination of beclomethasone dipropionate 50 μg pMDI (daily dose: BDP 200 μg) plus formoterol fumarate 6 μg pMDI (daily dose: FF 24 μg) (all treatments administered via the AeroChamber Plus™ spacer device) in terms of pulmonary function (change from baseline in pre-dose morning FEV1 after a 12-week treatment period) in peadiatric patients with “partly controlled” persistent asthma. BDP = Beclomethasone dipropionate FF=Formoterol fumarate CHF 1535=Fixed combination of BDP and FF pMDI=Pressurised metered dose inhaler
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practices (GCP) guidelines, and local law requirements. Other than routine care, no specific measures for protection of trial subjects were implemented.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Sep 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
    Poland: 185
    Country: Number of subjects enrolled
    Slovakia: 35
    Country: Number of subjects enrolled
    Bulgaria: 111
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Hungary: 108
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Russian Federation: 74
    Country: Number of subjects enrolled
    Ukraine: 77
    Country: Number of subjects enrolled
    Romania: 15
    Worldwide total number of subjects
    638
    EEA total number of subjects
    487
    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)
    638
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Overall, 779 patients were screened; of these 638 patients were randomized.

    Pre-assignment
    Screening details
    		 Pre-screening visit was performed 3-7 days before screening visit. At screening visit, inclusion/exclusion criteria were assessed, followed by a Run-in period of 2 weeks when patients stopped their current asthma treatment and received BDP 100mcg pMDI.

    Period 1
    Period 1 title
    Overall trial (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
    Placebo was provided to assure a complete double-blind, double-dummy design. The canisters/actuators of CHF 1535 and FF pMDI were of identical appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment A - fixed combination CHF 1535 50/6 μg
    Arm description
    		 Treatment A: CHF 1535 50/6 μg (total daily dose: BDP 200 μg/FF 24 μg) - 2 inhalations CHF 1535 50/6 μg pMDI via AeroChamber Plus spacer device - 2 inhalations of BDP placebo pMDI with AeroChamber Plus spacer device, twice a day BDP=Beclomethasone dipropionate FF=Formoterol fumarate CHF 1535=Fixed combination of BDP 50μg and FF 6 μg
    Arm type
    		 Experimental

    Investigational medicinal product name
    CHF 1535 50/6 µg
    Investigational medicinal product code
    Other name
    BDP/FF, Fixed combination of beclomethasone dipropionate and formoterol fumarate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    CHF 1535 50/6 μg pMDI via AeroChamber Plus spacer device - 2 inhalations twice a day CHF 1535 50/6 μg=Fixed combination of BDPμg and FF 50μg/6 μg BDP=Beclomethasone dipropionate FF=Formoterol fumarate pMDI=pressurised Metered Dose Inhaler

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Extrafine BDP placebo
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations twice a day

    Arm title
    		 Treatment B - free combination BDP + FF
    Arm description
    		 Treatment B: (total daily dose: BDP 200 μg + FF 24 μg) - 2 inhalations BDP 50 μg pMDI via AeroChamber Plus spacer device - 2 inhalations of FF 6 μg pMDI with AeroChamber Plus spacer device, twice a day BDP = Beclomethasone dipropionate FF=Formoterol fumarate
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Beclomethasone dipropionate (BDP)
    Investigational medicinal product code
    Other name
    Beclomethasone dipropionate, Ventolair
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    BDP 50 μg pMDI via AeroChamber Plus spacer device - 2 inhalations twice a day BDP=Beclomethasone dipropionate pMDI=pressurised Metered Dose Inhaler

    Investigational medicinal product name
    Formoterol fumarate (FF)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    FF 6 μg pMDI via AeroChamber Plus spacer device - 2 inhalations twice a day. FF=Formoterol fumarate pMDI=pressurised Metered Dose Inhaler

    Arm title
    		 Treatment C - monotherapy BDP
    Arm description
    		 Treatment C: (total daily dose: BDP 200 μg) - 2 inhalations BDP 50 μg pMDI via AeroChamber Plus spacer device - 2 inhalations of CHF 1535 placebo pMDI with AeroChamber Plus spacer device, twice a day
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Beclomethasone dipropionate (BDP)
    Investigational medicinal product code
    Other name
    Beclomethasone dipropionate, Ventolair
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    BDP 50 μg pMDI via AeroChamber Plus spacer device - 2 inhalations twice a day BDP=Beclomethasone dipropionate pMDI=pressurised Metered Dose Inhaler

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    CHF 1535 placebo pMDI
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    - 2 inhalations of CHF 1535 placebo pMDI with AeroChamber Plus spacer device, twice a day BDP = Beclomethasone dipropionate FF=Formoterol fumarate CHF 1535=Fixed combination of BDP and FF pMDI=pressurised Metered Dose Inhaler

    Number of subjects in period 1
    		Treatment A - fixed combination CHF 1535 50/6 μg Treatment B - free combination BDP + FF Treatment C - monotherapy BDP
    Started
    211
    213
    214
    Completed
    208
    205
    204
    Not completed
    3
    8
    10
         Consent withdrawn by subject
    2
    4
    6
         inclusion/exclusion criteria not met
    -
    2
    2
         Technical issues: metered dose inhaler & spacer
    1
    1
    1
         Lost to follow-up
    -
    1
    -
         Protocol deviation
    -
    -
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Treatment A - fixed combination CHF 1535 50/6 μg
    Reporting group description
    		 Treatment A: CHF 1535 50/6 μg (total daily dose: BDP 200 μg/FF 24 μg) - 2 inhalations CHF 1535 50/6 μg pMDI via AeroChamber Plus spacer device - 2 inhalations of BDP placebo pMDI with AeroChamber Plus spacer device, twice a day BDP=Beclomethasone dipropionate FF=Formoterol fumarate CHF 1535=Fixed combination of BDP 50μg and FF 6 μg

    Reporting group title
    Treatment B - free combination BDP + FF
    Reporting group description
    		 Treatment B: (total daily dose: BDP 200 μg + FF 24 μg) - 2 inhalations BDP 50 μg pMDI via AeroChamber Plus spacer device - 2 inhalations of FF 6 μg pMDI with AeroChamber Plus spacer device, twice a day BDP = Beclomethasone dipropionate FF=Formoterol fumarate

    Reporting group title
    Treatment C - monotherapy BDP
    Reporting group description
    		 Treatment C: (total daily dose: BDP 200 μg) - 2 inhalations BDP 50 μg pMDI via AeroChamber Plus spacer device - 2 inhalations of CHF 1535 placebo pMDI with AeroChamber Plus spacer device, twice a day

    Reporting group values
    		 Treatment A - fixed combination CHF 1535 50/6 μg Treatment B - free combination BDP + FF Treatment C - monotherapy BDP Total
    Number of subjects
    		 211 213 214 638
    Age categorical
    Units: Subjects
        5-8 years
    		 98 95 95 288
        9-12 years
    		 112 113 114 339
        not recorded
    		 1 5 5 11
    Gender categorical
    Units: Subjects
        Female
    		 78 69 71 218
        Male
    		 132 139 138 409
        not recorded
    		 1 5 5 11
    Race
    Units: Subjects
        White
    		 208 207 207 622
        Asian
    		 0 0 1 1
        Other
    		 1 1 1 3
        Not Available
    		 1 0 0 1
        Not part of ITT
    		 1 5 5 11

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Treatment A - fixed combination CHF 1535 50/6 μg
    Reporting group description
    		 Treatment A: CHF 1535 50/6 μg (total daily dose: BDP 200 μg/FF 24 μg) - 2 inhalations CHF 1535 50/6 μg pMDI via AeroChamber Plus spacer device - 2 inhalations of BDP placebo pMDI with AeroChamber Plus spacer device, twice a day BDP=Beclomethasone dipropionate FF=Formoterol fumarate CHF 1535=Fixed combination of BDP 50μg and FF 6 μg

    Reporting group title
    Treatment B - free combination BDP + FF
    Reporting group description
    		 Treatment B: (total daily dose: BDP 200 μg + FF 24 μg) - 2 inhalations BDP 50 μg pMDI via AeroChamber Plus spacer device - 2 inhalations of FF 6 μg pMDI with AeroChamber Plus spacer device, twice a day BDP = Beclomethasone dipropionate FF=Formoterol fumarate

    Reporting group title
    Treatment C - monotherapy BDP
    Reporting group description
    		 Treatment C: (total daily dose: BDP 200 μg) - 2 inhalations BDP 50 μg pMDI via AeroChamber Plus spacer device - 2 inhalations of CHF 1535 placebo pMDI with AeroChamber Plus spacer device, twice a day

    Primary: 1_FEV1 change from baseline to end of treatment (week 12)

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    End point title
    		 1_FEV1 change from baseline to end of treatment (week 12)
    End point description
    Pre-dose morning FEV1. Shown value is the mean change from baseline, after 12 weeks of treatment.
    End point type
    Primary
    End point timeframe
    Baseline to end of treatment (Week 12).
    End point values
    		 Treatment A - fixed combination CHF 1535 50/6 μg Treatment B - free combination BDP + FF Treatment C - monotherapy BDP
    Number of subjects analysed
    194 [1]
    193 [2]
    192 [3]
    Units: liters
        arithmetic mean (standard deviation)
    0.153 ± 0.231
    0.194 ± 0.294
    0.135 ± 0.248
    Notes
    [1] - ITT population
    [2] - ITT population
    [3] - ITT population
    Statistical analysis title
    		 Comparison between treatments (A vs C)
    Statistical analysis description
    Primary endpoint analysis: adjusted mean difference between treatments at week 12.
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment C - monotherapy BDP
    Number of subjects included in analysis
    386
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.482
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.018
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.033
         upper limit
    		 0.07
    Statistical analysis title
    		 Comparison between treatments (A vs B)
    Statistical analysis description
    Primary endpoint analysis: adjusted mean difference between treatments at week 12.
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment B - free combination BDP + FF
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.099
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.043
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.094
         upper limit
    		 0.008

    Secondary: 2a_FEV1 change from baseline to week 4, 8

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    End point title
    		 2a_FEV1 change from baseline to week 4, 8
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 4, 8. For statistical analysis in relation to week12, see primary endpoint.
    End point values
    		 Treatment A - fixed combination CHF 1535 50/6 μg Treatment B - free combination BDP + FF Treatment C - monotherapy BDP
    Number of subjects analysed
    210 [4]
    208 [5]
    209 [6]
    Units: liters
    arithmetic mean (standard deviation)
        Week 4
    0.135 ± 0.245
    0.143 ± 0.233
    0.125 ± 0.244
        Week 8
    0.177 ± 0.232
    0.178 ± 0.239
    0.155 ± 0.249
        Week 12
    0.153 ± 0.231
    0.194 ± 0.294
    0.135 ± 0.248
    Notes
    [4] - ITT population For week 4 N=197 For week 8 N=197 For week 12 N=194
    [5] - ITT population For week 4 N=196 For week 8 N=193 For week 12 N=193
    [6] - ITT population For week 4 N=191 For week 8 N=192 For week 12 N=192
    Statistical analysis title
    		 Comparison between treatments at week 4 (A vs C)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment C - monotherapy BDP
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.527
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.015
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.032
         upper limit
    		 0.063
    Statistical analysis title
    		 Comparison between treatments at week 8 (A vs C)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment C - monotherapy BDP
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.317
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.024
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.023
         upper limit
    		 0.071
    Statistical analysis title
    		 Comparison between treatments at week 4 (A vs B)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment B - free combination BDP + FF
    Number of subjects included in analysis
    418
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.965
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -0.001
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.048
         upper limit
    		 0.046
    Statistical analysis title
    		 Comparison between treatments at week 8 (A vs B)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment B - free combination BDP + FF
    Number of subjects included in analysis
    418
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.977
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.001
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.046
         upper limit
    		 0.048

    Secondary: 2b_FVC change from baseline to week 4, 8, 12

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    End point title
    		 2b_FVC change from baseline to week 4, 8, 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 4, 8, 12.
    End point values
    		 Treatment A - fixed combination CHF 1535 50/6 μg Treatment B - free combination BDP + FF Treatment C - monotherapy BDP
    Number of subjects analysed
    210 [7]
    208 [8]
    209 [9]
    Units: liters
    arithmetic mean (standard deviation)
        Week 4
    0.099 ± 0.256
    0.119 ± 0.22
    0.123 ± 0.265
        Week 8
    0.161 ± 0.274
    0.152 ± 0.232
    0.153 ± 0.24
        Week 12
    0.139 ± 0.261
    0.166 ± 0.275
    0.14 ± 0.25
    Notes
    [7] - ITT population For week 4 N=197 For week 8 N=197 For week 12 N=193
    [8] - ITT population For week 4 N=194 For week 8 N=191 For week 12 N=191
    [9] - ITT population For week 4 N=190 For week 8 N=191 For week 12 N=191
    Statistical analysis title
    		 Comparison between treatments at week 4 (A vs C)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment C - monotherapy BDP
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.477
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.018
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.067
         upper limit
    		 0.031
    Statistical analysis title
    		 Comparison between treatments at week 8 (A vs C)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment C - monotherapy BDP
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.014
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.035
         upper limit
    		 0.063
    Statistical analysis title
    		 Comparison between treatments at week 12 (A vs C)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment C - monotherapy BDP
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.994
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.051
         upper limit
    		 0.052
    Statistical analysis title
    		 Comparison between treatments at week 4 (A vs B)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment B - free combination BDP + FF
    Number of subjects included in analysis
    418
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.677
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.059
         upper limit
    		 0.039
    Statistical analysis title
    		 Comparison between treatments at week 8 (A vs B)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment B - free combination BDP + FF
    Number of subjects included in analysis
    418
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.5
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.017
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.032
         upper limit
    		 0.066
    Statistical analysis title
    		 Comparison between treatments at week 12 (A vs B)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment B - free combination BDP + FF
    Number of subjects included in analysis
    418
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.282
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.028
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 0.023

    Secondary: 3a_Morning PEF - change from baseline to end of treatment (week 12)

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    End point title
    		 3a_Morning PEF - change from baseline to end of treatment (week 12)
    End point description
    Pre-dose morning PEF was recorded on the electronic peak flow meter during each inter-visit period in the randomised population.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment (week 12); entire treatment period.
    End point values
    		 Treatment A - fixed combination CHF 1535 50/6 μg Treatment B - free combination BDP + FF Treatment C - monotherapy BDP
    Number of subjects analysed
    199 [10]
    199 [11]
    199 [12]
    Units: liters/min
        arithmetic mean (standard deviation)
    18.73 ± 27.28
    14.83 ± 31.38
    9.13 ± 30.6
    Notes
    [10] - ITT population
    [11] - ITT population
    [12] - ITT population
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs C)
    Statistical analysis description
    Only morning PEF measurements performed before morning study medication intake were considered.
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment C - monotherapy BDP
    Number of subjects included in analysis
    398
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    8.904
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.296
         upper limit
    		 14.512
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs B)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment B - free combination BDP + FF
    Number of subjects included in analysis
    398
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.336
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    2.751
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.861
         upper limit
    		 8.362

    Secondary: 3b_Evening PEF - change from baseline to end of treatment (week 12)

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    End point title
    		 3b_Evening PEF - change from baseline to end of treatment (week 12)
    End point description
    Pre-dose evening PEF was recorded on the electronic peak flow meter during each inter-visit period in the randomised population.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment (week 12); entire treatment period.
    End point values
    		 Treatment A - fixed combination CHF 1535 50/6 μg Treatment B - free combination BDP + FF Treatment C - monotherapy BDP
    Number of subjects analysed
    199 [13]
    199 [14]
    199 [15]
    Units: liters/minute
        arithmetic mean (standard deviation)
    12.4 ± 29.02
    11.37 ± 32.4
    6.7 ± 28.99
    Notes
    [13] - ITT population
    [14] - ITT population
    [15] - ITT population
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs C)
    Statistical analysis description
    Only evening PEF measurements performed before evening study medication intake were considered.
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment C - monotherapy BDP
    Number of subjects included in analysis
    398
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.053
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    5.574
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.062
         upper limit
    		 11.21
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs B)
    Statistical analysis description
    Only evening PEF measurements performed before evening study medication intake were considered.
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment B - free combination BDP + FF
    Number of subjects included in analysis
    398
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.919
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.294
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.344
         upper limit
    		 5.932

    Secondary: 4_PEF - change from baseline in daily variability

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    End point title
    		 4_PEF - change from baseline in daily variability
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment (week 12); entire treatment period.
    End point values
    		 Treatment A - fixed combination CHF 1535 50/6 μg Treatment B - free combination BDP + FF Treatment C - monotherapy BDP
    Number of subjects analysed
    196 [16]
    192 [17]
    194 [18]
    Units: percent
        arithmetic mean (standard deviation)
    -1.79 ± 6.73
    -1.01 ± 7.57
    -0.43 ± 6.39
    Notes
    [16] - ITT population
    [17] - ITT population
    [18] - ITT population
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs C)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment C - monotherapy BDP
    Number of subjects included in analysis
    390
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.019
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -1.118
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.051
         upper limit
    		 -0.184
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs B)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment B - free combination BDP + FF
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.454
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.357
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.292
         upper limit
    		 0.578

    Secondary: 5a_Asthma symptom score - daytime - change from baseline

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    End point title
    		 5a_Asthma symptom score - daytime - change from baseline
    End point description
    Asthma symptom score was recorded in the portable peak flow meter (used as an electronic diary) twice daily in the morning and in the evening. Shown value is the mean change from baseline, after 12 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment (week 12); entire treatment period.
    End point values
    		 Treatment A - fixed combination CHF 1535 50/6 μg Treatment B - free combination BDP + FF Treatment C - monotherapy BDP
    Number of subjects analysed
    208 [19]
    205 [20]
    207 [21]
    Units: asthma symptom score
        arithmetic mean (standard deviation)
    -0.53 ± 1.12
    -0.48 ± 0.98
    -0.51 ± 1.07
    Notes
    [19] - ITT population
    [20] - ITT population
    [21] - ITT population
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs C)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment C - monotherapy BDP
    Number of subjects included in analysis
    415
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.646
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.043
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.227
         upper limit
    		 0.141
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs B)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment B - free combination BDP + FF
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.571
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.053
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.237
         upper limit
    		 0.131

    Secondary: 5b_Asthma symptom score - evening - change from baseline

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    End point title
    		 5b_Asthma symptom score - evening - change from baseline
    End point description
    Asthma symptom scores was recorded in the portable peak flow meter (used as an electronic diary) twice daily in the morning and in the evening. Shown value is the mean change from baseline, after 12 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment (week 12); entire treatment period.
    End point values
    		 Treatment A - fixed combination CHF 1535 50/6 μg Treatment B - free combination BDP + FF Treatment C - monotherapy BDP
    Number of subjects analysed
    207 [22]
    206 [23]
    207 [24]
    Units: asthma symptom score
        arithmetic mean (standard deviation)
    -0.41 ± 1.05
    -0.29 ± 0.92
    -0.36 ± 1
    Notes
    [22] - ITT population
    [23] - ITT population
    [24] - ITT population
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs C)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment C - monotherapy BDP
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.499
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.235
         upper limit
    		 0.114
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs B)
    Comparison groups
    Treatment B - free combination BDP + FF v Treatment A - fixed combination CHF 1535 50/6 μg
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.213
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.111
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.285
         upper limit
    		 0.064

    Secondary: 6_Asthma symptom-free days - change from baseline

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    End point title
    		 6_Asthma symptom-free days - change from baseline
    End point description
    Asthma symptom scores were recorded in the portable peak flow meter (used as an electronic diary) twice daily in the morning and in the evening. An asthma symptom-free day is a day with total day-time and night-time asthma symptom scores = 0. Shown value is the mean change from baseline, after 12 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment (week 12); entire treatment period.
    End point values
    		 Treatment A - fixed combination CHF 1535 50/6 μg Treatment B - free combination BDP + FF Treatment C - monotherapy BDP
    Number of subjects analysed
    208 [25]
    206 [26]
    206 [27]
    Units: days
        arithmetic mean (standard deviation)
    22.01 ± 33.35
    25.44 ± 30.71
    23.39 ± 31.19
    Notes
    [25] - ITT population
    [26] - ITT population
    [27] - ITT population
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs C)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment C - monotherapy BDP
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.734
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.939
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.353
         upper limit
    		 4.475
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs B)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment B - free combination BDP + FF
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.428
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -2.189
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.604
         upper limit
    		 3.226

    Secondary: 7_Rescue medication use - change from baseline

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    End point title
    		 7_Rescue medication use - change from baseline
    End point description
    Use of rescue medication (number of salbutamol puffs) were recorded in the portable peak flow meter (used as an electronic diary) twice daily in the morning and in the evening. The recorded data was downloaded and checked by the investigator at each visit. Shown value is the adjusted mean change from baseline (number of puffs per day), after 12 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment (week 12); entire treatment period.
    End point values
    		 Treatment A - fixed combination CHF 1535 50/6 μg Treatment B - free combination BDP + FF Treatment C - monotherapy BDP
    Number of subjects analysed
    207 [28]
    204 [29]
    205 [30]
    Units: number of puffs per day
        arithmetic mean (standard deviation)
    -0.18 ± 0.77
    -0.09 ± 0.71
    -0.17 ± 0.87
    Notes
    [28] - ITT population
    [29] - ITT population
    [30] - ITT population
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs C)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment C - monotherapy BDP
    Number of subjects included in analysis
    412
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.857
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.013
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.151
         upper limit
    		 0.126
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs B)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment B - free combination BDP + FF
    Number of subjects included in analysis
    411
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.402
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.059
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.198
         upper limit
    		 0.079

    Secondary: 8_Rescue medication-free days - percentage - change from baseline

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    End point title
    		 8_Rescue medication-free days - percentage - change from baseline
    End point description
    Use of rescue medication (number of salbutamol puffs) were recorded in the portable peak flow meter (used as an electronic diary) twice daily in the morning and in the evening. The recorded data was downloaded and checked by the investigator at each visit. Shown value is the mean change from baseline (percentage of rescue medication use-free days), after 12 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment (week 12); entire treatment period.
    End point values
    		 Treatment A - fixed combination CHF 1535 50/6 μg Treatment B - free combination BDP + FF Treatment C - monotherapy BDP
    Number of subjects analysed
    208 [31]
    206 [32]
    206 [33]
    Units: days
        arithmetic mean (standard deviation)
    16.41 ± 28.31
    13.17 ± 26.78
    11.76 ± 31.18
    Notes
    [31] - ITT population
    [32] - ITT population
    [33] - ITT population
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs C)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment C - monotherapy BDP
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.077
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    3.819
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.417
         upper limit
    		 8.054
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs B)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment B - free combination BDP + FF
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.21
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    2.704
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.529
         upper limit
    		 6.937

    Secondary: 9_Asthma control days - change from baseline

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    End point title
    		 9_Asthma control days - change from baseline
    End point description
    Asthma control days were recorded in the portable peak flow meter (used as an electronic diary) twice daily in the morning and in the evening. An asthma control day is a day with total day-time and night-time asthma symptom scores = 0 and no puffs of rescue medication taken. Shown value is the percentage asthma control days, presented as the adjusted mean change from baseline, after 12 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment (week 12); entire treatment period.
    End point values
    		 Treatment A - fixed combination CHF 1535 50/6 μg Treatment B - free combination BDP + FF Treatment C - monotherapy BDP
    Number of subjects analysed
    208 [34]
    206 [35]
    206 [36]
    Units: days
        arithmetic mean (standard deviation)
    22.25 ± 32.59
    26.48 ± 31.88
    22.44 ± 31.44
    Notes
    [34] - ITT population
    [35] - ITT population
    [36] - ITT population
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs C)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment C - monotherapy BDP
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.92
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.284
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.233
         upper limit
    		 5.801
    Statistical analysis title
    		 Change from baseline to entire treatment (A vs B)
    Comparison groups
    Treatment A - fixed combination CHF 1535 50/6 μg v Treatment B - free combination BDP + FF
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.338
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -2.695
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.216
         upper limit
    		 2.826

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Run-in phase (week -2) to Follow-up (week 14)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Treatment A - fixed combination BDP/FF
    Reporting group description
    		 Treatment A: (total daily dose: BDP 200 μg/FF 24 μg) 2 inhalations CHF 1535 50/6 μg pMDI via AeroChamber Plus spacer device + 2 inhalations of BDP placebo pMDI with AeroChamber Plus spacer device, twice a day.

    Reporting group title
    Treatment B - free combination BDP + FF
    Reporting group description
    		 Treatment B: (total daily dose: BDP 200 μg + FF 24 μg) 2 inhalations BDP 50 μg pMDI via AeroChamber Plus spacer device + 2 inhalations of FF 6 μg pMDI with AeroChamber Plus spacer device, twice a day.

    Reporting group title
    Treatment C - monotherapy BDP
    Reporting group description
    		 Treatment C: (total daily dose: BDP 200 μg) 2 inhalations BDP 50 μg pMDI via AeroChamber Plus spacer device + 2 inhalations of CHF 1535 placebo pMDI with AeroChamber Plus spacer device, twice a day.

    Serious adverse events
    		 Treatment A - fixed combination BDP/FF Treatment B - free combination BDP + FF Treatment C - monotherapy BDP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 211 (0.95%)
    2 / 210 (0.95%)
    1 / 213 (0.47%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Chest injury
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 210 (0.48%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 210 (0.48%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enteritis
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 210 (0.00%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 210 (0.00%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Post streptococcal glomerulonephritis
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 210 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Tonsillitis
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 210 (0.00%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment A - fixed combination BDP/FF Treatment B - free combination BDP + FF Treatment C - monotherapy BDP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 211 (29.86%)
    61 / 210 (29.05%)
    56 / 213 (26.29%)
    Respiratory, thoracic and mediastinal disorders
    Asthma
    Additional description: "Asthma" is the Preferred Term of the event "asthma exacerbation".
         subjects affected / exposed
    11 / 211 (5.21%)
    7 / 210 (3.33%)
    11 / 213 (5.16%)
         occurrences all number
    12
    8
    12
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 211 (7.58%)
    9 / 210 (4.29%)
    11 / 213 (5.16%)
         occurrences all number
    23
    10
    13
    Pharyngitis
         subjects affected / exposed
    5 / 211 (2.37%)
    16 / 210 (7.62%)
    8 / 213 (3.76%)
         occurrences all number
    5
    17
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None.
    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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