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    Clinical Trial Results:
    A Single Dose, Randomised, Double Blind, Double Dummy, Placebo Controlled, 3-way Crossover Clinical Study, comparing the Onset of Relief from Methacholine-induced Bronchoconstriction with CHF1535 100/6 μg NEXThaler® versus CHF1535 100/6 μg pMDI in Asthmatic Patients.

    Summary
    EudraCT number
    		 2016-003672-47
    Trial protocol
    		 GB  
    Global end of trial date
    19 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Sep 2018
    First version publication date
    28 Sep 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CCD-01535BD1-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03108534
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy, 43126
    Public contact
    Chiesi Farmaceutici S.p.A., Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., +39 0521 2791, clinicaltrials_info@chiesi.com
    Scientific contact
    Chiesi Farmaceutici S.p.A., Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., +39 0521 2791, clinicaltrials_info@chiesi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate, in terms of pulmonary function, the non-inferiority of CHF1535 100/6 μg NEXThaler® vs CHF1535 100/6 μg pMDI on the onset of relief from methacholine-induced bronchospasm in asthmatic subjects on low-medium doses of Inhaled corticosteroids (ICS) or ICS with long-acting β2 agonist (LABA) fixed or free combination.
    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
    		 Patients could continue their previous therapy with ICS or ICS/LABA with ICS at medium-low doses during the overall trial duration. In case they were in treatment with ICS/LABA fixed combination, they were switched to the free components in order to allow the LABA withdrawal before each visit.
    Evidence for comparator
    		 CHF1535 100/6 μg pMDI
    Actual start date of recruitment
    28 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 65
    Worldwide total number of subjects
    65
    EEA total number of subjects
    65
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    65
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The 65 subjects who positively passed screening were randomised to one of the six treatment sequences: ABC (11), ACB (9), BAC (12), BCA (9), CAB (12), CBA (12) where A stands for the Test treatment CHF1535 100/6 μg NEXThaler®, B for CHF1535 100/6 μg pMDI and C for placebo. 60 of the randomised subjects completed the study.

    Pre-assignment
    Screening details
    		 In total, 181 subjects diagnosed with asthma were screened of whom 116 (64.1%) failed screening.

    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, Carer
    Blinding implementation details
    The randomisation list was provided to the labelling facility but was not available to the subjects, investigators, monitors or employees of the centre involved in the management of the study before unblinding of the data, unless in case of emergency. The Sponsor’s clinical team was also blinded during the study as they did not have direct access to the randomisation list.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sequence A-B-C
    Arm description
    		 A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo; B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo; C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo.
    Arm type
    		 experimental - active comparator - placebo

    Investigational medicinal product name
    CHF1535 NEXThaler
    Investigational medicinal product code
    Other name
    Beclometasone dipropionate + formoterol fumarate
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg NEXThaler®; The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF1535 pMDI
    Investigational medicinal product code
    Other name
    Beclometasone dipropionate + formoterol fumarate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg pMDI; The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF 1535 NEXThaler Placebo
    Investigational medicinal product code
    Other name
    placebo
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo. The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF1535 pMDI Placebo
    Investigational medicinal product code
    Other name
    placebo
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg pMDI matched placebo. The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Arm title
    		 Sequence A-C-B
    Arm description
    		 A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo; C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo. B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo;
    Arm type
    		 experimental - placebo - active comparator

    Investigational medicinal product name
    CHF1535 NEXThaler
    Investigational medicinal product code
    Other name
    Beclometasone dipropionate + formoterol fumarate
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg NEXThaler; The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF1535 pMDI
    Investigational medicinal product code
    Other name
    Beclometasone dipropionate + formoterol fumarate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg pMDI; The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF 1535 NEXThaler Placebo
    Investigational medicinal product code
    Other name
    placebo
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo. The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF1535 pMDI Placebo
    Investigational medicinal product code
    Other name
    placebo
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg pMDI matched placebo. The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Arm title
    		 Sequence B-A-C
    Arm description
    		 B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo; A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo; C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo.
    Arm type
    		 active comparator - experimental - placebo

    Investigational medicinal product name
    CHF1535 NEXThaler
    Investigational medicinal product code
    Other name
    Beclometasone dipropionate + formoterol fumarate
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg NEXThaler®. The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF1535 pMDI
    Investigational medicinal product code
    Other name
    Beclometasone dipropionate + formoterol fumarate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg pMDI; The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF 1535 NEXThaler Placebo
    Investigational medicinal product code
    Other name
    placebo
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo. The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF1535 pMDI Placebo
    Investigational medicinal product code
    Other name
    placebo
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg pMDI matched placebo. The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Arm title
    		 Sequence B-C-A
    Arm description
    		 B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo; C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo. A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo;
    Arm type
    		 Active comparator - placebo - experimental

    Investigational medicinal product name
    CHF1535 NEXThaler
    Investigational medicinal product code
    Other name
    Beclometasone dipropionate + formoterol fumarate
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg NEXThaler®; The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF1535 pMDI
    Investigational medicinal product code
    Other name
    Beclometasone dipropionate + formoterol fumarate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg pMDI; The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF 1535 NEXThaler Placebo
    Investigational medicinal product code
    Other name
    placebo
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo. The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF1535 pMDI Placebo
    Investigational medicinal product code
    Other name
    placebo
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg pMDI matched placebo. The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Arm title
    		 Sequence C-A-B
    Arm description
    		 C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo. A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo; B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo;
    Arm type
    		 placebo - experimental - active comparator

    Investigational medicinal product name
    CHF1535 NEXThaler
    Investigational medicinal product code
    Other name
    Beclometasone dipropionate + formoterol fumarate
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg NEXThaler®; The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF1535 pMDI
    Investigational medicinal product code
    Other name
    Beclometasone dipropionate + formoterol fumarate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg pMDI; The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF 1535 NEXThaler Placebo
    Investigational medicinal product code
    Other name
    placebo
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo. The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF1535 pMDI Placebo
    Investigational medicinal product code
    Other name
    placebo
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg pMDI matched placebo. The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Arm title
    		 Sequence C-B-A
    Arm description
    		 C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo. B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo; A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo;
    Arm type
    		 placebo - active comparator - experimental

    Investigational medicinal product name
    CHF1535 NEXThaler
    Investigational medicinal product code
    Other name
    Beclometasone dipropionate + formoterol fumarate
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg NEXThaler®; The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF1535 pMDI
    Investigational medicinal product code
    Other name
    Beclometasone dipropionate + formoterol fumarate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg pMDI; The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF 1535 NEXThaler Placebo
    Investigational medicinal product code
    Other name
    placebo
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo. The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Investigational medicinal product name
    CHF1535 pMDI Placebo
    Investigational medicinal product code
    Other name
    placebo
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    One inhalation of CHF1535 100/6 μg pMDI matched placebo. The subjects took the study drug in an upright position and were instructed to hold their breath for 5 to 10 seconds or for as long as was comfortable. Each inhalation was separated by at least 30 seconds.

    Number of subjects in period 1
    		Sequence A-B-C Sequence A-C-B Sequence B-A-C Sequence B-C-A Sequence C-A-B Sequence C-B-A
    Started
    11
    9
    12
    9
    12
    12
    Completed
    9
    8
    12
    9
    12
    10
    Not completed
    2
    1
    0
    0
    0
    2
         Due to an AE of lower respiratory tract infection
    -
    1
    -
    -
    -
    -
         Subject had a drop in FEV1 >45% at Visit 3
    -
    -
    -
    -
    -
    1
         Subject did not drop to 30% FEV1 at Visit 2
    -
    -
    -
    -
    -
    1
         Lost to follow-up
    1
    -
    -
    -
    -
    -
         Subject did not reach 65% FEV1 at Visit 2
    1
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence A-B-C
    Reporting group description
    		 A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo; B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo; C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo.

    Reporting group title
    Sequence A-C-B
    Reporting group description
    		 A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo; C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo. B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo;

    Reporting group title
    Sequence B-A-C
    Reporting group description
    		 B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo; A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo; C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo.

    Reporting group title
    Sequence B-C-A
    Reporting group description
    		 B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo; C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo. A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo;

    Reporting group title
    Sequence C-A-B
    Reporting group description
    		 C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo. A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo; B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo;

    Reporting group title
    Sequence C-B-A
    Reporting group description
    		 C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo. B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo; A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo;

    Reporting group values
    		 Sequence A-B-C Sequence A-C-B Sequence B-A-C Sequence B-C-A Sequence C-A-B Sequence C-B-A Total
    Number of subjects
    		 11 9 12 9 12 12 65
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 11 9 12 9 12 12 65
        From 65-84 years
    		 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.5 ± 11.3 42.6 ± 10.8 44.2 ± 10.1 37.6 ± 10.5 45.9 ± 8.1 41.8 ± 11.8 -
    Gender categorical
    Units: Subjects
        Female
    		 2 4 3 7 6 3 25
        Male
    		 9 5 9 2 6 9 40

    End points

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    End points reporting groups
    Reporting group title
    Sequence A-B-C
    Reporting group description
    		 A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo; B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo; C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo.

    Reporting group title
    Sequence A-C-B
    Reporting group description
    		 A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo; C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo. B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo;

    Reporting group title
    Sequence B-A-C
    Reporting group description
    		 B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo; A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo; C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo.

    Reporting group title
    Sequence B-C-A
    Reporting group description
    		 B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo; C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo. A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo;

    Reporting group title
    Sequence C-A-B
    Reporting group description
    		 C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo. A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo; B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo;

    Reporting group title
    Sequence C-B-A
    Reporting group description
    		 C - Placebo: One inhalation of CHF1535 100/6 μg NEXThaler® matched placebo + one inhalation of CHF1535 100/6 μg pMDI matched placebo. B -Reference treatment (CHF1535 100/6 μg pMDI): One inhalation of CHF1535 100/6 μg pMDI + one inhalation of CHF1535 100/6 μg NEXThaler® matched placebo; A - test treatment (CHF1535 100/6 μg NEXThaler®): One inhalation of CHF1535 100/6 μg NEXThaler® + one inhalation of CHF1535 100/6 μg pMDI matched placebo;

    Subject analysis set title
    CHF1535 NEXThaler (Treatment A) - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention-to-treat population (ITT): all randomised subjects who received at least one dose of the study treatment and with at least one available evaluation of efficacy after randomisation;

    Subject analysis set title
    CHF1535pMDI (Treatment B) - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention-to-treat population (ITT): all randomised subjects who received at least one dose of the study treatment and with at least one available evaluation of efficacy after randomisation;

    Subject analysis set title
    Placebo (Treatment C) - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention-to-treat population (ITT): all randomised subjects who received at least one dose of the study treatment and with at least one available evaluation of efficacy after randomisation;

    Subject analysis set title
    CHF1535 NEXThaler (Treatment A) - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-protocol population (PP): all subjects from the ITT population without any major protocol violations (i.e. wrong inclusions, poor compliance, non-permitted medications).

    Subject analysis set title
    CHF1535pMDI (Treatment B) - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-protocol population (PP): all subjects from the ITT population without any major protocol violations (i.e. wrong inclusions, poor compliance, non-permitted medications).

    Subject analysis set title
    Placebo (Treatment C) - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-protocol population (PP): all subjects from the ITT population without any major protocol violations (i.e. wrong inclusions, poor compliance, non-permitted medications).

    Primary: Change in FEV1 from post diluent to 5 minutes after study drug intake

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    End point title
    		 Change in FEV1 from post diluent to 5 minutes after study drug intake
    End point description
    For eligible subjects at treatment period: FEV1 before and during methacholine challenge as part of the methacholine challenge test procedure (number of times could vary based on the subject’s individual response to methacholine).
    End point type
    Primary
    End point timeframe
    At Visits 1, 2 and 3
    End point values
    		 CHF1535 NEXThaler (Treatment A) - ITT CHF1535pMDI (Treatment B) - ITT Placebo (Treatment C) - ITT CHF1535 NEXThaler (Treatment A) - PP CHF1535pMDI (Treatment B) - PP Placebo (Treatment C) - PP
    Number of subjects analysed
    63
    62
    63
    60
    57
    60
    Units: Liters
        arithmetic mean (standard deviation)
    -0.527 ± 0.238
    -0.497 ± 0.257
    -0.730 ± 0.246
    -0.527 ± 0.240
    -0.502 ± 0.262
    -0.723 ± 0.249
    Statistical analysis title
    		 CHF1535 NEXThaler vs CHF1535 pMDI
    Statistical analysis description
    The value N=125, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    CHF1535 NEXThaler (Treatment A) - ITT v CHF1535pMDI (Treatment B) - ITT
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.939 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.065
    Notes
    [1] - The pre-defined non-inferiority margin for testing non-inferiority hypothesis was NIm= -0.120 L.
    [2] - From ANCOVA Model including treatment, period and patient as fixed effects and post-diluent FEV1 and FEV1 at the end of methacholine challenge test as covariates.
    Statistical analysis title
    		 CHF1535 NEXThaler vs Placebo
    Statistical analysis description
    The value N=126, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    CHF1535 NEXThaler (Treatment A) - ITT v Placebo (Treatment C) - ITT
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.224
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.162
         upper limit
    		 0.286
    Notes
    [3] - Conventional p-value to claim superiority of one arm vs. the other: p < 0.05.
    [4] - From ANCOVA Model including treatment, period and patient as fixed effects and post-diluent FEV1 and FEV1 at the end of methacholine challenge test as covariates.
    Statistical analysis title
    		 CHF1535 pMDI vs Placebo
    Statistical analysis description
    The value N=125, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    CHF1535pMDI (Treatment B) - ITT v Placebo (Treatment C) - ITT
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.001 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.222
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.283
    Notes
    [5] - Conventional p-value to claim superiority of one arm vs. the other: p < 0.05.
    [6] - From ANCOVA Model including treatment, period and patient as fixed effects and post-diluent FEV1 and FEV1 at the end of methacholine challenge test as covariates.
    Statistical analysis title
    		 CHF1535 NEXThaler vs CHF1535 pMDI
    Statistical analysis description
    The value N=117, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    CHF1535 NEXThaler (Treatment A) - PP v CHF1535pMDI (Treatment B) - PP
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    P-value
    		 = 0.766 [8]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.056
         upper limit
    		 0.075
    Notes
    [7] - The pre-defined non-inferiority margin for testing non-inferiority hypothesis was NIm= -0.120 L
    [8] - From ANCOVA Model including treatment, period and patient as fixed effects and post-diluent FEV1 and FEV1 at the end of methacholine challenge test as covariates.
    Statistical analysis title
    		 CHF1535 NEXThaler vs placebo
    Statistical analysis description
    The value N=120, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    CHF1535 NEXThaler (Treatment A) - PP v Placebo (Treatment C) - PP
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.001 [10]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.224
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.159
         upper limit
    		 0.288
    Notes
    [9] - Conventional p-value to claim superiority of one arm vs. the other: p < 0.05.
    [10] - From ANCOVA Model including treatment, period and patient as fixed effects and post-diluent FEV1 and FEV1 at the end of methacholine challenge test as covariates.
    Statistical analysis title
    		 CHF1535 pMDI vs placebo
    Statistical analysis description
    The value N=117, shown below, is generated automatically and is due to innate error of the EudraCT database system.
    Comparison groups
    CHF1535pMDI (Treatment B) - PP v Placebo (Treatment C) - PP
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.001 [12]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.214
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.149
         upper limit
    		 0.278
    Notes
    [11] - Conventional p-value to claim superiority of one arm vs. the other: p < 0.05.
    [12] - From ANCOVA Model including treatment, period and patient as fixed effects and post-diluent FEV1 and FEV1 at the end of methacholine challenge test as covariates.

    Secondary: Change in FEV1 from post-diluent at 1, 10, 20 and 30 minutes after drug intake

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    End point title
    		 Change in FEV1 from post-diluent at 1, 10, 20 and 30 minutes after drug intake
    End point description
    For eligible subjects at treatment period: FEV1 before and during methacholine challenge as part of the methacholine challenge test procedure (number of times could vary based on the subject’s individual response to methacholine). After study drug intake at the following time points (FEV1 only): 1, 5, 10, 20 and 30 minutes post-dose. Data from minute 1-post-dose measurements are reported here. A table with results including all the timepoints (1, 10, 20, and 30 minutes) is attached.
    End point type
    Secondary
    End point timeframe
    At visits 1, 2 and 3.
    End point values
    		 CHF1535 NEXThaler (Treatment A) - ITT CHF1535pMDI (Treatment B) - ITT Placebo (Treatment C) - ITT
    Number of subjects analysed
    63
    62
    63
    Units: Liters
        arithmetic mean (confidence interval 95%)
    -0.645 (-0.684 to -0.605)
    -0.647 (-0.687 to -0.608)
    -0.842 (-0.881 to -0.802)
    Attachments
    		 Untitled (Filename: Tabella 9_ANCOVA Model on the Change in FEV1.pdf)
    Statistical analysis title
    		 CHF135 NEXThaler vs CHF1535 pMDI
    Statistical analysis description
    Change in FEV1 (L) from post-diluent to 1, 10, 20 and 30 minutes after drug intake was analysed separately for each post-dose time point using the same statistical model considered for the primary efficacy variable.
    Comparison groups
    CHF1535 NEXThaler (Treatment A) - ITT v CHF1535pMDI (Treatment B) - ITT
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.919 [14]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0053
         upper limit
    		 0.059
    Notes
    [13] - Inequality.
    [14] - From ANCOVA model including treatment, period and patient as fixed effects and post-diluent FEV1 and FEV1 at the end of methacholine challenge test as covariates.
    Statistical analysis title
    		 CHF135 NEXThaler vs Placebo
    Statistical analysis description
    Change in FEV1 (L) from post-diluent to 1, 10, 20 and 30 minutes after drug intake was analysed separately for each post-dose time point using the same statistical model considered for the primary efficacy variable.
    Comparison groups
    CHF1535 NEXThaler (Treatment A) - ITT v Placebo (Treatment C) - ITT
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 < 0.001 [16]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.197
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.141
         upper limit
    		 0.253
    Notes
    [15] - Inequality.
    [16] - From ANCOVA model including treatment, period and patient as fixed effects and post-diluent FEV1 and FEV1 at the end of methacholine challenge test as covariates.
    Statistical analysis title
    		 CHF135 pMDI vs Placebo
    Statistical analysis description
    Change in FEV1 (L) from post-diluent to 1, 10, 20 and 30 minutes after drug intake was analysed separately for each post-dose time point using the same statistical model considered for the primary efficacy variable.
    Comparison groups
    CHF1535pMDI (Treatment B) - ITT v Placebo (Treatment C) - ITT
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 < 0.001 [18]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.194
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.139
         upper limit
    		 0.25
    Notes
    [17] - Inequality.
    [18] - From ANCOVA model including treatment, period and patient as fixed effects and post-diluent FEV1 and FEV1 at the end of methacholine challenge test as covariates.

    Secondary: Time to recovery in FEV1

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    End point title
    		 Time to recovery in FEV1
    End point description
    Recovery and “time to” are defined as follows: - Recovery: return to 85% of the post-diluent value. Recovery is reached for values > 85%; - “Time to”: datetime at which % recovery in FEV1 vs. post-diluent > 85% - datetime of last inhalation, in min. Reported data come from confirmatory analysis, which was performed on all subjects, those who recovered with their time to recovery at any time and those who did not recover with time to recovery extrapolated.
    End point type
    Secondary
    End point timeframe
    The FEV1 was collected at the post-diluent timepoint and at 1, 5, 10, 20 and 30 minutes after drug intake.
    End point values
    		 CHF1535 NEXThaler (Treatment A) - ITT CHF1535pMDI (Treatment B) - ITT Placebo (Treatment C) - ITT
    Number of subjects analysed
    63
    62
    63
    Units: min
        median (inter-quartile range (Q1-Q3))
    8.01 (4.46 to 16.69)
    7.52 (3.50 to 17.07)
    28.17 (13.28 to 38.43)
    Statistical analysis title
    		 CHF1535 NEXThaler vs CHF1535 pMDI
    Statistical analysis description
    A hazard ratio < 1 indicates that patients treated with CHF1535 pMDI or Placebo are at lower probability of recovering in FEV1 than CHF1535 NEXThaler treated patients. To be applied for any Cox model.
    Comparison groups
    CHF1535 NEXThaler (Treatment A) - ITT v CHF1535pMDI (Treatment B) - ITT
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.75 [20]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.673
         upper limit
    		 1.733
    Notes
    [19] - Inequality.
    [20] - From a Cox proportional hazard model stratified by subject and with treatment as factor.
    Statistical analysis title
    		 CHF1535 NEXThaler vs Placebo
    Statistical analysis description
    A hazard ratio < 1 indicates that patients treated with CHF1535 pMDI or Placebo are at lower probability of recovering in FEV1 than CHF1535 NEXThaler treated patients. To be applied for any Cox model.
    Comparison groups
    CHF1535 NEXThaler (Treatment A) - ITT v Placebo (Treatment C) - ITT
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 < 0.001 [22]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.229
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 0.403
    Notes
    [21] - Inequality.
    [22] - From a Cox proportional hazard model stratified by subject and with treatment as factor.

    Secondary: FEV1 AUC0-10min normalised by time

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    End point title
    		 FEV1 AUC0-10min normalised by time
    End point description
    The area under the FEV1 vs. time curve observed from end of challenge to 10 min after methacholine challenge. The area was computed using the linear trapezoidal rule. Values are reported as adjusted means.
    End point type
    Secondary
    End point timeframe
    Timepoints considered for evaluation of AUC were: FEV1 values at 1, 5, 10 min after drug intake.
    End point values
    		 CHF1535 NEXThaler (Treatment A) - ITT CHF1535pMDI (Treatment B) - ITT Placebo (Treatment C) - ITT
    Number of subjects analysed
    63
    61
    63
    Units: liter
        arithmetic mean (standard error)
    2.26 ± 0.02
    2.25 ± 0.02
    2.07 ± 0.02
    Statistical analysis title
    		 CHF1535 NEXThaler vs CHF1535 pMDI
    Comparison groups
    CHF1535 NEXThaler (Treatment A) - ITT v CHF1535pMDI (Treatment B) - ITT
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.656 [24]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.06
    Notes
    [23] - Inequality.
    [24] - From an ANCOVA model including treatment, period and subject as fixed effects, FEV1 post-diluent and FEV1 at the end of the methacholine challenge test as covariates.
    Statistical analysis title
    		 CHF1535 NEXThaler vs Placebo
    Comparison groups
    CHF1535 NEXThaler (Treatment A) - ITT v Placebo (Treatment C) - ITT
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 < 0.001 [26]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.23
    Notes
    [25] - Inequality.
    [26] - From an ANCOVA model including treatment, period and subject as fixed effects, FEV1 post-diluent and FEV1 at the end of the methacholine challenge test as covariates.
    Statistical analysis title
    		 CHF1535 pMDI vs Placebo
    Comparison groups
    CHF1535pMDI (Treatment B) - ITT v Placebo (Treatment C) - ITT
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 < 0.001 [28]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 0.22
    Notes
    [27] - Inequality.
    [28] - From an ANCOVA model including treatment, period and subject as fixed effects, FEV1 post-diluent and FEV1 at the end of the methacholine challenge test as covariates.

    Secondary: Change in Borg scale from the end of methacholine challenge test to 1, 3, 5, 10, 20 and 30 minutes after study drug intake

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    End point title
    		 Change in Borg scale from the end of methacholine challenge test to 1, 3, 5, 10, 20 and 30 minutes after study drug intake
    End point description
    Assessments were performed at the following time points: post-diluent, post-challenge and at 1, 3, 5, 10, 20 and 30 minutes post-dose. Data from minute 1-post-dose measurements are reported here. A table with the results including all the timepoints (1, 3, 5, 10, 20, and 30 minutes) is attached.
    End point type
    Secondary
    End point timeframe
    At 1, 3, 5, 10, 20 and 30 minutes post-dose.
    End point values
    		 CHF1535 NEXThaler (Treatment A) - ITT CHF1535pMDI (Treatment B) - ITT Placebo (Treatment C) - ITT
    Number of subjects analysed
    63
    62
    63
    Units: score
        arithmetic mean (confidence interval 95%)
    -0.788 (-1.015 to -0.561)
    -1.146 (-1.376 to -0.915)
    -0.597 (-0.824 to -0.369)
    Attachments
    		 Untitled (Filename: Table 10_ANCOVA Model on the Change in Borg Scale.pdf)
    Statistical analysis title
    		 CHF1535 NEXThaler vs CHF1535 pMDI
    Comparison groups
    CHF1535 NEXThaler (Treatment A) - ITT v CHF1535pMDI (Treatment B) - ITT
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    P-value
    		 = 0.031 [30]
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.358
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.034
         upper limit
    		 0.681
    Notes
    [29] - Inequality.
    [30] - From an ANCOVA model with treatment, period and subject included as fixed effects, Borg scale post-diluent and Borg Scale at the end of methacholine challenge test as covariates.
    Statistical analysis title
    		 CHF1535 NEXThaler vs placebo
    Comparison groups
    CHF1535 NEXThaler (Treatment A) - ITT v Placebo (Treatment C) - ITT
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    P-value
    		 = 0.242 [32]
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    -0.191
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.513
         upper limit
    		 0.131
    Notes
    [31] - Inequality.
    [32] - From an ANCOVA model with treatment, period and subject included as fixed effects, Borg scale post-diluent and Borg Scale at the end of methacholine challenge test as covariates.
    Statistical analysis title
    		 CHF1535 pMDI vs placebo
    Comparison groups
    CHF1535pMDI (Treatment B) - ITT v Placebo (Treatment C) - ITT
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    P-value
    		 < 0.001 [34]
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    -0.549
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.87
         upper limit
    		 -0.227
    Notes
    [33] - Inequality.
    [34] - From an ANCOVA model with treatment, period and subject included as fixed effects, Borg scale post-diluent and Borg Scale at the end of methacholine challenge test as covariates.

    Secondary: Time to recovery in Borg scale

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    End point title
    		 Time to recovery in Borg scale
    End point description
    Time (min) needed to reach 50% decrease from the post-methacholine value. Recovery is calculated as % Change in Borg scale from the post-methacholine value.
    End point type
    Secondary
    End point timeframe
    The Borg Scale was collected at the end of methacholine challenge test (before drug intake) and at 1, 3, 5, 10, 20 and 30 min after drug intake.
    End point values
    		 CHF1535 NEXThaler (Treatment A) - ITT CHF1535pMDI (Treatment B) - ITT Placebo (Treatment C) - ITT
    Number of subjects analysed
    63
    62
    63
    Units: minutes
        median (inter-quartile range (Q1-Q3))
    4.25 (2.50 to 10.0)
    4.00 (1.00 to 8.75)
    10.0 (3.00 to 20.0)
    Statistical analysis title
    		 CHF1535 NEXThaler vs CHF1535 pMDI
    Comparison groups
    CHF1535 NEXThaler (Treatment A) - ITT v CHF1535pMDI (Treatment B) - ITT
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 = 0.609 [36]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.128
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.712
         upper limit
    		 1.787
    Notes
    [35] - Inequality.
    [36] - From a Cox proportional hazard model stratified by subject and with treatment as factor.
    Statistical analysis title
    		 CHF1535 NEXThaler vs placebo
    Comparison groups
    CHF1535 NEXThaler (Treatment A) - ITT v Placebo (Treatment C) - ITT
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 = 0.042 [38]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.607
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.374
         upper limit
    		 0.983
    Notes
    [37] - Inequality.
    [38] - From a Cox proportional hazard model stratified by subject and with treatment as factor.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event assessment was made at each Visit, from Visit 0 (screening visit), to Visit 3, through Visits 1 and 2, and subsequent follow-up phone call (5 to 14 days after the last administration).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    CHF1535 NEXthaler (Treatment A) - safety
    Reporting group description
    		 -

    Reporting group title
    CHF1535 pMDI (Treatment B) - safety
    Reporting group description
    		 -

    Reporting group title
    Placebo (Treatment C) - safety
    Reporting group description
    		 -

    Serious adverse events
    		 CHF1535 NEXthaler (Treatment A) - safety CHF1535 pMDI (Treatment B) - safety Placebo (Treatment C) - safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1.6%
    Non-serious adverse events
    		 CHF1535 NEXthaler (Treatment A) - safety CHF1535 pMDI (Treatment B) - safety Placebo (Treatment C) - safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 63 (6.35%)
    4 / 62 (6.45%)
    5 / 63 (7.94%)
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences all number
    1
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Mar 2017
    The aim of this substantial amendment is to modify the required wash-out period prior to screening of the following non-permitted concomitant medications: - Long-acting anticholinergics from ‘8 weeks prior to screening’ to ‘4 weeks prior to screening’ - Leukotriene modifiers from ‘8 weeks prior to screening’ to ‘4 weeks prior to screening’

    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.
    There are no limitations or caveats to this summary of results.
    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
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