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    Clinical Trial Results:
    A randomized, multi-centre, double-blind, double dummy placebo controlled single-dose cross-over study to demonstrate that 12 and 24 µg of formoterol delivered by Concept1 has a bronchodilator efficacy which is equivalent to the same dose of formoterol delivered by Aerolizer® inadult and adolescent patients with persistent asthma Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2006-003225-87
    Trial protocol
    		 DE  
    Global end of trial date
    21 May 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jul 2018
    First version publication date
    06 Jul 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CFOR258D2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00443482
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Novartis Pharmaceuticals AG, Novartis Pharmaceuticals AG, +41 613241111,
    Scientific contact
    Novartis Pharmaceuticals AG, Novartis Pharmaceuticals AG, +41 613241111,
    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
    21 May 2007
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 May 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to compare the efficacy of two doses of formoterol, 12 microgram (mcg) and 24 mcg, delivered by Concept1 inhaler device with corresponding doses of formoterol delivered by Aerolizer inhaler device, to demonstrate that two doses of formoterol delivered by the Concept1 device are equivalent to the same doses delivered by the Aerolizer for bronchodilator efficacy in subjects with persistent asthma.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed. Subjects who experienced an asthma exacerbation following randomisation were withdrawn from the study. The investigator initiated treatment for such asthma exacerbations as he/she best deemed appropriate. Subjects were provided with an identical formulation of inhaled short-acting β2-agonist (salbutamol) as rescue medication. Subjects were instructed not to exceed 8 puffs of rescue medication per 24 hour period. If rescue medication was taken within 6 hours prior to visit, then visit was to be rescheduled to next possible day.
    Background therapy
    		 Subjects received regular anti-inflammatory asthma therapy at a fixed dose regimen, for one month prior to start of pre-randomisation/screening and was continued unchanged throughout the study, unless the subject experienced an asthma exacerbation requiring use of additional anti-inflammatory therapy in opinion of investigator.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Feb 2007
    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
    Germany: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    42
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted in 4 centres in Germany.

    Pre-assignment
    Screening details
    		 A total of 53 subjects were screened, out of which 50 subjects were randomised into the study.

    Period 1
    Period 1 title
    Treatment Period I
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Assessor
    Blinding implementation details
    A double-dummy design was used because the identity of the study drugs could not be disguised due to different inhalation devices (Concept1 and Aerolizer) that can be readily distinguished. Unblinding was allowed only in case of subjects emergencies and at the conclusion of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Formoterol fumarate 12 mcg via Concept1 device
    Arm description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Formoterol fumarate (Concept1)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 12 mcg inhaled orally via Concept1 device.

    Arm title
    		 Formoterol fumarate 24 mcg via Concept1 device
    Arm description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Concept1 inhaler device.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Formoterol fumarate (Concept1)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 24 mcg inhaled orally via Concept1 device.

    Arm title
    		 Formoterol fumarate 12 mcg via Aerolizer device
    Arm description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Aerolizer inhaler device.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Formoterol fumarate (Aerolizer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 12 mcg inhaled orally via Aerolizer device.

    Arm title
    		 Formoterol fumarate 24 mcg via Aerolizer device
    Arm description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Aerolizer inhaler device.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Formoterol fumarate (Aerolizer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 24 mcg inhaled orally via Aerolizer device.

    Arm title
    		 Placebo
    Arm description
    		 Subjects inhaled placebo matching to formoterol capsule orally via Concept1 and Aerolizer device.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo capsule inhaled orally via Concept1 and Aerolizer device.

    Number of subjects in period 1
    		Formoterol fumarate 12 mcg via Concept1 device Formoterol fumarate 24 mcg via Concept1 device Formoterol fumarate 12 mcg via Aerolizer device Formoterol fumarate 24 mcg via Aerolizer device Placebo
    Started
    10
    10
    10
    10
    10
    Completed
    10
    10
    10
    10
    10
    Period 2
    Period 2 title
    Treatment Period II
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Assessor
    Blinding implementation details
    A double-dummy design was used because the identity of the study drugs could not be disguised due to different inhalation devices (Concept1 and Aerolizer) that can be readily distinguished. Unblinding was allowed only in case of subjects emergencies and at the conclusion of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Formoterol fumarate 12 mcg via Concept1 device
    Arm description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Formoterol fumarate (Concept1)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 12 mcg inhaled orally via Concept1 device.

    Arm title
    		 Formoterol fumarate 24 mcg via Concept1 device
    Arm description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Formoterol fumarate (Concept1)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 24 mcg inhaled orally via Concept1 device.

    Arm title
    		 Formoterol fumarate 12 mcg via Aerolizer device
    Arm description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Formoterol fumarate (Aerolizer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 12 mcg inhaled orally via Aerolizer device.

    Arm title
    		 Formoterol fumarate 24 mcg via Aerolizer device
    Arm description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Formoterol fumarate (Aerolizer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 24 mcg inhaled orally via Aerolizer device.

    Arm title
    		 Placebo
    Arm description
    		 Subjects inhaled placebo matching to formoterol capsule orally via Concept1 and Aerolizer device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo capsule inhaled orally via Concept1 and Aerolizer device.

    Number of subjects in period 2
    		Formoterol fumarate 12 mcg via Concept1 device Formoterol fumarate 24 mcg via Concept1 device Formoterol fumarate 12 mcg via Aerolizer device Formoterol fumarate 24 mcg via Aerolizer device Placebo
    Started
    10
    10
    10
    10
    10
    Completed
    10
    10
    10
    10
    10
    Period 3
    Period 3 title
    Treatment Period III
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Data analyst, Assessor, Subject
    Blinding implementation details
    A double-dummy design was used because the identity of the study drugs could not be disguised due to different inhalation devices (Concept1 and Aerolizer) that can be readily distinguished. Unblinding was allowed only in case of subjects emergencies and at the conclusion of the study. The treatment period was separated from the next by a washout period of 3 days.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Formoterol fumarate 12 mcg via Concept1 device
    Arm description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Formoterol fumarate (Concept1)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 12 mcg inhaled orally via Concept1 device.

    Arm title
    		 Formoterol fumarate 24 mcg via Concept1 device
    Arm description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Formoterol fumarate (Concept1)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 24 mcg inhaled orally via Concept1 device.

    Arm title
    		 Formoterol fumarate 12 mcg via Aerolizer device
    Arm description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Formoterol fumarate (Aerolizer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 12 mcg inhaled orally via Aerolizer device.

    Arm title
    		 Formoterol fumarate 24 mcg via Aerolizer device
    Arm description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Formoterol fumarate (Aerolizer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 24 mcg inhaled orally via Aerolizer device.

    Arm title
    		 Placebo
    Arm description
    		 Subjects inhaled placebo matching to formoterol capsule orally via Concept1 and Aerolizer device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo capsule inhaled orally via Concept1 and Aerolizer device.

    Number of subjects in period 3
    		Formoterol fumarate 12 mcg via Concept1 device Formoterol fumarate 24 mcg via Concept1 device Formoterol fumarate 12 mcg via Aerolizer device Formoterol fumarate 24 mcg via Aerolizer device Placebo
    Started
    10
    10
    10
    10
    10
    Completed
    10
    10
    10
    9
    10
    Not completed
    0
    0
    0
    1
    0
         Lost to follow-up
    -
    -
    -
    1
    -
    Period 4
    Period 4 title
    Treatment Period IV
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Data analyst, Assessor, Subject
    Blinding implementation details
    A double-dummy design was used because the identity of the study drugs could not be disguised due to different inhalation devices (Concept1 and Aerolizer) that can be readily distinguished. Unblinding was allowed only in case of subjects emergencies and at the conclusion of the study. The treatment period was separated from the next by a washout period of 3 days.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Formoterol fumarate 12 mcg via Concept1 device
    Arm description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Formoterol fumarate (Concept1)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 12 mcg inhaled orally via Concept1 device.

    Arm title
    		 Formoterol fumarate 24 mcg via Concept1 device
    Arm description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Formoterol fumarate (Concept1)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 24 mcg inhaled orally via Concept1 device.

    Arm title
    		 Formoterol fumarate 12 mcg via Aerolizer device
    Arm description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Formoterol fumarate (Aerolizer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 12 mcg inhaled orally via Aerolizer device.

    Arm title
    		 Formoterol fumarate 24 mcg via Aerolizer device
    Arm description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Formoterol fumarate (Aerolizer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 24 mcg inhaled orally via Aerolizer device.

    Arm title
    		 Placebo
    Arm description
    		 Subjects inhaled placebo matching to formoterol capsule orally via Concept1 and Aerolizer device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo capsule inhaled orally via Concept1 and Aerolizer device.

    Number of subjects in period 4 [1]
    		Formoterol fumarate 12 mcg via Concept1 device Formoterol fumarate 24 mcg via Concept1 device Formoterol fumarate 12 mcg via Aerolizer device Formoterol fumarate 24 mcg via Aerolizer device Placebo
    Started
    10
    10
    10
    9
    10
    Completed
    9
    10
    10
    10
    10
    Not completed
    1
    0
    0
    0
    0
         Lost to follow-up
    1
    -
    -
    -
    -
    Joined
    0
    0
    0
    1
    0
         Transferred in from other group/arm
    -
    -
    -
    1
    -
    Notes
    [1] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: Due to the cross-over design of the study, subjects were transferred from one arm of the period to another arm of the next period in a predefined treatment sequence after each period.
    Period 5
    Period 5 title
    Treatment Period V
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Assessor
    Blinding implementation details
    A double-dummy design was used because the identity of the study drugs could not be disguised due to different inhalation devices (Concept1 and Aerolizer) that can be readily distinguished. Unblinding was allowed only in case of subjects emergencies and at the conclusion of the study. The treatment period was separated from the next by a washout period of 3 days.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Formoterol fumarate 12 mcg via Concept1 device
    Arm description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Formoterol fumarate (Concept1)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 12 mcg inhaled orally via Concept1 device.

    Arm title
    		 Formoterol fumarate 24 mcg via Concept1 device
    Arm description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Formoterol fumarate (Concept1)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 24 mcg inhaled orally via Concept1 device.

    Arm title
    		 Formoterol fumarate 12 mcg via Aerolizer device
    Arm description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Formoterol fumarate (Aerolizer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 12 mcg inhaled orally via Aerolizer device.

    Arm title
    		 Formoterol fumarate 24 mcg via Aerolizer device
    Arm description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Formoterol fumarate (Aerolizer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol capsules 24 mcg inhaled orally via Aerolizer device.

    Arm title
    		 Placebo
    Arm description
    		 Subjects inhaled placebo matching to formoterol capsule orally via Concept1 and Aerolizer device. A wash-out period of 3 days was maintained between two treatment periods.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo capsule inhaled orally via Concept1 and Aerolizer device.

    Number of subjects in period 5 [2]
    		Formoterol fumarate 12 mcg via Concept1 device Formoterol fumarate 24 mcg via Concept1 device Formoterol fumarate 12 mcg via Aerolizer device Formoterol fumarate 24 mcg via Aerolizer device Placebo
    Started
    9
    10
    10
    10
    10
    Completed
    10
    10
    10
    10
    9
    Not completed
    0
    0
    0
    0
    1
         Lost to follow-up
    -
    -
    -
    -
    1
    Joined
    1
    0
    0
    0
    0
         Transferred in from other group/arm
    1
    -
    -
    -
    -
    Notes
    [2] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: Due to the cross-over design of the study, subjects were transferred from one arm of the period to another arm of the next period in a predefined treatment sequence after each period.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period I
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Period I Total
    Number of subjects
    		 50 50
    Age categorical
    Units: Subjects
        Adolescent (18-64 years)
    		 42 42
        Adults (65-74 years)
    		 8 8
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.1 ( 13.24 ) -
    Gender categorical
    Units: Subjects
        Female
    		 24 24
        Male
    		 26 26

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Formoterol fumarate 12 mcg via Concept1 device
    Reporting group description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device.

    Reporting group title
    Formoterol fumarate 24 mcg via Concept1 device
    Reporting group description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Concept1 inhaler device.

    Reporting group title
    Formoterol fumarate 12 mcg via Aerolizer device
    Reporting group description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Aerolizer inhaler device.

    Reporting group title
    Formoterol fumarate 24 mcg via Aerolizer device
    Reporting group description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Aerolizer inhaler device.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects inhaled placebo matching to formoterol capsule orally via Concept1 and Aerolizer device.
    Reporting group title
    Formoterol fumarate 12 mcg via Concept1 device
    Reporting group description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Formoterol fumarate 24 mcg via Concept1 device
    Reporting group description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Formoterol fumarate 12 mcg via Aerolizer device
    Reporting group description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Formoterol fumarate 24 mcg via Aerolizer device
    Reporting group description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects inhaled placebo matching to formoterol capsule orally via Concept1 and Aerolizer device. A wash-out period of 3 days was maintained between two treatment periods.
    Reporting group title
    Formoterol fumarate 12 mcg via Concept1 device
    Reporting group description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Formoterol fumarate 24 mcg via Concept1 device
    Reporting group description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Formoterol fumarate 12 mcg via Aerolizer device
    Reporting group description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Formoterol fumarate 24 mcg via Aerolizer device
    Reporting group description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects inhaled placebo matching to formoterol capsule orally via Concept1 and Aerolizer device. A wash-out period of 3 days was maintained between two treatment periods.
    Reporting group title
    Formoterol fumarate 12 mcg via Concept1 device
    Reporting group description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Formoterol fumarate 24 mcg via Concept1 device
    Reporting group description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Formoterol fumarate 12 mcg via Aerolizer device
    Reporting group description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Formoterol fumarate 24 mcg via Aerolizer device
    Reporting group description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects inhaled placebo matching to formoterol capsule orally via Concept1 and Aerolizer device. A wash-out period of 3 days was maintained between two treatment periods.
    Reporting group title
    Formoterol fumarate 12 mcg via Concept1 device
    Reporting group description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Formoterol fumarate 24 mcg via Concept1 device
    Reporting group description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Formoterol fumarate 12 mcg via Aerolizer device
    Reporting group description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Formoterol fumarate 24 mcg via Aerolizer device
    Reporting group description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Aerolizer inhaler device. A wash-out period of 3 days was maintained between two treatment periods.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects inhaled placebo matching to formoterol capsule orally via Concept1 and Aerolizer device. A wash-out period of 3 days was maintained between two treatment periods.

    Subject analysis set title
    Formoterol fumarate 12 mcg via Concept1 device
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who received formoterol 12 mcg capsule orally via Concept1 inhaler device in this cross-over study.

    Subject analysis set title
    Formoterol fumarate 24 mcg via Concept1 device
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who received formoterol 24 mcg capsule orally via Concept1 inhaler device in this cross-over study.

    Subject analysis set title
    Formoterol fumarate 12 mcg via Aerolizer device
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who received formoterol 12 mcg capsule orally via Aerolizer inhaler device in this cross-over study.

    Subject analysis set title
    Formoterol fumarate 24 mcg via Aerolizer device
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who received formoterol 24 mcg capsule orally via Aerolizer inhaler device in this cross-over study.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who received placebo matching to formoterol capsule orally via Concept1 and Aerolizer inhaler device in this cross-over study.

    Primary: Area under curve of forced expiratory volume FEV1-AUC(0-12) at 12 hours

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    End point title
    		 Area under curve of forced expiratory volume FEV1-AUC(0-12) at 12 hours [1]
    End point description
    FEV1 was defined as the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured using spirometry tests. The FEV1 standardized area under the curve (AUC0-12) was defined as area under the serum concentration-time curve from time 0 to time of the last time point with measurable concentration (0 to 12 hours). AUC of FEV1 followed by single dose of study medication was standardized with respect to length of time completed in the observation period. The primary analysis was performed in Intent-to-treat (ITT) population, defined as all randomized subjects who received at least one treatment. Due to cross-over design of the study, only subjects who received at least two treatments contributed to the primary analysis.
    End point type
    Primary
    End point timeframe
    12 hours
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis for the primary end point has been provided in the attachment.
    End point values
    		 Formoterol fumarate 12 mcg via Concept1 device Formoterol fumarate 24 mcg via Concept1 device Formoterol fumarate 12 mcg via Aerolizer device Formoterol fumarate 24 mcg via Aerolizer device Placebo
    Number of subjects analysed
    49
    50
    50
    49
    49
    Units: Litre(s)
        least squares mean (standard error)
    2.71 ( 0.019 )
    2.73 ( 0.019 )
    2.67 ( 0.019 )
    2.73 ( 0.019 )
    2.41 ( 0.019 )
    Attachments
    		 FEV1-AUC(0-12) for Formoterol_Statistical analysis
    No statistical analyses for this end point

    Secondary: Area under curve of forced expiratory volume (FEV1-AUC) serial measurement

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    End point title
    		 Area under curve of forced expiratory volume (FEV1-AUC) serial measurement
    End point description
    FEV1 was defined as the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured using spirometry tests. The FEV1-AUC was defined as area under the serum concentration-time curve from time 0 to time of the last time point with measurable concentration. AUC of FEV1 followed by single dose of study medication was standardized with respect to length of time completed in the observation period. The primary analysis was performed in ITT population. Due to cross-over design of the study, only subjects who received at least two treatments contributed to the primary analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 15, 30 minutes, 1, 2, 3, 4, 6, 8, 10, 11 and 12 hours post dosing
    End point values
    		 Formoterol fumarate 12 mcg via Concept1 device Formoterol fumarate 24 mcg via Concept1 device Formoterol fumarate 12 mcg via Aerolizer device Formoterol fumarate 24 mcg via Aerolizer device Placebo
    Number of subjects analysed
    49
    50
    50
    49
    49
    Units: Litre(s)
    arithmetic mean (standard deviation)
        15 min
    2.7 ( 0.753 )
    2.74 ( 0.722 )
    2.63 ( 0.706 )
    2.69 ( 0.759 )
    2.36 ( 0.736 )
        30 min
    2.72 ( 0.778 )
    2.78 ( 0.756 )
    2.66 ( 0.72 )
    2.71 ( 0.774 )
    2.37 ( 0.742 )
        1 hour
    2.76 ( 0.787 )
    2.81 ( 0.76 )
    2.67 ( 0.727 )
    2.76 ( 0.802 )
    2.38 ( 0.751 )
        2 hours
    2.79 ( 0.775 )
    2.82 ( 0.777 )
    2.73 ( 0.748 )
    2.78 ( 0.808 )
    2.42 ( 0.766 )
        3 hours
    2.8 ( 0.802 )
    2.83 ( 0.784 )
    2.71 ( 0.75 )
    2.79 ( 0.799 )
    2.43 ( 0.788 )
        4 hours
    2.78 ( 0.794 )
    2.82 ( 0.787 )
    2.72 ( 0.748 )
    2.77 ( 0.811 )
    2.43 ( 0.783 )
        6 hours
    2.73 ( 0.806 )
    2.76 ( 0.793 )
    2.64 ( 0.776 )
    2.73 ( 0.801 )
    2.42 ( 0.795 )
        8 hours
    2.65 ( 0.829 )
    2.7 ( 0.77 )
    2.6 ( 0.753 )
    2.71 ( 0.798 )
    2.4 ( 0.788 )
        10 hours
    2.62 ( 0.842 )
    2.65 ( 0.819 )
    2.57 ( 0.789 )
    2.64 ( 0.809 )
    2.39 ( 0.781 )
        11 hours
    2.62 ( 0.816 )
    2.64 ( 0.792 )
    2.56 ( 0.79 )
    2.61 ( 0.814 )
    2.37 ( 0.787 )
        12 hours
    2.59 ( 0.846 )
    2.61 ( 0.772 )
    2.55 ( 0.785 )
    2.59 ( 0.825 )
    2.37 ( 0.787 )
    No statistical analyses for this end point

    Secondary: Urinary excretion of formoterol from 0 to 12 hours (Ae0-12)

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    End point title
    		 Urinary excretion of formoterol from 0 to 12 hours (Ae0-12)
    End point description
    Urinary excretion of formoterol from 0 to 12 hours (Ae0-12) was defined as amount of unchanged formoterol excreted in urine within the 0 to 12 h post-dose collection interval. Ae0-12 was calculated from the formoterol concentrations in urine and the urine volumes using non-compartmental method(s) with WinNonlin Pro (version 5.01). Ae0-12 is reported in nanomoles (nmol) of formoterol free base. Formoterol was measured in urine using Liquid Chromatography–Mass Spectrometry (LC-MS)/MS method. The limit of quantification for urine formoterol was 0.0174 nmol/L. The analysis was was performed in the PK population, defined as all completed subjects with quantifiable PK measurements.
    End point type
    Secondary
    End point timeframe
    Pre­dose, 15, 30 minutes, 1, 2, 3, 4, 6, 8, 10, 11 and 12 hours post dosing
    End point values
    		 Formoterol fumarate 12 mcg via Concept1 device Formoterol fumarate 24 mcg via Concept1 device Formoterol fumarate 12 mcg via Aerolizer device Formoterol fumarate 24 mcg via Aerolizer device
    Number of subjects analysed
    45
    46
    41
    46
    Units: nanomole(s)
        arithmetic mean (standard deviation)
    1.22 ( 0.42 )
    2.46 ( 0.805 )
    1.3 ( 0.505 )
    2.25 ( 0.77 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events are monitored from date of First Subject First Visit (FSFV) until Last Subject Last Visit (LSLV). All other adverse events are monitored from First Subject First Treatment until Last Subject Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Formoterol Concept1 12 mcg
    Reporting group description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Concept1 inhaler device.

    Reporting group title
    Formoterol Aerolizer 24 mcg
    Reporting group description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Aerolizer inhaler device.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects inhaled placebo matching to formoterol capsule orally via Concept1 and Aerolizer device.

    Reporting group title
    Formoterol Concept1 24 mcg
    Reporting group description
    		 Subjects inhaled formoterol 24 mcg capsule orally via Concept1 inhaler device.

    Reporting group title
    Formoterol Aerolizer 12 mcg
    Reporting group description
    		 Subjects inhaled formoterol 12 mcg capsule orally via Aerolizer inhaler device.

    Serious adverse events
    		 Formoterol Concept1 12 mcg Formoterol Aerolizer 24 mcg Placebo Formoterol Concept1 24 mcg Formoterol Aerolizer 12 mcg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Formoterol Concept1 12 mcg Formoterol Aerolizer 24 mcg Placebo Formoterol Concept1 24 mcg Formoterol Aerolizer 12 mcg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 49 (4.08%)
    5 / 49 (10.20%)
    2 / 49 (4.08%)
    3 / 50 (6.00%)
    3 / 50 (6.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 49 (2.04%)
    2 / 49 (4.08%)
    2 / 49 (4.08%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    2
    2
    1
    1
    Tremor
         subjects affected / exposed
    1 / 49 (2.04%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
    2 / 50 (4.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    2
    0
    2
    1
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Psychiatric disorders
    Restlessness
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jun 2006
    Adolescent subjects were excluded from the study.
    19 Dec 2006
    PK sampling and analysis was included to the protocol as requested by the Food and Drug Administration (FDA). The exclusion criteria was updated to exclude severe asthmatic subjects as per recommendation from German Ethics Committee.
    24 Jan 2007
    Updated urine collection procedures.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial 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
    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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