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    Clinical Trial Results:
    A phase II randomised, double-blind, placebo-controlled incomplete crossover trial with 4-week treatment periods to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler once daily in the evening in children 6 to 11 years old with moderate persistent asthma.

    Summary
    EudraCT number
    		 2010-022458-18
    Trial protocol
    		 DE   LV   LT   HU  
    Global end of trial date
    25 Sep 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jun 2016
    First version publication date
    17 Apr 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    205.425
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01383499
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim Pharma GmbH & Co. KG
    Sponsor organisation address
    Binger Strasse 173 , Ingelheim am Rhein , Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim Pharma GmbH & Co. KG , +1 800 243 0127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim Pharma GmbH & Co. KG , +1 800 243 0127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000035-PIP02-09
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Oct 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Sep 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Sep 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy and safety of 3 doses of tiotripium solution for inhalation in comparison to placebo delivered by the Respimat® inhaler on top of usual care in children (6 to 11 years old) with moderate persistent asthma. In addition, pharmacokinetic profiling in this age group was evaluated.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required. Rescue medication, open-label salbutamol 100 micrograms per puff was administered as needed.
    Background therapy
    		 Patients maintained their inhaled corticosteroids (ICS) background therapy.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Aug 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Hungary: 34
    Country: Number of subjects enrolled
    Latvia: 58
    Country: Number of subjects enrolled
    Lithuania: 31
    Country: Number of subjects enrolled
    Russian Federation: 17
    Country: Number of subjects enrolled
    Ukraine: 17
    Worldwide total number of subjects
    171
    EEA total number of subjects
    137
    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)
    171
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in the trial. Subjects had to meet all inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated. Therefore, out of 171 enrolled patients, only 101 were randomised.

    Period 1
    Period 1 title
    Period 1 (4 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tio R5/Placebo/Tio R1.25
    Arm description
    		 Patients treated with Tiotropium 5 mcg in Period 1, with Placebo in Period 2 and with Tiotropium 1.25 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium 5 micrograms /Placebo/ Tiotropium 1.25 micrograms
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R5 - 2 puffs once daily for a total dose of 5 micrograms (evening dosing) Placebo - 2 puffs once daily (evening dosing) Tio R1.25 - 2 puffs once daily for a total dose of 1.25 micrograms (evening dosing)

    Arm title
    		 Tio R1.25/Tio R5/Tio R2.5
    Arm description
    		 Patients treated with Tiotropium 1.25 mcg in Period 1, with Tiotropium 5 mcg in Period 2 and with Tiotropium 2.5 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium 1.25 micrograms/Tiotropium 5 micrograms/Tiotropium 2.5 micrograms
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R1.25 - 2 puffs once daily for a total dose of 1.25 micrograms (evening dosing) Tio R5 - 2 puffs once daily for a total dose of 5 micrograms (evening dosing) Tio R2.5 - 2 puffs once daily for a total dose of 2.5 micrograms (evening dosing)

    Arm title
    		 Placebo/Tio R2.5/Tio R5
    Arm description
    		 Patients treated with Placebo in Period 1, with Tiotropium 2.5 mcg in Period 2 and with Tiotropium 5 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Placebo/ Tiotropium 2.5 micrograms/ Tiotropium 5 micrograms
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo - 2 puffs once daily (evening dosing) Tio R2.5 - 2 puffs once daily for a total dose of 2.5 micrograms (evening dosing) Tio R5 - 2 puffs once daily for a total dose of 5 micrograms (evening dosing)

    Arm title
    		 Tio R2.5/Tio R1.25/Placebo
    Arm description
    		 Patients treated with Tiotropium 2.5 mcg in Period 1, with Tiotropium 1.25 mcg in Period 2 and with Placebo in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium 2.5 micrograms / Tiotropium 1.25 micrograms/ /Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R2.5 - 2 puffs once daily for a total dose of 2.5 micrograms (evening dosing) Tio R1.25 - 2 puffs once daily for a total dose of 1.25 micrograms (evening dosing) Placebo - 2 puffs once daily (evening dosing)

    Number of subjects in period 1
    		Tio R5/Placebo/Tio R1.25 Tio R1.25/Tio R5/Tio R2.5 Placebo/Tio R2.5/Tio R5 Tio R2.5/Tio R1.25/Placebo
    Started
    27
    24
    25
    25
    Completed
    26
    24
    25
    25
    Not completed
    1
    0
    0
    0
         Consent withdrawn by subject
    1
    -
    -
    -
    Period 2
    Period 2 title
    Period 2 (4 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tio R5/Placebo/Tio R1.25
    Arm description
    		 Patients treated with Tiotropium 5 mcg in Period 1, with Placebo in Period 2 and with Tiotropium 1.25 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium 5 micrograms /Placebo/ Tiotropium 1.25 micrograms
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R5 - 2 puffs once daily for a total dose of 5 micrograms (evening dosing) Placebo - 2 puffs once daily (evening dosing) Tio R1.25 - 2 puffs once daily for a total dose of 1.25 micrograms (evening dosing)

    Arm title
    		 Tio R1.25/Tio R5/Tio R2.5
    Arm description
    		 Patients treated with Tiotropium 1.25 mcg in Period 1, with Tiotropium 5 mcg in Period 2 and with Tiotropium 2.5 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium 1.25 micrograms / Tiotropium 5 micrograms / Tiotropium 2.5 micrograms
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R1.25 - 2 puffs once daily for a total dose of 1.25 micrograms (evening dosing) Tio R5 - 2 puffs once daily for a total dose of 5 micrograms (evening dosing) Tio R2.5 - 2 puffs once daily for a total dose of 2.5 micrograms (evening dosing)

    Arm title
    		 Placebo/Tio R2.5/Tio R5
    Arm description
    		 Patients treated with Placebo in Period 1, with Tiotropium 2.5 mcg in Period 2 and with Tiotropium 5 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Placebo / Tiotropium 2.5 micrograms /Tiotropium 5 micrograms
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo - 2 puffs once daily (evening dosing) Tio R2.5 - 2 puffs once daily for a total dose of 2.5 micrograms (evening dosing) Tio R5 - 2 puffs once daily for a total dose of 5 micrograms (evening dosing)

    Arm title
    		 Tio R2.5/Tio R1.25/Placebo
    Arm description
    		 Patients treated with Tiotropium 2.5 mcg in Period 1, with Tiotropium 1.25 mcg in Period 2 and with Placebo in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium 2.5 micrograms / Tiotropium 1.25 micrograms /Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R2.5 - 2 puffs once daily for a total dose of 2.5 micrograms (evening dosing) Tio R1.25 - 2 puffs once daily for a total dose of 1.25 micrograms (evening dosing) Placebo - 2 puffs once daily (evening dosing)

    Number of subjects in period 2
    		Tio R5/Placebo/Tio R1.25 Tio R1.25/Tio R5/Tio R2.5 Placebo/Tio R2.5/Tio R5 Tio R2.5/Tio R1.25/Placebo
    Started
    26
    24
    25
    25
    Completed
    26
    24
    25
    25
    Period 3
    Period 3 title
    Period 3 (4 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tio R5/Placebo/Tio R1.25
    Arm description
    		 Patients treated with Tiotropium 5 mcg in Period 1, with Placebo in Period 2 and with Tiotropium 1.25 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium 5 micrograms /Placebo/ Tiotropium 1.25 micrograms
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R5 - 2 puffs once daily for a total dose of 5 micrograms (evening dosing) Placebo - 2 puffs once daily (evening dosing) Tio R1.25 - 2 puffs once daily for a total dose of 1.25 micrograms (evening dosing)

    Arm title
    		 Tio R1.25/Tio R5/Tio R2.5
    Arm description
    		 Patients treated with Tiotropium 1.25 mcg in Period 1, with Tiotropium 5 mcg in Period 2 and with Tiotropium 2.5 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium 1.25 micrograms / Tiotropium 5 micrograms / Tiotropium 2.5 micrograms
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R1.25 - 2 puffs once daily for a total dose of 1.25 micrograms (evening dosing) Tio R5 - 2 puffs once daily for a total dose of 5 micrograms (evening dosing) Tio R2.5 - 2 puffs once daily for a total dose of 2.5 micrograms (evening dosing)

    Arm title
    		 Placebo/Tio R2.5/Tio R5
    Arm description
    		 Patients treated with Placebo in Period 1, with Tiotropium 2.5 mcg in Period 2 and with Tiotropium 5 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Placebo / Tiotropium 2.5 micrograms /Tiotropium 5 micrograms
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo - 2 puffs once daily (evening dosing) Tio R2.5 - 2 puffs once daily for a total dose of 2.5 micrograms (evening dosing) Tio R5 - 2 puffs once daily for a total dose of 5 micrograms (evening dosing)

    Arm title
    		 Tio R2.5/Tio R1.25/Placebo
    Arm description
    		 Patients treated with Tiotropium 2.5 mcg in Period 1, with Tiotropium 1.25 mcg in Period 2 and with Placebo in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium 2.5 micrograms / Tiotropium 1.25 micrograms/Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R2.5 - 2 puffs once daily for a total dose of 2.5 micrograms (evening dosing) Tio R1.25 - 2 puffs once daily for a total dose of 1.25 micrograms (evening dosing) Placebo - 2 puffs once daily (evening dosing)

    Number of subjects in period 3
    		Tio R5/Placebo/Tio R1.25 Tio R1.25/Tio R5/Tio R2.5 Placebo/Tio R2.5/Tio R5 Tio R2.5/Tio R1.25/Placebo
    Started
    26
    24
    25
    25
    Completed
    26
    24
    25
    25
    Period 4
    Period 4 title
    Overall trial (treatment period)
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo
    Arm description
    		 Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. One patient was randomised to placebo arm but not treated.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication.

    Arm title
    		 Tio R1.25
    Arm description
    		 Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. One patient was randomised to Tio R1.25 arm, but was not treated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium 1.25 micrograms
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication.

    Arm title
    		 Tio R2.5
    Arm description
    		 Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium 2.5 micrograms
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication.

    Arm title
    		 Tio R5
    Arm description
    		 Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium 5 micrograms
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Since the baseline characteristics are presented for the overall trial and at least one defined period had to be selected as a baseline period, overall trial (treatment period) was used to report the baseline characteristics.
    Number of subjects in period 4
    		Placebo Tio R1.25 Tio R2.5 Tio R5
    Started
    76
    75
    74
    76
    Completed
    76
    75
    74
    75
    Not completed
    0
    0
    0
    1
         Consent withdrawn by subject
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Overall trial (treatment period)
    Reporting group description
    		 -

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one of the trial medication.
    Reporting group values
    		 Overall trial (treatment period) Total
    Number of subjects
    		 101 101
    Age categorical
    Units: Subjects
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 8.8 ( 1.7 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 32 32
        Male
    		 69 69
    Study Specific Characteristic |
    Forced expiratory volume in 1s (FEV1)
    Units: Litre
        arithmetic mean (standard deviation)
    		 1.64 ( 0.386 ) -

    End points

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    End points reporting groups
    Reporting group title
    Tio R5/Placebo/Tio R1.25
    Reporting group description
    		 Patients treated with Tiotropium 5 mcg in Period 1, with Placebo in Period 2 and with Tiotropium 1.25 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.

    Reporting group title
    Tio R1.25/Tio R5/Tio R2.5
    Reporting group description
    		 Patients treated with Tiotropium 1.25 mcg in Period 1, with Tiotropium 5 mcg in Period 2 and with Tiotropium 2.5 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.

    Reporting group title
    Placebo/Tio R2.5/Tio R5
    Reporting group description
    		 Patients treated with Placebo in Period 1, with Tiotropium 2.5 mcg in Period 2 and with Tiotropium 5 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.

    Reporting group title
    Tio R2.5/Tio R1.25/Placebo
    Reporting group description
    		 Patients treated with Tiotropium 2.5 mcg in Period 1, with Tiotropium 1.25 mcg in Period 2 and with Placebo in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.
    Reporting group title
    Tio R5/Placebo/Tio R1.25
    Reporting group description
    		 Patients treated with Tiotropium 5 mcg in Period 1, with Placebo in Period 2 and with Tiotropium 1.25 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.

    Reporting group title
    Tio R1.25/Tio R5/Tio R2.5
    Reporting group description
    		 Patients treated with Tiotropium 1.25 mcg in Period 1, with Tiotropium 5 mcg in Period 2 and with Tiotropium 2.5 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.

    Reporting group title
    Placebo/Tio R2.5/Tio R5
    Reporting group description
    		 Patients treated with Placebo in Period 1, with Tiotropium 2.5 mcg in Period 2 and with Tiotropium 5 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.

    Reporting group title
    Tio R2.5/Tio R1.25/Placebo
    Reporting group description
    		 Patients treated with Tiotropium 2.5 mcg in Period 1, with Tiotropium 1.25 mcg in Period 2 and with Placebo in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.
    Reporting group title
    Tio R5/Placebo/Tio R1.25
    Reporting group description
    		 Patients treated with Tiotropium 5 mcg in Period 1, with Placebo in Period 2 and with Tiotropium 1.25 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.

    Reporting group title
    Tio R1.25/Tio R5/Tio R2.5
    Reporting group description
    		 Patients treated with Tiotropium 1.25 mcg in Period 1, with Tiotropium 5 mcg in Period 2 and with Tiotropium 2.5 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.

    Reporting group title
    Placebo/Tio R2.5/Tio R5
    Reporting group description
    		 Patients treated with Placebo in Period 1, with Tiotropium 2.5 mcg in Period 2 and with Tiotropium 5 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.

    Reporting group title
    Tio R2.5/Tio R1.25/Placebo
    Reporting group description
    		 Patients treated with Tiotropium 2.5 mcg in Period 1, with Tiotropium 1.25 mcg in Period 2 and with Placebo in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. One patient was randomised to placebo arm but not treated.

    Reporting group title
    Tio R1.25
    Reporting group description
    		 Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication. One patient was randomised to Tio R1.25 arm, but was not treated.

    Reporting group title
    Tio R2.5
    Reporting group description
    		 Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication.

    Reporting group title
    Tio R5
    Reporting group description
    		 Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication

    Primary: Forced Expiratory Volume (FEV1) Peak (0-3h) Response

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    End point title
    		 Forced Expiratory Volume (FEV1) Peak (0-3h) Response
    End point description
    The FEV1 peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FEV1 measured within the first 3 hours post dosing and the FEV1 baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model. FAS= Full analysis set which is defined as patients randomised, treated, with baseline data and at least one on-treatment efficacy measurement after 4 weeks on treatment within a period.
    End point type
    Primary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    76 [1]
    75 [2]
    74 [3]
    75 [4]
    Units: Litre
        least squares mean (standard error)
    0.185 ( 0.025 )
    0.261 ( 0.026 )
    0.29 ( 0.026 )
    0.272 ( 0.026 )
    Notes
    [1] - FAS
    [2] - FAS
    [3] - FAS
    [4] - FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Mixed model repeated measures (MMRM) was used. This MMRM model includes treatment, period and common baseline as fixed effects, and patient as random effect. Difference was calculated as Tio R5 minus Placebo. The actual number of subjects analyzed is 75. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis below (151) does not reflect the actual number.
    Comparison groups
    Placebo v Tio R5
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [5]
    Method
    		 Mixed model repeated measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.087
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.042
         upper limit
    		 0.132
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.023
    Notes
    [5] - First step of closed testing procedure, where the active treatments are compared to placebo. If this statistical test is significant at the 0.05 alpha level then proceed to comparison of the next lower dose to placebo.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Mixed model repeated measures was used (MMRM). This MMRM model includes treatment, period and common baseline as fixed effects, and patient as random effect. Difference was calculated as Tio R2.5 minus Placebo. The actual number of subjects analyzed is 74. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis below (150) does not reflect the actual number.
    Comparison groups
    Placebo v Tio R2.5
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed model repeated measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.104
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.059
         upper limit
    		 0.149
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.023
    Notes
    [6] - Second step of closed testing procedure. If this statistical test is significant at the 0.05 alpha level then proceed to comparison of the next lower dose to placebo.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Mixed model repeated measures was used (MMRM). This MMRM model includes treatment, period and common baseline as fixed effects, and patient as random effect. Difference was calculated as Tio R1.25 minus Placebo The actual number of subjects analyzed is 75. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis below (151) does not reflect the actual number.
    Comparison groups
    Placebo v Tio R1.25
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0011
    Method
    		 Mixed model repeated measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.075
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.023
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Mixed model repeated measures was used (MMRM). This MMRM model includes treatment, period and common baseline as fixed effects, and patient as random effect. Difference was calculated as Tio R5 minus Tio R1.25. The actual number of subjects analyzed is 74. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis below (150) does not reflect the actual number.
    Comparison groups
    Tio R1.25 v Tio R5
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [7]
    Method
    		 Mixed model repeated measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.012
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.034
         upper limit
    		 0.057
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.023
    Notes
    [7] - This statistical analysis was evaluated only descriptively
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Mixed model repeated measures was used. This MMRM model includes treatment, period and common baseline as fixed effects, and patient as random effect. Difference was calculated as Tio R5 minus Tio R2.5 The actual number of subjects analyzed is 73. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis below (149) does not reflect the actual number.
    Comparison groups
    Tio R5 v Tio R2.5
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [8]
    Method
    		 Mixed model repeated measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.017
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.063
         upper limit
    		 0.028
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.023
    Notes
    [8] - This statistical analysis was evaluated only descriptively.
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Mixed model repeated measures was used. This MMRM model includes treatment, period and common baseline as fixed effects, and patient as random effect. Difference was calculated as Tio R2.5 minus Tio R1.25. The actual number of subjects analyzed is 73. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis below (149) does not reflect the actual number.
    Comparison groups
    Tio R1.25 v Tio R2.5
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [9]
    Method
    		 Mixed models repeated measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.029
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.016
         upper limit
    		 0.074
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.023
    Notes
    [9] - This statistical analysis was evaluated only descriptively.

    Secondary: Trough FEV1 Response

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    End point title
    		 Trough FEV1 Response
    End point description
    The trough FEV1 is defined as the pre-dose FEV1 measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    76 [10]
    75 [11]
    74 [12]
    75 [13]
    Units: Litre
        least squares mean (standard error)
    0.085 ( 0.026 )
    0.16 ( 0.026 )
    0.19 ( 0.026 )
    0.183 ( 0.026 )
    Notes
    [10] - FAS
    [11] - FAS
    [12] - FAS
    [13] - FAS
    No statistical analyses for this end point

    Secondary: Forced Vital Capacity (FVC) Peak (0-3h) Response

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    End point title
    		 Forced Vital Capacity (FVC) Peak (0-3h) Response
    End point description
    The FVC peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FVC measured within the first 3 hours post dosing and the FVC baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    76 [14]
    75 [15]
    74 [16]
    75 [17]
    Units: Litre
        least squares mean (standard error)
    0.202 ( 0.029 )
    0.208 ( 0.029 )
    0.253 ( 0.029 )
    0.239 ( 0.029 )
    Notes
    [14] - FAS
    [15] - FAS
    [16] - FAS
    [17] - FAS
    No statistical analyses for this end point

    Secondary: FVC Trough Response

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    End point title
    		 FVC Trough Response
    End point description
    The trough FVC response is defined as the pre-dose FVC measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    76 [18]
    75 [19]
    74 [20]
    75 [21]
    Units: Litre
        least squares mean (standard error)
    0.06 ( 0.03 )
    0.109 ( 0.03 )
    0.107 ( 0.03 )
    0.113 ( 0.03 )
    Notes
    [18] - FAS
    [19] - FAS
    [20] - FAS
    [21] - FAS
    No statistical analyses for this end point

    Secondary: FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response

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    End point title
    		 FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response
    End point description
    FEV1 (AUC0-3h) will be calculated as the area under the curve from 0 to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    76 [22]
    75 [23]
    74 [24]
    75 [25]
    Units: Litre
        least squares mean (standard error)
    0.11 ( 0.025 )
    0.178 ( 0.025 )
    0.208 ( 0.025 )
    0.201 ( 0.025 )
    Notes
    [22] - FAS
    [23] - FAS
    [24] - FAS
    [25] - FAS
    No statistical analyses for this end point

    Secondary: FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response

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    End point title
    		 FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response
    End point description
    FVC (AUC0-3h) will be calculated as the area under the curve from 0 to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    76 [26]
    75 [27]
    74 [28]
    75 [29]
    Units: Litre
        least squares mean (standard error)
    0.087 ( 0.027 )
    0.097 ( 0.027 )
    0.134 ( 0.027 )
    0.11 ( 0.027 )
    Notes
    [26] - FAS
    [27] - FAS
    [28] - FAS
    [29] - FAS
    No statistical analyses for this end point

    Secondary: Mean Morning Peak Expiratory Flow (PEF) Response

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    End point title
    		 Mean Morning Peak Expiratory Flow (PEF) Response
    End point description
    Mean morning PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    76 [30]
    75 [31]
    73 [32]
    75 [33]
    Units: Litre/min
        least squares mean (standard error)
    -0.928 ( 5.103 )
    14.474 ( 5.127 )
    12.045 ( 5.177 )
    15.439 ( 5.127 )
    Notes
    [30] - FAS
    [31] - FAS
    [32] - FAS- Only patients with baseline and week 4 values were analysed
    [33] - FAS
    No statistical analyses for this end point

    Secondary: Mean Evening PEF Response

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    End point title
    		 Mean Evening PEF Response
    End point description
    Mean Evening PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    76 [34]
    75 [35]
    73 [36]
    75 [37]
    Units: Litre/min
        least squares mean (standard error)
    -0.568 ( 5.081 )
    9.91 ( 5.103 )
    6.991 ( 5.15 )
    15.91 ( 5.103 )
    Notes
    [34] - FAS
    [35] - FAS
    [36] - FAS- Only patients with baseline and week 4 values were analysed
    [37] - FAS
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, daytime and night-time use)

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    End point title
    		 Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, daytime and night-time use)
    End point description
    Mean number of inhalations (puffs) of unscheduled rescue salbutamol therapy during whole day (24 h, daytime and night-time use). Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    76 [38]
    75 [39]
    73 [40]
    75 [41]
    Units: Puffs
    least squares mean (standard error)
        24 h
    -0.664 ( 0.105 )
    -0.691 ( 0.105 )
    -0.314 ( 0.106 )
    -0.55 ( 0.105 )
        Daytime
    -0.338 ( 0.061 )
    -0.348 ( 0.062 )
    -0.13 ( 0.062 )
    -0.258 ( 0.062 )
        Night-time
    -0.354 ( 0.06 )
    -0.355 ( 0.06 )
    -0.18 ( 0.06 )
    -0.272 ( 0.06 )
    Notes
    [38] - FAS
    [39] - FAS
    [40] - FAS- Only patients with baseline and week 4 values were analysed
    [41] - FAS
    No statistical analyses for this end point

    Secondary: Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ)

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    End point title
    		 Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ)
    End point description
    ACQ is a questionnaire consisting of seven point Likert scale ranging from 0 to 6, whereby 0 represents good control and 6 represents poor control of asthma. The scale describes the frequency and severity of asthma symptoms. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    76 [42]
    75 [43]
    74 [44]
    75 [45]
    Units: Score
        least squares mean (standard error)
    0.966 ( 0.066 )
    0.909 ( 0.066 )
    0.846 ( 0.066 )
    0.879 ( 0.066 )
    Notes
    [42] - FAS
    [43] - FAS
    [44] - FAS
    [45] - FAS
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Number of Nighttime Awakenings

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    End point title
    		 Change From Baseline in Mean Number of Nighttime Awakenings
    End point description
    Mean number of nighttime awakenings due to asthma symptoms as assessed by patients eDiary incorporated in the AM3® device. Analysis adjusted for treatment, period, patient and baseline using a mixed model. The scores for this question used the following scale where: 1='Did not wake up', 2='Woke up once', 3='Woke up 2-5 times', 4='Woke up more than 5 times' and 5='Was awake all night'.
    End point type
    Secondary
    End point timeframe
    Baseline and last week of treatment (week 4)
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    76 [46]
    75 [47]
    73 [48]
    75 [49]
    Units: scores on a scale
        least squares mean (standard error)
    -0.135 ( 0.034 )
    -0.104 ( 0.034 )
    -0.08 ( 0.034 )
    -0.099 ( 0.034 )
    Notes
    [46] - FAS
    [47] - FAS
    [48] - FAS- Only patients with baseline and week 4 values were analysed
    [49] - FAS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    4 weeks + 30 days if in last period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication.

    Reporting group title
    Tio R1.25
    Reporting group description
    		 Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication.

    Reporting group title
    Tio R2.5
    Reporting group description
    		 Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication.

    Reporting group title
    Tio R5
    Reporting group description
    		 Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top of maintenance therapy with an inhaled corticosteroid controller medication.

    Serious adverse events
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 76 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 76 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Although non-serious adverse events were reported, the 5% threshold wasn’t reached on a preferred term level.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Feb 2012
    This amendment introduced changes to clarify wording and study procedures/data to be collected, to introduce some administrative changes, and to correct minor typographical errors and inconsistencies between the synopsis, study flow charts, the eCRF, and the text of the protocol, or to align procedures in this protocol with the other tiotropium studies. In addition, there was a change in the sample size calculation, as a result of which the numbers of patients to be randomised was changed from 92 to 104. This was required based on unblinded information of completed trials with tiotropium in asthma that necessitated an update of the expected standard deviation for the primary endpoint FEV 1 peak 0-3h 0.228L to 0.280L and the expected drop-out rate from 30% to 8%. For pharmacokinetic analyses, the '2/3rd rule' (used for the presentation of descriptive statistics) was ignored during this trial. Instead, it was decided to display descriptive statistics for concentrations and PK parameters if at least three individual values were available.

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

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