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    Clinical Trial Results:
    A randomised, double-blind, placebo-controlled, parallel-group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 µg and 5 µg once daily) over 12 weeks as add-on controller therapy on top of usual care in adolescents (12 to 17 years old) with severe persistent asthma.

    Summary
    EudraCT number
    		 2010-021778-13
    Trial protocol
    		 LV   HU   BG   DE   IT   PT   Outside EU/EEA  
    Global end of trial date
    16 Oct 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    205.456
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim Pharma GmbH & Co. KG
    Sponsor organisation address
    Binger Strasse 173 , 55216 Ingelheim am Rhein , Germany,
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure , Boehringer Ingelheim Pharma GmbH & Co. KG, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure , Boehringer Ingelheim Pharma GmbH & Co. KG, +1 8002430127, 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
    08 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial is to demonstrate superiority of tiotropium (5 µg and possibly 2.5 µg once daily in the evening) over placebo with regard to the primary pulmonary function endpoint after 12 weeks of treatment.
    Protection of trial subjects
    The safety of the patients was of paramount importance and was ensured by monitoring the patients closely for AEs. At-home monitoring of lung function was conducted throughout the entire run-in and treatment periods with the AM3®. The AM3® device was programmed to alert the patient to contact the doctor if significant PEF deterioration occurred or if the patient reported taking high amounts of rescue medication. Patients continued taking their usual maintenance therapy, including ICS and other controller medications and had free access to rescue medication (salbutamol), thus limiting the risk that patients might experience a significant asthmatic adverse event. Moreover, to control acute exacerbations during the trial all patients had access through the investigator to appropriate medications, as medically necessary. To further guarantee the safety of the patients a set of rules leading to withdrawal of patients with severe asthma deterioration was implemented and all procedures and examinations were evaluated for their safety and feasibility in adolescents. Furthermore, an independent Data Safety Monitoring Board was established to monitor safety.
    Background therapy
    		 Patients maintained their background therapy, including ICS in combination with a LABA and/or LTRA and/or sustained release theophylline.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jan 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    Latvia: 57
    Country: Number of subjects enrolled
    Hungary: 123
    Country: Number of subjects enrolled
    Bulgaria: 56
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Guatemala: 26
    Country: Number of subjects enrolled
    Israel: 8
    Country: Number of subjects enrolled
    Mexico: 15
    Country: Number of subjects enrolled
    Portugal: 12
    Country: Number of subjects enrolled
    Argentina: 67
    Country: Number of subjects enrolled
    Philippines: 8
    Country: Number of subjects enrolled
    Ukraine: 88
    Country: Number of subjects enrolled
    United States: 36
    Country: Number of subjects enrolled
    South Africa: 24
    Worldwide total number of subjects
    554
    EEA total number of subjects
    278
    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)
    1
    Adolescents (12-17 years)
    553
    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 the trial. Subjects attended sites for the management of adolescent patients diagnosed with asthma which ensure the subjects met all inclusion/exclusion criteria. Subjects were not to be randomised to the trial if any entry criteria were violated. Thus, out of 554 enrolled patients, 329 were randomised.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tio R2.5
    Arm description
    		 Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium Bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 puffs once daily for a total dose of 2.5 µg that is 1.25 mcg per puff (calculated as free cation, ex mouthpiece, evening dosing) via Respimat inhaler.

    Arm title
    		 Tio R5
    Arm description
    		 Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium Bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 puffs once daily for a total dose of 5 µg that is 2.5 mcg per puff (calculated as free cation, ex mouthpiece, evening dosing) via Respimat inhaler.

    Arm title
    		 Placebo Respimat
    Arm description
    		 Inhalation of placebo solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.
    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
    Two puffs of a solution via Respimat inhaler once daily in the evening.

    Number of subjects in period 1 [1]
    		Tio R2.5 Tio R5 Placebo Respimat
    Started
    127
    130
    135
    Completed
    126
    130
    132
    Not completed
    1
    0
    3
         Other reason not defined
    1
    -
    -
         Adverse event, non-fatal
    -
    -
    1
         Protocol deviation
    -
    -
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number 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.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tio R2.5
    Reporting group description
    		 Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.

    Reporting group title
    Tio R5
    Reporting group description
    		 Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.

    Reporting group title
    Placebo Respimat
    Reporting group description
    		 Inhalation of placebo solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.

    Reporting group values
    		 Tio R2.5 Tio R5 Placebo Respimat Total
    Number of subjects
    		 127 130 135 392
    Age categorical
    Units: Subjects
    Age continuous
    Treated Set (TS): includes all randomized subjects who were dispensed study medication and were documented to take at least 1 dose of the investigational treatment.
    Units: years
        arithmetic mean (standard deviation)
    		 14.4 ( 1.8 ) 14.3 ( 1.6 ) 14.1 ( 1.7 ) -
    Gender categorical
    Treated Set (TS)
    Units: Subjects
        Female
    		 47 47 56 150
        Male
    		 80 83 79 242

    End points

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    End points reporting groups
    Reporting group title
    Tio R2.5
    Reporting group description
    		 Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.

    Reporting group title
    Tio R5
    Reporting group description
    		 Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.

    Reporting group title
    Placebo Respimat
    Reporting group description
    		 Inhalation of placebo solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.

    Primary: FEV1 peak0-3h Change From Baseline

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    End point title
    		 FEV1 peak0-3h Change From Baseline
    End point description
    Change from baseline in peak forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak0-3) measured at week 12. Full Analysis Set (FAS): included all randomized patients who were dispensed study medication and were documented to have taken at least 1 dose of investigational treatment. In FAS we have 127, 130, 135 patients. Currently reported numbers are numbers of patients with endpoint at week 12 (from MMRM output).
    End point type
    Primary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Tio R2.5 Tio R5 Placebo Respimat
    Number of subjects analysed
    126 [1]
    130 [2]
    132 [3]
    Units: Liter(s)
        least squares mean (standard error)
    0.55 ( 0.046 )
    0.528 ( 0.045 )
    0.438 ( 0.045 )
    Notes
    [1] - Full Analysis Set (FAS)
    [2] - FAS
    [3] - FAS
    Statistical analysis title
    		 Tio R2.5 vs Placebo
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). The model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions The first statistical test is Tio R5 vs Placebo and then Tio R2.5 vs Placebo because it was pre-specified order of hierarchical testing.
    Comparison groups
    Tio R2.5 v Placebo Respimat
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.0457 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.111
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.002
         upper limit
    		 0.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.055
    Notes
    [4] - Difference calculated as Tio R2.5 minus placebo
    [5] - Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo.
    Statistical analysis title
    		 Placebo vs Tio R5
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). The model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions The first statistical test is Tio R5 vs Placebo and then Tio R2.5 vs Placebo because it was pre-specified order of hierarchical testing.
    Comparison groups
    Placebo Respimat v Tio R5
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.1039 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.019
         upper limit
    		 0.198
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.055
    Notes
    [6] - Difference calculated as Tio R5 minus placebo
    [7] - Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo.

    Secondary: Trough FEV1 Change From Baseline

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    End point title
    		 Trough FEV1 Change From Baseline
    End point description
    Change from baseline in Trough (pre-dose) Forced expiratory volume in 1 second (FEV1) measured at week 12. In FAS we have 127, 130, 135 patients. Currently reported numbers are numbers of patients with endpoint at week 12 (from MMRM output).
    End point type
    Secondary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Tio R2.5 Tio R5 Placebo Respimat
    Number of subjects analysed
    126 [8]
    130 [9]
    132 [10]
    Units: Liters
        least squares mean (standard error)
    0.345 ( 0.048 )
    0.284 ( 0.048 )
    0.23 ( 0.048 )
    Notes
    [8] - FAS
    [9] - FAS
    [10] - FAS
    Statistical analysis title
    		 Tio R2.5 vs Placebo
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). Model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions The first statistical test is Tio R5 vs Placebo and then Tio R2.5 vs Placebo because it was pre-specified order of hierarchical testing.
    Comparison groups
    Tio R2.5 v Placebo Respimat
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0509 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.115
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.231
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.059
    Notes
    [11] - Difference calculated as Tio R2.5 minus placebo
    [12] - Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo.
    Statistical analysis title
    		 Tio R5 vs Placebo
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). Model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions The first statistical test is Tio R5 vs Placebo and then Tio R2.5 vs Placebo because it was pre-specified order of hierarchical testing.
    Comparison groups
    Tio R5 v Placebo Respimat
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.3605 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.054
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.061
         upper limit
    		 0.168
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.058
    Notes
    [13] - Difference calculated as Tio R5 minus placebo
    [14] - Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo.

    Secondary: FEV1 AUC (0-3h) Change From Baseline

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    End point title
    		 FEV1 AUC (0-3h) Change From Baseline
    End point description
    Change from baseline of area under the curve (AUC) from 0 to 3 hours for FEV1 (FEV1 AUC 0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). In FAS we have 127, 130, 135 patients. Currently reported numbers are numbers of patients with endpoint at week 12.
    End point type
    Secondary
    End point timeframe
    Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks
    End point values
    		 Tio R2.5 Tio R5 Placebo Respimat
    Number of subjects analysed
    126 [15]
    130 [16]
    132 [17]
    Units: litre(s)
        least squares mean (standard error)
    0.449 ( 0.043 )
    0.423 ( 0.043 )
    0.336 ( 0.043 )
    Notes
    [15] - FAS
    [16] - FAS
    [17] - FAS
    Statistical analysis title
    		 Placebo vs Tio R2.5
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). The model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Placebo Respimat v Tio R2.5
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0338
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.113
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.009
         upper limit
    		 0.217
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.053
    Statistical analysis title
    		 Placebo vs Tio R5
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). The model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Placebo Respimat v Tio R5
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0999
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.087
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.017
         upper limit
    		 0.191
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.053

    Secondary: FVC AUC (0-3h) Change From Baseline

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    End point title
    		 FVC AUC (0-3h) Change From Baseline
    End point description
    Change from baseline of area under the curve (AUC) from 0 to 3 hours for FVC (Forced vital capacity) (FVC AUC0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). In FAS we have 127, 130, 135 patients. Currently reported numbers are numbers of patients with endpoint at week 12.
    End point type
    Secondary
    End point timeframe
    Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks
    End point values
    		 Tio R2.5 Tio R5 Placebo Respimat
    Number of subjects analysed
    126 [18]
    130 [19]
    132 [20]
    Units: litre(s)
        least squares mean (standard error)
    0.262 ( 0.047 )
    0.227 ( 0.046 )
    0.175 ( 0.045 )
    Notes
    [18] - FAS
    [19] - FAS
    [20] - FAS
    Statistical analysis title
    		 Tio R2.5 vs Placebo
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). The model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Tio R2.5 v Placebo Respimat
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1252
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.087
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.024
         upper limit
    		 0.198
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.057
    Statistical analysis title
    		 Tio R5 vs Placebo
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). The model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Tio R5 v Placebo Respimat
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3549
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.052
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.058
         upper limit
    		 0.163
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.056

    Secondary: Use of PRN Rescue Medication During the Day change from baseline

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    End point title
    		 Use of PRN Rescue Medication During the Day change from baseline
    End point description
    Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the day (24 hour period) based on the weekly mean at week 12. In FAS we have 127, 130, 135 patients. Currently reported numbers are numbers of patients with endpoint at week 12.
    End point type
    Secondary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Tio R2.5 Tio R5 Placebo Respimat
    Number of subjects analysed
    124 [21]
    130 [22]
    131 [23]
    Units: number of puffs of rescue medication
        least squares mean (standard error)
    -0.483 ( 0.122 )
    -0.54 ( 0.12 )
    -0.482 ( 0.118 )
    Notes
    [21] - FAS
    [22] - FAS
    [23] - FAS
    Statistical analysis title
    		 Tio R2.5 vs Placebo
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). The model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Tio R2.5 v Placebo Respimat
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.996
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.001
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.301
         upper limit
    		 0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.153
    Statistical analysis title
    		 Tio R5 vs Placebo
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). The model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Tio R5 v Placebo Respimat
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.703
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.058
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.355
         upper limit
    		 0.239
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.151

    Secondary: Use of PRN Rescue Medication During the Daytime change from baseline

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    End point title
    		 Use of PRN Rescue Medication During the Daytime change from baseline
    End point description
    Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the daytime based on the weekly mean at week 12. In FAS we have 127, 130, 135 patients. Currently reported numbers are numbers of patients with endpoint at week 12.
    End point type
    Secondary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Tio R2.5 Tio R5 Placebo Respimat
    Number of subjects analysed
    124 [24]
    130 [25]
    131 [26]
    Units: number of puffs of rescue medication
        least squares mean (standard error)
    -0.295 ( 0.075 )
    -0.312 ( 0.073 )
    -0.262 ( 0.073 )
    Notes
    [24] - FAS
    [25] - FAS
    [26] - FAS
    Statistical analysis title
    		 Tio R2.5 vs Placebo
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). The model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Tio R2.5 v Placebo Respimat
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7309
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.032
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.217
         upper limit
    		 0.153
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.094
    Statistical analysis title
    		 Tio R5 vs Placebo
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). The model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Tio R5 v Placebo Respimat
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5954
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.049
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.232
         upper limit
    		 0.133
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.093

    Secondary: Use of PRN Rescue Medication During the Night-time change from baseline

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    End point title
    		 Use of PRN Rescue Medication During the Night-time change from baseline
    End point description
    Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the night-time based on the weekly mean at week 12. In FAS we have 127, 130, 135 patients. Currently reported numbers are numbers of patients with endpoint at week 12.
    End point type
    Secondary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Tio R2.5 Tio R5 Placebo Respimat
    Number of subjects analysed
    124 [27]
    129 [28]
    131 [29]
    Units: number of puffs of rescue medication
        least squares mean (standard error)
    -0.092 ( 0.066 )
    -0.159 ( 0.065 )
    -0.18 ( 0.064 )
    Notes
    [27] - FAS
    [28] - FAS
    [29] - FAS
    Statistical analysis title
    		 Tio R2.5 vs Placebo
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). The model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Tio R2.5 v Placebo Respimat
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2841
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.089
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.074
         upper limit
    		 0.252
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.083
    Statistical analysis title
    		 Placebo vs Tio R5
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). The model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Placebo Respimat v Tio R5
    Number of subjects included in analysis
    260
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.795
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.021
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 0.182
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.082

    Secondary: Time to First Severe Asthma Exacerbation During the 12-week treatment period

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    End point title
    		 Time to First Severe Asthma Exacerbation During the 12-week treatment period
    End point description
    Time in days to first severe asthma exacerbation during the 12 week treatment period. The median time to first severe asthma exacerbation was not calculable, so the number of patients who experienced a severe asthma exacerbation are presented for the measured values. A severe asthma exacerbation was defined as a subgroup of all asthma exacerbations that required an initiation of treatment with systemic corticosteroids for at least 3 days or, in case of ongoing and preexisting systemic corticosteroid therapy, requiring at least doubling of previous daily doses of systemic corticosteroids for at least 3 days. In FAS we have 127, 130, 135 patients. Currently reported numbers are numbers of patients with endpoint during 12 weeks period.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Tio R2.5 Tio R5 Placebo Respimat
    Number of subjects analysed
    127 [30]
    130 [31]
    135 [32]
    Units: participant(s)
        cumulative failure
    1
    2
    1
        cumulative censored
    126
    128
    134
    Notes
    [30] - FAS
    [31] - FAS
    [32] - FAS
    Statistical analysis title
    		 Tio R2.5 vs Placebo
    Statistical analysis description
    Cox's proportional regression model with treatment as effect
    Comparison groups
    Tio R2.5 v Placebo Respimat
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9671
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 16.95
    Statistical analysis title
    		 Tio R5 vs Placebo
    Statistical analysis description
    Cox's proportional regression model with treatment as an effect
    Comparison groups
    Tio R5 v Placebo Respimat
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5557
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 22.7

    Secondary: Analysis of Time to First Asthma Exacerbation during the 12 week treatment period

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    End point title
    		 Analysis of Time to First Asthma Exacerbation during the 12 week treatment period
    End point description
    Time in days to first asthma exacerbation during the 12 week treatment period. The median time to first asthma exacerbation was not calculable, so the number of patients who experienced an asthma exacerbation are presented for the measured values. In FAS we have 127, 130, 135 patients. Currently reported numbers are numbers of patients with endpoint during 12 weeks period.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Tio R2.5 Tio R5 Placebo Respimat
    Number of subjects analysed
    127 [33]
    130 [34]
    135 [35]
    Units: participant(s)
        cumulative failure
    18
    15
    25
        cumulative censored
    109
    115
    110
    Notes
    [33] - FAS
    [34] - FAS
    [35] - FAS
    Statistical analysis title
    		 Tio R2.5 vs Placebo
    Statistical analysis description
    Cox's proportional regression model with treatment as a effect.
    Comparison groups
    Tio R2.5 v Placebo Respimat
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3567
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.38
    Statistical analysis title
    		 Placebo vs Tio R5
    Statistical analysis description
    Cox's proportional regression model with treatment as a effect.
    Comparison groups
    Placebo Respimat v Tio R5
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1168
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 1.14

    Secondary: Clinically Relevant Abnormalities for Physical Examination, ECG, Vital Signs and Laboratory Tests

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    End point title
    		 Clinically Relevant Abnormalities for Physical Examination, ECG, Vital Signs and Laboratory Tests
    End point description
    Clinically relevant abnormalities for physical examination, ECG, vital signs and laboratory tests. New abnormal findings or worsening of baseline conditions were reported as adverse events.
    End point type
    Secondary
    End point timeframe
    From first drug administration until 30 days after last drug intake, up to 142 days
    End point values
    		 Tio R2.5 Tio R5 Placebo Respimat
    Number of subjects analysed
    127 [36]
    130 [37]
    135 [38]
    Units: percentage of subjects with events
    number (not applicable)
        peak expiratory flow rate decrease
    9
    5
    13
        blood glucose decrease
    1
    0
    0
    Notes
    [36] - TS
    [37] - TS
    [38] - TS
    No statistical analyses for this end point

    Secondary: FVC peak0-3h Change From Baseline

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    End point title
    		 FVC peak0-3h Change From Baseline
    End point description
    Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak0-3h) after 12 weeks of treatment. In FAS we have 127, 130, 135 patients. Currently reported numbers are numbers of patients with endpoint during 12 weeks period.
    End point type
    Secondary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Tio R2.5 Tio R5 Placebo Respimat
    Number of subjects analysed
    126 [39]
    130 [40]
    132 [41]
    Units: litre(s)
        least squares mean (standard error)
    0.37 ( 0.049 )
    0.342 ( 0.048 )
    0.279 ( 0.048 )
    Notes
    [39] - FAS
    [40] - FAS
    [41] - FAS
    Statistical analysis title
    		 Tio R2.5 vs Placebo
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). Model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Tio R2.5 v Placebo Respimat
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1264
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.091
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.026
         upper limit
    		 0.207
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.059
    Statistical analysis title
    		 Tio R5 vs Placebo
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). Model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Tio R5 v Placebo Respimat
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2845
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.063
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.053
         upper limit
    		 0.179
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.059

    Secondary: ACQ Total Score Responders

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    End point title
    		 ACQ Total Score Responders
    End point description
    Responder rates based on the ACQ total score after 12 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (- 0.5 <change from trial baseline <0.5) and worsening (change from trial baseline ≥0.5) The ACQ is a scale containing 7 questions, each question has a 7- point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. In FAS we have 127, 130, 135 patients. Currently reported numbers are numbers of patients with endpoint at week 12.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Tio R2.5 Tio R5 Placebo Respimat
    Number of subjects analysed
    127 [42]
    130 [43]
    135 [44]
    Units: Percentage of participants
    number (not applicable)
        Responder
    74.8
    73.1
    73.3
        No change
    22
    26.2
    23.7
        Worsening
    3.1
    0.8
    3
    Notes
    [42] - FAS
    [43] - FAS
    [44] - FAS
    No statistical analyses for this end point

    Secondary: Control of Asthma as Assessed by ACQ Total Score

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    End point title
    		 Control of Asthma as Assessed by ACQ Total Score
    End point description
    Asthma Control Questionnaire (ACQ) total score measured at week 12. The ACQ is a scale containing 7 questions. Each question has a 7 point scale which ranges from 0 to 6. A score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ total score was calculated as the mean of the responses to all 7 questions. In FAS we have 127, 130, 135 patients. Currently reported numbers are numbers of patients with endpoint at week 12.
    End point type
    Secondary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Tio R2.5 Tio R5 Placebo Respimat
    Number of subjects analysed
    126 [45]
    130 [46]
    132 [47]
    Units: unit of ACQ total score
        least squares mean (standard error)
    1.292 ( 0.066 )
    1.27 ( 0.065 )
    1.234 ( 0.064 )
    Notes
    [45] - FAS
    [46] - FAS
    [47] - FAS
    Statistical analysis title
    		 Placebo vs Tio R2.5
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). Model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Placebo Respimat v Tio R2.5
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4762
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.058
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.102
         upper limit
    		 0.219
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.082
    Statistical analysis title
    		 Tio R5 vs Placebo
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). Model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Tio R5 v Placebo Respimat
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6558
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.036
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.123
         upper limit
    		 0.196
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.081

    Secondary: Control of Asthma as Assessed by ACQ6 Score.

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    End point title
    		 Control of Asthma as Assessed by ACQ6 Score.
    End point description
    Asthma Control Questionnaire (ACQ) score measured at week 12. The ACQ is a scale containing 7 questions, each question has a 7 point scale which ranges from 0 to 6. A score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ6 score was calculated as the mean of the responses to the first 6 questions of the ACQ. In FAS we have 127, 130, 135 patients. Currently reported numbers are numbers of patients with endpoint at week 12.
    End point type
    Secondary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Tio R2.5 Tio R5 Placebo Respimat
    Number of subjects analysed
    126 [48]
    130 [49]
    132 [50]
    Units: unit on an ACQ6 scale
        least squares mean (standard error)
    1.262 ( 0.071 )
    1.197 ( 0.07 )
    1.144 ( 0.069 )
    Notes
    [48] - FAS
    [49] - FAS
    [50] - FAS
    Statistical analysis title
    		 Tio R2.5 vs Placebo
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). Model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Tio R2.5 v Placebo Respimat
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1819
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.118
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.055
         upper limit
    		 0.292
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.088
    Statistical analysis title
    		 Placebo vs Tio R5
    Statistical analysis description
    A restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). Model was adjusted for treatment, country, week, baseline, treatment*week and baseline*week interactions
    Comparison groups
    Placebo Respimat v Tio R5
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5448
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.053
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.119
         upper limit
    		 0.226
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.088

    Secondary: ACQ6 Score Responders

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    End point title
    		 ACQ6 Score Responders
    End point description
    Responder rates based on the ACQ6 score after 12 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline <= -0.5), no change (-0.5 < change from trial baseline <0.5) and worsening (change from trial baseline >= 0.5). The ACQ is a scale containing 7 questions, each question has a 7- point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ6 was calculated as the mean of the responses to the first 6 questions of the ACQ. In FAS we have 127, 130, 135 patients. Currently reported numbers are numbers of patients with endpoint at week 12.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Tio R2.5 Tio R5 Placebo Respimat
    Number of subjects analysed
    127 [51]
    130 [52]
    135 [53]
    Units: percentage of participants
    number (not applicable)
        Responder
    74
    74.6
    74.1
        No change
    19.7
    23.1
    23.7
        Worsening
    6.3
    2.3
    2.2
    Notes
    [51] - FAS
    [52] - FAS
    [53] - FAS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration until 30 days after the last drug administration, up to 142 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Inhalation of placebo solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.

    Reporting group title
    Tio R2.5
    Reporting group description
    		 Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.

    Reporting group title
    Tio R5
    Reporting group description
    		 Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care.

    Serious adverse events
    		 Placebo Tio R2.5 Tio R5
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 127 (0.79%)
    2 / 130 (1.54%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 127 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 127 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 127 (0.79%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pyoderma
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 127 (0.79%)
    0 / 130 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Tio R2.5 Tio R5
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 135 (17.04%)
    23 / 127 (18.11%)
    16 / 130 (12.31%)
    Investigations
    Peak expiratory flow rate decreased
         subjects affected / exposed
    13 / 135 (9.63%)
    9 / 127 (7.09%)
    5 / 130 (3.85%)
         occurrences all number
    19
    17
    12
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    14 / 135 (10.37%)
    14 / 127 (11.02%)
    14 / 130 (10.77%)
         occurrences all number
    19
    25
    16

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Mar 2011
    This amendment introduced changes to clarify wording and study procedures/data to be collected, to introduce some administrative changes (e.g. information regarding the planned number of participating countries was updated), 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 and update the information and risk assessment for tiotropium based on newly available data. It was also clarified that patients could return to their pre-study medication during the follow-up period.Entrance criteria were amended as noted in Section 9.3. Of particular note, to take into account that the trial population spanned a wide range from a 12-year-old child to a 17-year old near-adult, showing enormous heterogeneity with regard to stature, body weight, development status, etc, inclusion criterion no. 4 (dose recommendations for ICS) was adjusted to avoid a bias toward the upper age range of patients.
    20 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. The text was also amended to update information on tiotropium based on recently completed trials and/or recently published data. Rather than specify the number of countries involved in the study, the text was revised to describe this as a multinational study. Entrance criteria were amended as noted in Section 9.3. A significant AE was defined, as follows: hepatic injury defined by the following alterations of liver parameters: an elevation of AST and/or ALT >3 fold ULN combined with an elevation of total bilirubin >2 fold ULN measured in the same blood draw sample. Information was provided to clarify recording of asthma exacerbations as AEs at a withdrawal or follow-up visit. There was a change in the sample size calculation, as a result of which the numbers of patients to be randomised was changed from 64 per treatment group to 125. This was required based on an update of the expected standard deviation for the primary endpoint FEV1 peak 0-3h 300 mL to 420 mL. The planned number of centres was increased from 40 to 80-90 following the increase in the planned sample size.
    28 Feb 2013
    This amendment introduced changes to clarify wording and study procedures/data to be collected, to introduce some administrative changes (including a change in the Coordinating Investigator), and to correct minor typographical errors and inconsistencies between the synopsis, study flow charts, the eCRF (including the addition of an eCRF to capture data from the Respimat® dose indicator), and the text of the protocol, or to align procedures in this protocol with the other tiotropium studies. The text was also amended to update information on tiotropium based on recently completed trials and/or recently published data. Entrance criteria were amended as noted in Section 9.3. In addition, there was a change in the sample size description, as a result of which the numbers of patients to be randomised was changed from 125 per treatment group to a total of 375 to clarify that recruitment would continue until overall 375 patients had been randomised.

    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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