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    Clinical Trial Results:
    A Phase III randomised, double blind, placebo-controlled, parallel group study to assess the efficacy and safety over 48 weeks of orally inhaled Tiotropium bromide (2.5 µg and 5 µg once daily ) delivered by the Respimat® inhaler in adolescents (12 to 17 years old) with moderate persistent asthma.

    Summary
    EudraCT number
    		 2010-021093-11
    Trial protocol
    		 LV   HU   ES   SK   IT   DE   NO   Outside EU/EEA  
    Global end of trial date
    27 Dec 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
    205.444
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01257230
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim Pharma GmbH & Co. KG
    Sponsor organisation address
    Binger Strasse 173, 55216 Ingelheim Rhein, Germany,
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure , Boehringer Ingelheim Pharma GmgH & Co. KG, +1 800243 0127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure , Boehringer Ingelheim Pharma GmgH & Co. KG, +1 800243 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
    22 Jan 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jun 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a confirmatory phase III trial to evaluate efficacy and safety of a 48-week treatment with two doses (2.5 μg and 5 μg) of tiotropium bromide compared to placebo administered via the Respimat® device in adolescent patients (12 to 17 years old) with moderate persistent asthma.
    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. Administration of rescue medication was allowed throughout the trial as medically needed. For the screening and treatment periods, open-label salbutamol/albuterol inhalers (100 μg per puff) were provided by the sponsor for use as rescue medication.
    Background therapy
    		 Patients maintained their ICS background therapy.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 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
    Slovakia: 45
    Country: Number of subjects enrolled
    Spain: 37
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Hungary: 135
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Latvia: 81
    Country: Number of subjects enrolled
    Chile: 57
    Country: Number of subjects enrolled
    Korea, Republic of: 29
    Country: Number of subjects enrolled
    Mexico: 19
    Country: Number of subjects enrolled
    Russian Federation: 71
    Country: Number of subjects enrolled
    Ukraine: 93
    Country: Number of subjects enrolled
    United States: 67
    Worldwide total number of subjects
    673
    EEA total number of subjects
    337
    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)
    672
    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 specialist sites which would then ensure that they (the subjects) met all strict inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any specific entry criteria were violated. Thus, out of 673 enrolled, 398 subjects were randomized.

    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
    		 Placebo respimat
    Arm description
    		 Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo respimat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Patients received placebo (tiotropium-matching placebo solution for inhalation). The patients were to inhale 2 puffs from the Respimat® inhaler (placebo) every evening.

    Arm title
    		 Tio R2.5
    Arm description
    		 Inhalation of 2.5μg tiotropium bromide solution (Tio R2.5) once daily for 48 weeks, delivered by the Respimat Inhaler.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Patients received 2.5 μg tiotropium (Tio R2.5). The patients were to inhale 2 puffs (1.25 mcg of tiotropium) per puff from the Respimat® inhaler every evening.

    Arm title
    		 Tio R5
    Arm description
    		 Inhalation of 5μg tiotropium bromide solution (Tio R5) once daily for 48 weeks, delivered by the Respimat Inhaler. One subject was not treated thus was not considered as starter nor non-completer.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Patients received 5 μg tiotropium (Tio R5). The patients were to inhale 2 puffs (2.5 mcg of tiotropium) from the Respimat® inhaler every evening.

    Number of subjects in period 1 [1]
    		Placebo respimat Tio R2.5 Tio R5
    Started
    138
    125
    134
    Completed
    132
    115
    129
    Not completed
    6
    10
    5
         Consent withdrawn by subject
    -
    4
    1
         Adverse event, non-fatal
    2
    -
    -
         Protocol deviation
    3
    -
    1
         not specified
    1
    5
    -
         Lack of efficacy
    -
    1
    -
         Reasons other than stated above
    -
    -
    3
    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. One patient in the Tio R5 arm has started but was not treated, thus does not feature in this flowchart.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo respimat
    Reporting group description
    		 Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler.

    Reporting group title
    Tio R2.5
    Reporting group description
    		 Inhalation of 2.5μg tiotropium bromide solution (Tio R2.5) once daily for 48 weeks, delivered by the Respimat Inhaler.

    Reporting group title
    Tio R5
    Reporting group description
    		 Inhalation of 5μg tiotropium bromide solution (Tio R5) once daily for 48 weeks, delivered by the Respimat Inhaler. One subject was not treated thus was not considered as starter nor non-completer.

    Reporting group values
    		 Placebo respimat Tio R2.5 Tio R5 Total
    Number of subjects
    		 138 125 134 397
    Age categorical
    Units: Subjects
    Age continuous
    Treated set (TS) which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication. TS was used in the description.
    Units: years
        arithmetic mean (standard deviation)
    		 14.2 ± 1.7 14.2 ± 1.8 14.5 ± 1.6 -
    Gender categorical
    Treated Set (TS)
    Units: Subjects
        Female
    		 50 44 45 139
        Male
    		 88 81 89 258

    End points

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    End points reporting groups
    Reporting group title
    Placebo respimat
    Reporting group description
    		 Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler.

    Reporting group title
    Tio R2.5
    Reporting group description
    		 Inhalation of 2.5μg tiotropium bromide solution (Tio R2.5) once daily for 48 weeks, delivered by the Respimat Inhaler.

    Reporting group title
    Tio R5
    Reporting group description
    		 Inhalation of 5μg tiotropium bromide solution (Tio R5) once daily for 48 weeks, delivered by the Respimat Inhaler. One subject was not treated thus was not considered as starter nor non-completer.

    Primary: FEV1 peak0-3 Change From Baseline

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    End point title
    		 FEV1 peak0-3 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 24. Note, the measured values presented are actually adjusted means. Full analysis set (FAS) was the same as the treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication. Missing data at a visit was imputed by the available data from the patient at that visit, completely missing visits were handled by the statistical model. In FAS we have 138, 125, 134 patients in each of 3 treatment arms. Currently reported numbers are numbers of patients with endpoint at week 24 (from MMRM output).
    End point type
    Primary
    End point timeframe
    baseline and 24 weeks
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    137 [1]
    120 [2]
    131 [3]
    Units: litre(s)
        least squares mean (standard error)
    0.373 ± 0.037
    0.507 ± 0.04
    0.547 ± 0.038
    Notes
    [1] - Full Analysis Set (FAS)
    [2] - FAS
    [3] - FAS
    Statistical analysis title
    		 Placebo vs Tio R2.5
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based Mixed Model Repeated Measures (MMRM). Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction. Patient was included as a random effect in the model. Difference calculated as Tio R2.5 minus placebo
    Comparison groups
    Placebo respimat v Tio R2.5
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0085 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.134
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.034
         upper limit
    		 0.234
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.051
    Notes
    [4] - 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
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model.
    Comparison groups
    Tio R5 v Placebo respimat
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.174
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.076
         upper limit
    		 0.272
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Notes
    [5] - 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 24. The measured values presented are actually adjusted means. In FAS we have 138, 125, 134 patients in each of 3 treatment arms. Currently reported numbers are numbers of patients with endpoint at week 24 (from MMRM output).
    End point type
    Secondary
    End point timeframe
    baseline and 24 weeks
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    137 [6]
    119 [7]
    131 [8]
    Units: litre(s)
        least squares mean (standard error)
    0.283 ± 0.04
    0.367 ± 0.044
    0.4 ± 0.041
    Notes
    [6] - FAS
    [7] - FAS
    [8] - FAS
    Statistical analysis title
    		 Placebo vs Tio R2.5
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R2.5 minus placebo.
    Comparison groups
    Placebo respimat v Tio R2.5
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1307 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.084
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.025
         upper limit
    		 0.194
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.056
    Notes
    [9] - 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
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R5 minus placebo
    Comparison groups
    Placebo respimat v Tio R5
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.032 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.117
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.223
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.054
    Notes
    [10] - Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo.

    Secondary: FVC peak0-3 Change From Baseline

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    End point title
    		 FVC peak0-3 Change From Baseline
    End point description
    Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 h after administration of trial medication (FVC peak0–3h) after 24 weeks of treatment. The measured values presented are actually adjusted means. In FAS we have 138, 125, 134 patients in each of 3 treatment arms. Currently reported numbers are numbers of patients with endpoint at week 24 (from MMRM output).
    End point type
    Secondary
    End point timeframe
    baseline and 24 weeks
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    137 [11]
    120 [12]
    131 [13]
    Units: litre(s)
        least squares mean (standard error)
    0.331 ± 0.041
    0.419 ± 0.045
    0.403 ± 0.043
    Notes
    [11] - FAS
    [12] - FAS
    [13] - FAS
    Statistical analysis title
    		 Placebo vs Tio R2.5
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R2.5 minus placebo
    Comparison groups
    Placebo respimat v Tio R2.5
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1231
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.088
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.024
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.057
    Statistical analysis title
    		 Placebo vs Tio R5
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R5 minus placebo
    Comparison groups
    Placebo respimat v Tio R5
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.195
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.072
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.037
         upper limit
    		 0.182
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.056

    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 h for FEV1 (FEV1 AUC 0–3h) after 24 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). The measured values presented are actually adjusted means. In FAS we have 138, 125, 134 patients in each of 3 treatment arms. Currently reported numbers are numbers of patients with endpoint at week 24.
    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 24 weeks.
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    137 [14]
    119 [15]
    131 [16]
    Units: litre(s)
        least squares mean (standard error)
    0.281 ± 0.035
    0.411 ± 0.038
    0.463 ± 0.036
    Notes
    [14] - FAS
    [15] - FAS
    [16] - FAS
    Statistical analysis title
    		 Placebo vs Tio R2.5
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R2.5 minus placebo
    Comparison groups
    Placebo respimat v Tio R2.5
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0079
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.034
         upper limit
    		 0.225
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.049
    Statistical analysis title
    		 Tio R5 vs Placebo
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R5 minus placebo
    Comparison groups
    Tio R5 v Placebo respimat
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.181
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.088
         upper limit
    		 0.275
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.048

    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 h for FVC (FVC AUC0–3h) after 24 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). The measured values presented are actually adjusted means. In FAS we have 138, 125, 134 patients in each of 3 treatment arms. Currently reported numbers are numbers of patients with endpoint at week 24 (from MMRM output).
    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 24 weeks.
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    137 [17]
    119 [18]
    131 [19]
    Units: litre(s)
        least squares mean (standard error)
    0.24 ± 0.039
    0.33 ± 0.042
    0.311 ± 0.04
    Notes
    [17] - FAS
    [18] - FAS
    [19] - FAS
    Statistical analysis title
    		 Placebo vs Tio R2.5
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R2.5 minus placebo
    Comparison groups
    Placebo respimat v Tio R2.5
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0945
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.016
         upper limit
    		 0.196
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.054
    Statistical analysis title
    		 Placebo vs Tio R5
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R5 minus placebo
    Comparison groups
    Placebo respimat v Tio R5
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1755
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.071
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.032
         upper limit
    		 0.175
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.053

    Secondary: Trough FVC Change From Baseline

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    End point title
    		 Trough FVC Change From Baseline
    End point description
    Change from baseline of Trough (pre-dose) forced vital capacity (FVC) measured 10 min before the administration of trial medication after 24 weeks of treatment. The measured values presented are actually adjusted means. In FAS we have 138, 125, 134 patients in each of 3 treatment arms. Currently reported numbers are numbers of patients with endpoint at week 24 (from MMRM output).
    End point type
    Secondary
    End point timeframe
    baseline and 24 weeks
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    137 [20]
    119 [21]
    131 [22]
    Units: litre(s)
        least squares mean (standard error)
    0.281 ± 0.043
    0.345 ± 0.047
    0.316 ± 0.045
    Notes
    [20] - FAS
    [21] - FAS
    [22] - FAS
    Statistical analysis title
    		 Placebo vs Tio R2.5
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R2.5 minus placebo
    Comparison groups
    Placebo respimat v Tio R2.5
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2921
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.063
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.055
         upper limit
    		 0.181
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Statistical analysis title
    		 Placebo vs Tio R5
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R5 minus placebo
    Comparison groups
    Placebo respimat v Tio R5
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5495
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.035
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.059

    Secondary: FEF25-75 Change From Baseline

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    End point title
    		 FEF25-75 Change From Baseline
    End point description
    Change from baseline in mean forced expiratory flow between 25% and 75% of the FVC (FEF25-75%), also known as maximum mid-expiratory flow, at individual time points after 24 weeks of treatment. The measured values presented are actually adjusted means. In FAS we have 138, 125, 134 patients in each of 3 treatment arms. Currently reported numbers are numbers of patients with endpoint at week 24.
    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 24 weeks.
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    137 [23]
    120 [24]
    131 [25]
    Units: litre(s)/Sec
    least squares mean (standard error)
        10 minutes pre-dose (N1=137, N2=119, N3=131)
    0.332 ± 0.072
    0.461 ± 0.079
    0.609 ± 0.074
        30 minutes post-dose (N1=137, N2=120, N3=131)
    0.372 ± 0.066
    0.536 ± 0.072
    0.763 ± 0.068
        1 hour post-dose (N1=137, N2=120, N3=131)
    0.359 ± 0.067
    0.596 ± 0.072
    0.835 ± 0.069
        2 hours post-dose (N1=137, N2=120, N3=131)
    0.403 ± 0.069
    0.615 ± 0.075
    0.857 ± 0.071
        3 hours post=dose (N1=137, N2=120, N3=131)
    0.347 ± 0.068
    0.653 ± 0.074
    0.85 ± 0.07
    Notes
    [23] - FAS
    [24] - FAS
    [25] - FAS
    No statistical analyses for this end point

    Secondary: Use of PRN Rescue Medication During the Day

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    End point title
    		 Use of PRN Rescue Medication During the Day
    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 24. The measured values presented are actually adjusted means. In FAS we have 138, 125, 134 patients in each of 3 treatment arms. Currently reported numbers are numbers of patients with endpoint at week 24 (from MMRM output).
    End point type
    Secondary
    End point timeframe
    baseline and 24 weeks
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    135 [26]
    117 [27]
    125 [28]
    Units: Number of puff(s) of rescue medication
        least squares mean (standard error)
    -0.524 ± 0.098
    -0.556 ± 0.104
    -0.48 ± 0.1
    Notes
    [26] - FAS
    [27] - FAS
    [28] - FAS
    Statistical analysis title
    		 Placebo vs Tio R2.5 at week 24
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R2.5 minus placebo
    Comparison groups
    Placebo respimat v Tio R2.5
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8253
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.032
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.312
         upper limit
    		 0.249
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.143
    Statistical analysis title
    		 Placebo vs Tio R5 at week 24
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R5 minus placebo
    Comparison groups
    Placebo respimat v Tio R5
    Number of subjects included in analysis
    260
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7559
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.044
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.232
         upper limit
    		 0.319
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.14

    Secondary: Use of PRN Rescue Medication During the Daytime

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    End point title
    		 Use of PRN Rescue Medication During the Daytime
    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 24. The measured values presented are actually adjusted means. In FAS we have 138, 125, 134 patients in each of 3 treatment arms. Currently reported numbers are numbers of patients with endpoint at week 24.
    End point type
    Secondary
    End point timeframe
    baseline and 24 weeks
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    132 [29]
    114 [30]
    122 [31]
    Units: Number of puff(s) of rescue medication
        least squares mean (standard error)
    -0.206 ± 0.066
    -0.209 ± 0.071
    -0.215 ± 0.068
    Notes
    [29] - FAS
    [30] - FAS
    [31] - FAS
    Statistical analysis title
    		 Placebo vs Tio R2.5 at week 24
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R2.5 minus placebo
    Comparison groups
    Placebo respimat v Tio R2.5
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.976
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.184
         upper limit
    		 0.178
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.092
    Statistical analysis title
    		 Placebo vs Tio R5 at week 24
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R5 minus placebo
    Comparison groups
    Placebo respimat v Tio R5
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9224
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.009
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.186
         upper limit
    		 0.168
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09

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

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    End point title
    		 Use of PRN Rescue Medication During the Night-time
    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 24. The measured values presented are actually adjusted means. In FAS we have 138, 125, 134 patients in each of 3 treatment arms. Currently reported numbers are numbers of patients with endpoint at week 24 (from MMRM output).
    End point type
    Secondary
    End point timeframe
    baseline and 24 weeks
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    132 [32]
    110 [33]
    124 [34]
    Units: Number of puff(s) of rescue medication
        least squares mean (standard error)
    -0.144 ± 0.059
    -0.122 ± 0.064
    -0.032 ± 0.061
    Notes
    [32] - FAS
    [33] - FAS
    [34] - FAS
    Statistical analysis title
    		 Tio R2.5 vs Placebo at week 24
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R2.5 minus placebo
    Comparison groups
    Tio R2.5 v Placebo respimat
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7852
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.023
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 0.185
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.083
    Statistical analysis title
    		 Placebo vs Tio R5 at week 24
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R5 minus placebo
    Comparison groups
    Placebo respimat v Tio R5
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1649
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.112
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.046
         upper limit
    		 0.271
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.081

    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
    Change from baseline in Asthma Control Questionnaire (ACQ) total score measured at week 24. 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. The measured values presented are actually adjusted means. In FAS we have 138, 125, 134 patients in each of 3 treatment arms. Currently reported numbers are numbers of patients with endpoint at week 24.
    End point type
    Secondary
    End point timeframe
    baseline and 24 weeks
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    136 [35]
    120 [36]
    132 [37]
    Units: unit(s) of ACQ scores
        least squares mean (standard error)
    1.213 ± 0.062
    1.053 ± 0.067
    1.116 ± 0.064
    Notes
    [35] - FAS
    [36] - FAS
    [37] - FAS
    Statistical analysis title
    		 Placebo vs Tio R2.5 at week 24
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R2.5 minus placebo
    Comparison groups
    Placebo respimat v Tio R2.5
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0653
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.087
    Statistical analysis title
    		 Placebo vs Tio R5 at week 24
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R5 minus placebo
    Comparison groups
    Placebo respimat v Tio R5
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2516
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.097
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.263
         upper limit
    		 0.069
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.084

    Secondary: Control of Asthma as Assessed by ACQ6

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    End point title
    		 Control of Asthma as Assessed by ACQ6
    End point description
    Change from baseline in AQC6 score at week 24. The ACQ6 score is calculated as the mean of the responses to the first 6 questions of the ACQ. 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. The measured values presented are actually adjusted means. In FAS we have 138, 125, 134 patients in each of 3 treatment arms. Currently reported numbers are numbers of patients with endpoint at week 24.
    End point type
    Secondary
    End point timeframe
    baseline and 24 weeks
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    136 [38]
    120 [39]
    132 [40]
    Units: unit(s) of ACQ6 score
        least squares mean (standard error)
    1.173 ± 0.068
    1.026 ± 0.073
    1.119 ± 0.07
    Notes
    [38] - FAS
    [39] - FAS
    [40] - FAS
    Statistical analysis title
    		 Placebo vs Tio R2.5 at week 24
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R2.5 minus placebo
    Comparison groups
    Placebo respimat v Tio R2.5
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.147
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.333
         upper limit
    		 0.038
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.095
    Statistical analysis title
    		 Placebo vs Tio R5 at week 24
    Statistical analysis description
    Using a restricted maximum likelihood (REML)-based MMRM. Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline-by-week-interaction Patient was included as a random effect in the model. Difference calculated as Tio R5 minus placebo
    Comparison groups
    Placebo respimat v Tio R5
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5589
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.054
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.235
         upper limit
    		 0.127
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.092

    Secondary: ACQ6 Responders

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    End point title
    		 ACQ6 Responders
    End point description
    Responder rates based on the ACQ6 after 24 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 ACQ6 score is calculated as the mean of the responses to the first 6 questions of the ACQ. 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.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    138 [41]
    125 [42]
    134 [43]
    Units: percentage of participants
    number (not applicable)
        responder
    69.6
    76.8
    72.4
        no change
    22.5
    20
    23.1
        worsening
    8
    3.2
    4.5
    Notes
    [41] - FAS
    [42] - FAS
    [43] - FAS
    No statistical analyses for this end point

    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 24 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.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    138 [44]
    125 [45]
    134 [46]
    Units: percentage of participants
    number (not applicable)
        responder
    66.7
    76
    74.6
        no change
    27.5
    21.6
    23.1
        worsening
    5.8
    2.4
    2.2
    Notes
    [44] - FAS
    [45] - FAS
    [46] - FAS
    No statistical analyses for this end point

    Secondary: Time to First Severe Asthma Exacerbation During the 48 Week Treatment Period

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    End point title
    		 Time to First Severe Asthma Exacerbation During the 48 Week Treatment Period
    End point description
    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 treatment with systemic corticosteroid for at least 3 days.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    138 [47]
    125 [48]
    134 [49]
    Units: participant(s)
    number (not applicable)
        cumulative failure
    9
    5
    2
        cumulative censored
    129
    120
    132
    Notes
    [47] - FAS
    [48] - FAS
    [49] - FAS
    Statistical analysis title
    		 Placebo vs Tio R2.5 during 48 weeks treatment
    Statistical analysis description
    Cox's proportional hazard regression model with treatment as an effect.
    Comparison groups
    Placebo respimat v Tio R2.5
    Number of subjects included in analysis
    263
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4023
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 1.87
    Statistical analysis title
    		 Placebo vs Tio R5 during 48 weeks treatment
    Statistical analysis description
    Cox's proportional hazard regression model with treatment as an effect.
    Comparison groups
    Placebo respimat v Tio R5
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.062
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 1.08

    Secondary: Time to First Asthma Exacerbation During the 48 Week Treatment Period

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    End point title
    		 Time to First Asthma Exacerbation During the 48 Week Treatment Period
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 Placebo respimat Tio R2.5 Tio R5
    Number of subjects analysed
    138 [50]
    125 [51]
    134 [52]
    Units: participants
    number (not applicable)
        cumulative failure
    37
    34
    30
        cumulative censored
    101
    91
    104
    Notes
    [50] - FAS
    [51] - FAS
    [52] - FAS
    Statistical analysis title
    		 Placebo vs Tio R2.5 during 48 weeks treatment
    Statistical analysis description
    Cox's proportional hazard regression model with treatment as an effect.
    Comparison groups
    Placebo respimat v Tio R2.5
    Number of subjects included in analysis
    263
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.87
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.66
    Statistical analysis title
    		 Placebo vs Tio R5 during 48 weeks treatment
    Statistical analysis description
    Cox's proportional hazard regression model with treatment as an effect.
    Comparison groups
    Placebo respimat v Tio R5
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4198
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.33

    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 416 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 48 weeks, delivered by the Respimat Inhaler.

    Reporting group title
    Tio R2.5
    Reporting group description
    		 Inhalation of 2.5μg tiotropium bromide solution (Tio R2.5) once daily for 48 weeks, delivered by the Respimat Inhaler.

    Reporting group title
    Tio R5
    Reporting group description
    		 Inhalation of 5μg tiotropium bromide solution (Tio R5) once daily for 48 weeks, delivered by the Respimat Inhaler.

    Serious adverse events
    		 Placebo Tio R2.5 Tio R5
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 138 (1.45%)
    2 / 125 (1.60%)
    3 / 134 (2.24%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Teratoma
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 125 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arterial injury
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 125 (0.80%)
    0 / 134 (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
    Hepatic rupture
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 125 (0.80%)
    0 / 134 (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
    Multiple injuries
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 125 (0.80%)
    0 / 134 (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
    Wound
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 125 (0.80%)
    0 / 134 (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
    Immune system disorders
    Allergy to plants
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 125 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 125 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 125 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 125 (0.80%)
    0 / 134 (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
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 125 (0.80%)
    0 / 134 (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
    Retroperitoneal haematoma
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 125 (0.80%)
    0 / 134 (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
    Hepatobiliary disorders
    Liver injury
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 125 (0.80%)
    0 / 134 (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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 125 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Compartment syndrome
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 125 (0.80%)
    0 / 134 (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
    Appendicitis
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 125 (0.80%)
    0 / 134 (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
    Gastroenteritis
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 125 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Tio R2.5 Tio R5
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    62 / 138 (44.93%)
    55 / 125 (44.00%)
    62 / 134 (46.27%)
    Investigations
    Peak expiratory flow rate decreased
         subjects affected / exposed
    8 / 138 (5.80%)
    9 / 125 (7.20%)
    6 / 134 (4.48%)
         occurrences all number
    21
    21
    18
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 138 (1.45%)
    7 / 125 (5.60%)
    9 / 134 (6.72%)
         occurrences all number
    8
    15
    17
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    32 / 138 (23.19%)
    27 / 125 (21.60%)
    23 / 134 (17.16%)
         occurrences all number
    81
    57
    41
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    17 / 138 (12.32%)
    13 / 125 (10.40%)
    20 / 134 (14.93%)
         occurrences all number
    24
    15
    27
    Respiratory tract infection viral
         subjects affected / exposed
    11 / 138 (7.97%)
    11 / 125 (8.80%)
    10 / 134 (7.46%)
         occurrences all number
    14
    12
    11
    Tonsillitis
         subjects affected / exposed
    7 / 138 (5.07%)
    2 / 125 (1.60%)
    1 / 134 (0.75%)
         occurrences all number
    7
    2
    1
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 138 (4.35%)
    2 / 125 (1.60%)
    7 / 134 (5.22%)
         occurrences all number
    6
    2
    7
    Viral infection
         subjects affected / exposed
    6 / 138 (4.35%)
    5 / 125 (4.00%)
    7 / 134 (5.22%)
         occurrences all number
    6
    5
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Feb 2011
    Global amendment no. 1 (dated 18 Feb 2011) was limited to administrative changes, corrections and clarifications. To follow the project standard and to establish consistency between studies, the definition for treatment-emergent AEs was extended to include all AEs occurring until 30 days (instead of 21 days as stipulated in the original protocol) after the last intake of trial drug.
    06 May 2011
    Significant changes to the CTP introduced by global amendment no. 2 (dated 06 May 2011) were to allow reversibility testing for inclusion criterion no. 7 to be repeated once within 2 weeks if the patient did not reverse sufficiently during the first test, and correction of the reporting period for both AEs and SAEs to until 30 days after the last intake of trial drug.
    06 Feb 2012
    Significant changes to the CTP introduced by global amendment no. 3 (dated 06 Feb 2012) included an increase in the washout period prior to Visit 1 for LABAs given twice daily from 24 h to 72 h (3 days) and for LABAs given once daily from 48 hours to 4 days to avoid their influence on screening spirometry values. Other changes included clarification of (S)AE reporting, and addition of AEs that are defined as ‘always serious adverse events’. Completion of question 7 of the ACQ at Visits 4, 6, and 8 was to be performed during programming of the dataset for the CTR and not by data management. The sample size was increased from 81 randomised patients per treatment group to 127 randomised patients per treatment group following an update to the expected SD for the primary endpoint of change from trial baseline in FEV1 peak0–3h from 270 mL to 340 mL (based on the results from previous trials of tiotropium in asthma).

    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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