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    Clinical Trial Results:
    A phase II/III, randomised, double-blind, placebo-controlled, parallel group trial to evaluate safety and efficacy of tiotropium inhalation solution (2.5 µg and 5 µg) administered once daily in the afternoon via Respimat® Inhaler for 12 weeks in patients 1 to 5 years old with persistent asthma

    Summary
    EudraCT number
    		 2011-005512-28
    Trial protocol
    		 NL   LT   LV   FI   DE   BE  
    Global end of trial date
    04 Dec 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    205.443
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01634113
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim Pharma GmbH & Co.KG
    Sponsor organisation address
    Binger Strasse 173 , Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim Pharma GmbH & Co.KG, +1 800 243 0127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim Pharma GmbH & Co.KG, +1 800 243 0127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000035-PIP02-09
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Nov 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial is to evaluate the safety and efficacy of two doses of tiotropium inhalation solution delivered via the Respimat® inhaler once daily in the afternoon in patients (1 to 5 years old) with persistent asthma on top of at least inhaled corticosteroid (ICS) treatment.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be randomised to trial treatment. 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. Salbutamol (albuterol) was provided as rescue medication for use as necessary during the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jul 2012
    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
    Belgium: 11
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Korea, Republic of: 11
    Country: Number of subjects enrolled
    Latvia: 18
    Country: Number of subjects enrolled
    Lithuania: 5
    Country: Number of subjects enrolled
    Malaysia: 8
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Philippines: 4
    Country: Number of subjects enrolled
    Ukraine: 28
    Country: Number of subjects enrolled
    United States: 22
    Worldwide total number of subjects
    129
    EEA total number of subjects
    56
    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)
    23
    Children (2-11 years)
    106
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all strictly implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo Respimat
    Arm description
    		 Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler.
    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
    2 actuations once daily in the afternoon. Dose not applicable.

    Arm title
    		 Tio R2.5
    Arm description
    		 Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
    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 actuations once daily in the afternoon, for a total dose of 2.5 μg.

    Arm title
    		 Tio R5
    Arm description
    		 Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler. One patient was randomised to the Tio R5 treatment arm, however this patient was not treated. Consequently, even though the actual number of subjects that started is 32, only 31 were reported to ensure consistent reporting with baseline characteristics which include only treated patients.
    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 actuations once daily in the afternoon, for a total dose of 5 μg.

    Number of subjects in period 1 [1]
    		Placebo Respimat Tio R2.5 Tio R5
    Started
    34
    36
    31
    Completed
    34
    36
    31
    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 dose of the trial medication.

    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 12 weeks, delivered by the Respimat Inhaler.

    Reporting group title
    Tio R2.5
    Reporting group description
    		 Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.

    Reporting group title
    Tio R5
    Reporting group description
    		 Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler. One patient was randomised to the Tio R5 treatment arm, however this patient was not treated. Consequently, even though the actual number of subjects that started is 32, only 31 were reported to ensure consistent reporting with baseline characteristics which include only treated patients.

    Reporting group values
    		 Placebo Respimat Tio R2.5 Tio R5 Total
    Number of subjects
    		 34 36 31 101
    Age categorical
    Units: Subjects
    Age Continuous
    Treated set (TS) which included all randomised patients who received at least one dose of trial medication represents the baseline analysis population.
    Units: years
        arithmetic mean (standard deviation)
    		 3.2 ( 1.4 ) 3.1 ( 1.5 ) 3.1 ( 1.3 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 13 17 10 40
        Male
    		 21 19 21 61

    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 12 weeks, delivered by the Respimat Inhaler.

    Reporting group title
    Tio R2.5
    Reporting group description
    		 Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.

    Reporting group title
    Tio R5
    Reporting group description
    		 Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler. One patient was randomised to the Tio R5 treatment arm, however this patient was not treated. Consequently, even though the actual number of subjects that started is 32, only 31 were reported to ensure consistent reporting with baseline characteristics which include only treated patients.

    Primary: Weekly mean combined daytime asthma symptom score

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    End point title
    		 Weekly mean combined daytime asthma symptom score
    End point description
    Change from baseline in weekly mean combined daytime asthma symptom score as assessed by the Paediatric Asthma Caregivers Diary (PACD) in last week (wk) of 12 wk treatment period. Diary consists of 3 questions to be answered each morning and 7 questions to be answered each evening. A week was defined as 7 days. Combined daytime score is the average of scores from questions 4 – 7 which are questions regarding severity of cough, wheezing, trouble breathing and interference with activities, scores for each question range from 0 (best) to 5 (worst). The wk 12 weekly mean is mean of the responses for each day averaged over the 7 days in wk 12, so combined daytime asthma symptom scores also range from 0 (best) to 5 (worst). The measured values presented are adjusted means. Full analysis set (FAS) included all randomised patients who received at least one dose of trial medication. Missing data was imputed by available data from patient during that wk, but no imputation for wks with no data.
    End point type
    Primary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo Respimat Tio R2.5 Tio R5
    Number of subjects analysed
    34 [1]
    36 [2]
    30 [3]
    Units: units on a scale
        arithmetic mean (standard error)
    -0.456 ( 0.084 )
    -0.535 ( 0.082 )
    -0.504 ( 0.089 )
    Notes
    [1] - FAS including patients with available endpoint data at week 12
    [2] - FAS including patients with available endpoint data at week 12
    [3] - FAS including patients with available endpoint data at week 12
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis of covariance (ANCOVA) was used. This ANCOVA model included the fixed, categorical effect of treatment as well as continuous fixed covariate of baseline. Difference calculated as Tio R2.5 minus placebo.
    Comparison groups
    Placebo Respimat v Tio R2.5
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.4963
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.312
         upper limit
    		 0.152
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.117
    Notes
    [4] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis of covariance (ANCOVA) was used. This ANCOVA model included the fixed, categorical effect of treatment as well as continuous fixed covariate of baseline. Difference calculated as Tio R5 minus placebo.
    Comparison groups
    Placebo Respimat v Tio R5
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.6936
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.048
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.292
         upper limit
    		 0.195
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.123
    Notes
    [5] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

    Primary: FEV1 peak (0-3h) Change From Baseline

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    End point title
    		 FEV1 peak (0-3h) Change From Baseline [6]
    End point description
    Change from baseline in peak Forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak (0-3h)) measured at week 12. Full analysis set (FAS) represents the analysed population. No imputation for missing data was employed.
    End point type
    Primary
    End point timeframe
    10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing was performed.
    End point values
    		 Placebo Respimat Tio R2.5 Tio R5
    Number of subjects analysed
    4 [7]
    7 [8]
    2 [9]
    Units: Litres
        arithmetic mean (standard deviation)
    0.158 ( 0.026 )
    0.13 ( 0.125 )
    0.145 ( 0.078 )
    Notes
    [7] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [8] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [9] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    No statistical analyses for this end point

    Secondary: Weekly mean Overnight asthma symptom score response

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    End point title
    		 Weekly mean Overnight asthma symptom score response
    End point description
    Change from baseline in weekly mean overnight asthma symptom score response as assessed by PACD in the last wk of 12 wk treatment period. Overnight score is score from the following question in PACD, "How much did your child cough last night after your child was put to bed for night until he/she awoke this morning?".This endpoint was determined only for patients with 2 or more nights with symptoms per week during baseline period. In this case, the baseline period is 7 days used to derive baseline value. Patient has a night with symptoms if question was answered with scores 1, 2, 3, 4 or 5 or patient received β-Agonist at least one time since he/she went to bed. Week was defined as 7 days. Scores range from 0 (best) to 4 (worst), value of 5 indicates severity of symptoms is unknown. Measured values presented are adjusted means. FAS represents analysed population. Missing data in a wk was imputed by available data from patient during that wk, but no imputation for wks with no data.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo Respimat Tio R2.5 Tio R5
    Number of subjects analysed
    31 [10]
    31 [11]
    28 [12]
    Units: units on a scale
        arithmetic mean (standard error)
    -0.671 ( 0.11 )
    -0.588 ( 0.111 )
    -0.655 ( 0.116 )
    Notes
    [10] - FAS including patients with available endpoint data at week 12
    [11] - FAS including patients with available endpoint data at week 12
    [12] - FAS including patients with available endpoint data at week 12
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis of covariance (ANCOVA) was used. This ANCOVA model included the fixed, categorical effect of treatment as well as continuous fixed covariate of baseline. Difference calculated as Tio R2.5 minus placebo.
    Comparison groups
    Placebo Respimat v Tio R2.5
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.5995
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.083
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.229
         upper limit
    		 0.394
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.157
    Notes
    [13] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis of covariance (ANCOVA) was used. This ANCOVA model included the fixed, categorical effect of treatment as well as continuous fixed covariate of baseline. Difference calculated as Tio R5 minus placebo.
    Comparison groups
    Placebo Respimat v Tio R5
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.9251
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.015
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.303
         upper limit
    		 0.333
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Notes
    [14] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

    Secondary: Weekly Percentage of days without asthma symptoms

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    End point title
    		 Weekly Percentage of days without asthma symptoms
    End point description
    Weekly Percentage of days without asthma symptoms at wk 12. A day without asthma symptoms was defined as a day during which the patient experienced no asthma symptoms, did not use rescue medication (salbutamol/albuterol) and had no asthma exacerbation/worsening requiring systemic corticosteroids, or unscheduled visits to a doctor’s office, emergency department, or hospital. A week was defined as 7 days. The measured values presented are adjusted means. FAS represents analysed population. Missing data in a wk was imputed by available data from patient during that wk, but no imputation for wks with no data.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Respimat Tio R2.5 Tio R5
    Number of subjects analysed
    34 [15]
    36 [16]
    30 [17]
    Units: percentage of days
        arithmetic mean (standard error)
    53.151 ( 7.405 )
    55.401 ( 7.181 )
    50.654 ( 7.873 )
    Notes
    [15] - FAS, including patients with available endpoint data at week 12
    [16] - FAS, including patients with available endpoint data at week 12
    [17] - FAS, including patients with available endpoint data at week 12
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis of covariance (ANCOVA) was used. This ANCOVA model included the fixed, categorical effect of treatment as well as continuous fixed covariate of baseline. Difference calculated as Tio R2.5 minus placebo.
    Comparison groups
    Placebo Respimat v Tio R2.5
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.8279
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.243
         upper limit
    		 22.743
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.324
    Notes
    [18] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis of covariance (ANCOVA) was used. This ANCOVA model included the fixed, categorical effect of treatment as well as continuous fixed covariate of baseline. Difference calculated as Tio R5 minus placebo.
    Comparison groups
    Placebo Respimat v Tio R5
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.8181
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.497
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.987
         upper limit
    		 18.994
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.826
    Notes
    [19] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

    Secondary: Weekly percentage of days with use of salbutamol (albuterol) rescue medication

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    End point title
    		 Weekly percentage of days with use of salbutamol (albuterol) rescue medication
    End point description
    Weekly percentage of days with use of salbutamol (albuterol) rescue medication at wk 12. A week was defined as 7 days. FAS represents analysed population. Missing data in a wk was imputed by available data from patient during that wk, but no imputation for wks with no data.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Respimat Tio R2.5 Tio R5
    Number of subjects analysed
    34 [20]
    36 [21]
    30 [22]
    Units: percentage of days
        arithmetic mean (standard deviation)
    24.94 ( 36.8 )
    24.23 ( 36.86 )
    24.88 ( 38.45 )
    Notes
    [20] - FAS, including patients with available endpoint data at week 12
    [21] - FAS, including patients with available endpoint data at week 12
    [22] - FAS, including patients with available endpoint data at week 12
    No statistical analyses for this end point

    Secondary: Weekly mean nighttime awakenings due to asthma symptoms

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    End point title
    		 Weekly mean nighttime awakenings due to asthma symptoms
    End point description
    Change from baseline in the weekly mean nighttime awakenings due to asthma symptoms as assessed by the PACD, in the last wk of the 12 wk treatment period. The weekly mean was calculated as the average of the weekly scores for the question “Did your child wake up during the night due to his/her asthma?” The question was answered on a 5-point verbal rating scale, with scores ranging from 1 (did not wake up) to 5 (was awake all night). A week was defined as 7 days. The measured values presented are adjusted means. FAS represents analysed population. Missing data in a wk was imputed by available data from patient during that wk, but no imputation for wks with no data.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo Respimat Tio R2.5 Tio R5
    Number of subjects analysed
    34 [23]
    36 [24]
    31 [25]
    Units: units on a scale
        arithmetic mean (standard error)
    -0.318 ( 0.08 )
    -0.257 ( 0.078 )
    -0.392 ( 0.084 )
    Notes
    [23] - FAS, including patients with available endpoint data at week 12
    [24] - FAS, including patients with available endpoint data at week 12
    [25] - FAS, including patients with available endpoint data at week 12
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis of covariance (ANCOVA) was used. This ANCOVA model included the fixed, categorical effect of treatment as well as continuous fixed covariate of baseline. Difference calculated as Tio R2.5 minus placebo.
    Comparison groups
    Placebo Respimat v Tio R2.5
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    P-value
    		 = 0.5869
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.061
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.161
         upper limit
    		 0.283
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.112
    Notes
    [26] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis of covariance (ANCOVA) was used. This ANCOVA model included the fixed, categorical effect of treatment as well as continuous fixed covariate of baseline. Difference calculated as Tio R5 minus placebo.
    Comparison groups
    Placebo Respimat v Tio R5
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.523
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.075
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.305
         upper limit
    		 0.156
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.116
    Notes
    [27] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

    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. FAS represents the analysed population. No imputation for missing data was employed.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo Respimat Tio R2.5 Tio R5
    Number of subjects analysed
    4 [28]
    7 [29]
    2 [30]
    Units: Litres
        arithmetic mean (standard deviation)
    0.06 ( 0.032 )
    0.017 ( 0.108 )
    0.085 ( 0.163 )
    Notes
    [28] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [29] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [30] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    No statistical analyses for this end point

    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 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). FAS represents the analysed population. No imputation for missing data was employed.
    End point type
    Secondary
    End point timeframe
    10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12
    End point values
    		 Placebo Respimat Tio R2.5 Tio R5
    Number of subjects analysed
    4 [31]
    7 [32]
    2 [33]
    Units: Litres
        arithmetic mean (standard deviation)
    0.104 ( 0.043 )
    0.072 ( 0.114 )
    0.077 ( 0.116 )
    Notes
    [31] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [32] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [33] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    No statistical analyses for this end point

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

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    End point title
    		 FVC peak (0-3h) 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 peak (0–3h)) after 12 weeks of treatment. FAS represents the analysed population. No imputation for missing data was employed.
    End point type
    Secondary
    End point timeframe
    10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12
    End point values
    		 Placebo Respimat Tio R2.5 Tio R5
    Number of subjects analysed
    4 [34]
    7 [35]
    2 [36]
    Units: Litres
        arithmetic mean (standard deviation)
    0.21 ( 0.054 )
    0.136 ( 0.143 )
    0.06 ( 0.085 )
    Notes
    [34] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [35] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [36] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    No statistical analyses for this end point

    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 12 weeks of treatment. FAS represents the analysed population. No imputation for missing data was employed.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo Respimat Tio R2.5 Tio R5
    Number of subjects analysed
    4 [37]
    7 [38]
    2 [39]
    Units: Litres
        arithmetic mean (standard deviation)
    0.155 ( 0.06 )
    -0.027 ( 0.133 )
    -0.05 ( 0.226 )
    Notes
    [37] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [38] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [39] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    No statistical analyses for this end point

    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 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). FAS represents the analysed population. No imputation for missing data was employed.
    End point type
    Secondary
    End point timeframe
    10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12
    End point values
    		 Placebo Respimat Tio R2.5 Tio R5
    Number of subjects analysed
    4 [40]
    7 [41]
    2 [42]
    Units: Litres
        arithmetic mean (standard deviation)
    0.164 ( 0.037 )
    0.035 ( 0.105 )
    0.003 ( 0.13 )
    Notes
    [40] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [41] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [42] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    No statistical analyses for this end point

    Secondary: Individual FEV1 measurements

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    End point title
    		 Individual FEV1 measurements
    End point description
    Change from baseline in individual FEV1 measurements at each timepoint after 12 weeks. FAS represents the analysed population. No imputation for missing data was employed.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo Respimat Tio R2.5 Tio R5
    Number of subjects analysed
    4 [43]
    7 [44]
    2 [45]
    Units: Litres
    arithmetic mean (standard deviation)
        Time: 0 hours
    0.06 ( 0.03 )
    0.02 ( 0.11 )
    0.09 ( 0.16 )
        Time: 30 minutes
    0.11 ( 0.09 )
    0.03 ( 0.13 )
    0.12 ( 0.11 )
        Time: 1 hour
    0.11 ( 0.08 )
    0.1 ( 0.13 )
    0.12 ( 0.04 )
        Time: 2 hours
    0.12 ( 0.05 )
    0.09 ( 0.13 )
    0.04 ( 0.16 )
        Time: 3 hours
    0.1 ( 0.05 )
    0.06 ( 0.13 )
    0.05 ( 0.11 )
    Notes
    [43] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [44] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [45] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    No statistical analyses for this end point

    Secondary: Individual FVC measurements

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    End point title
    		 Individual FVC measurements
    End point description
    Change from baseline in individual FVC measurements at each timepoint after 12 weeks. FAS represents the analysed population. No imputation for missing data was employed.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo Respimat Tio R2.5 Tio R5
    Number of subjects analysed
    4 [46]
    7 [47]
    2 [48]
    Units: Litres
    arithmetic mean (standard deviation)
        Time: 0 hours
    0.16 ( 0.06 )
    -0.03 ( 0.13 )
    -0.05 ( 0.23 )
        Time: 30 minutes
    0.13 ( 0.07 )
    0.04 ( 0.15 )
    0.06 ( 0.08 )
        Time: 1 hour
    0.18 ( 0.04 )
    0.06 ( 0.14 )
    0.05 ( 0.1 )
        Time: 2 hours
    0.16 ( 0.04 )
    0.02 ( 0.1 )
    -0.03 ( 0.16 )
        Time: 3 hours
    0.19 ( 0.07 )
    0.04 ( 0.13 )
    -0.03 ( 0.13 )
    Notes
    [46] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [47] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    [48] - FAS including only 5 years old capable of providing technical acceptable pulmonary function tests
    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 intake until 30 days after the last drug intake, up to 119 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo Respimat
    Reporting group description
    		 Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler.

    Reporting group title
    Tio R2.5
    Reporting group description
    		 Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler

    Reporting group title
    Tio R5
    Reporting group description
    		 Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler

    Serious adverse events
    		 Placebo Respimat Tio R2.5 Tio R5
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 36 (0.00%)
    0 / 31 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
    0 / 31 (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
    Bronchopneumonia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
    0 / 31 (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 Respimat Tio R2.5 Tio R5
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 34 (70.59%)
    19 / 36 (52.78%)
    16 / 31 (51.61%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
    1 / 31 (3.23%)
         occurrences all number
    0
    3
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 34 (17.65%)
    3 / 36 (8.33%)
    3 / 31 (9.68%)
         occurrences all number
    11
    3
    5
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 36 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    3
    0
    4
    Mouth ulceration
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 36 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    0
    Vomiting
         subjects affected / exposed
    3 / 34 (8.82%)
    3 / 36 (8.33%)
    1 / 31 (3.23%)
         occurrences all number
    3
    4
    1
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 36 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    9 / 34 (26.47%)
    5 / 36 (13.89%)
    2 / 31 (6.45%)
         occurrences all number
    12
    6
    3
    Cough
         subjects affected / exposed
    3 / 34 (8.82%)
    4 / 36 (11.11%)
    2 / 31 (6.45%)
         occurrences all number
    4
    4
    2
    Nasal congestion
         subjects affected / exposed
    1 / 34 (2.94%)
    3 / 36 (8.33%)
    1 / 31 (3.23%)
         occurrences all number
    1
    3
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 36 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    6
    0
    3
    Wheezing
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 36 (2.78%)
    1 / 31 (3.23%)
         occurrences all number
    3
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 36 (2.78%)
    2 / 31 (6.45%)
         occurrences all number
    6
    1
    2
    Ear infection
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 36 (2.78%)
    1 / 31 (3.23%)
         occurrences all number
    2
    1
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 36 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    3
    Nasopharyngitis
         subjects affected / exposed
    5 / 34 (14.71%)
    7 / 36 (19.44%)
    2 / 31 (6.45%)
         occurrences all number
    8
    9
    5
    Pharyngitis
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 36 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    0
    Pneumonia
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 36 (2.78%)
    0 / 31 (0.00%)
         occurrences all number
    2
    1
    0
    Respiratory tract infection viral
         subjects affected / exposed
    4 / 34 (11.76%)
    3 / 36 (8.33%)
    3 / 31 (9.68%)
         occurrences all number
    4
    3
    3
    Rhinitis
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 36 (5.56%)
    3 / 31 (9.68%)
         occurrences all number
    3
    2
    8
    Sinusitis
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 36 (2.78%)
    1 / 31 (3.23%)
         occurrences all number
    2
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 34 (2.94%)
    3 / 36 (8.33%)
    5 / 31 (16.13%)
         occurrences all number
    1
    5
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Dec 2012
    Impulse oscillometry (IOS) was added as an efficacy assessment for children aged 2-5 years (at Visit 1) who were able to perform technically acceptable IOS measurements and were not participating in the PFT or Rint measurements. The assessment was included as an alternative option to collect pulmonary function data in pre-schoolers for sites that did not have Rint equipment but experience in IOS and IOS equipment available. Furthermore, the information on prohibited and allowed medications during the trial was detailed and it was explicitly stated that randomised patients who withdrew prematurely were not replaced.
    07 May 2013
    When the Paediatric Committee (PDCO) of the European Medicines Agency (EMA) agreed to the Paediatric Investigation Plan (PIP) for tiotropium in January 2013, they also requested the sponsor to recruit 30 patients aged 1 to 2 years. The inclusion of these patients was ensured by an adjustable screening cap per age group that was implemented in IVRS/IWRS. Furthermore, the amount of blood that was allowed to be collected for laboratory testing was amended to follow the respective guideline of the European Commission. To reduce the burden of daily completion of the PACD and additional diary card when the screening period was prolonged due to illness, this protocol amendment also implemented the option to temporarily interrupt filling of both forms.

    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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