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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled parallel group study to investigate the safety and efficacy of two doses of tiotropium bromide (2.5 µg and 5 µg) administered once daily via the Respimat device for 12 weeks in patients with cystic fibrosis.

    Summary
    EudraCT number
    		 2008-001156-43
    Trial protocol
    		 FR   BE   DE   NL   GB   PT   IT  
    Global end of trial date
    02 Apr 2010

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

    Trial information

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    Trial identification
    Sponsor protocol code
    205.339
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00737100
    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 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim Pharma GmbH & Co. KG, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000035-PIP01-07
    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
    27 Apr 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Apr 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study evaluates the effects of 12-week treatment with two doses of tiotropium bromide (2.5 μg q.d. and 5 μg q.d.) compared to placebo administered via the Respimat® device on lung function in patients with CF.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were 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 at any point during the study as medically needed. Open-label salbutamol/albuterol MDI (100 μg per puff) was provided as rescue medication by BI.
    Background therapy
    		 Patients maintained their background therapy , including inhaled corticosteroids (ICS).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Sep 2008
    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
    Netherlands: 10
    Country: Number of subjects enrolled
    Portugal: 20
    Country: Number of subjects enrolled
    United Kingdom: 49
    Country: Number of subjects enrolled
    Belgium: 35
    Country: Number of subjects enrolled
    France: 126
    Country: Number of subjects enrolled
    Germany: 74
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Australia: 28
    Country: Number of subjects enrolled
    New Zealand: 11
    Country: Number of subjects enrolled
    Russian Federation: 36
    Country: Number of subjects enrolled
    United States: 221
    Worldwide total number of subjects
    620
    EEA total number of subjects
    324
    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)
    168
    Adolescents (12-17 years)
    100
    Adults (18-64 years)
    348
    From 65 to 84 years
    4
    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 subject) met all strictly implemented inclusion/exclusion criteria. Subjects were not randomised to trial treatment if any one of the specific entry criteria were violated.

    Period 1
    Period 1 title
    Overall trial (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
    Arm description
    		 Patients randomised to receive matching placebo
    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 inhalations once daily at the same time of day, ideally in the morning between 6 am and 10 am.

    Arm title
    		 Tiotropium Respimat 2.5 Micrograms
    Arm description
    		 Patients randomised to receive Tiotropium Respimat 2.5 micrograms once daily
    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
    2 inhalations once daily at the same time of day, ideally in the morning between 6 am and 10 am.

    Arm title
    		 Tiotropium Respimat 5 Micrograms
    Arm description
    		 Patients randomised to receive Tiotropium Respimat 5.0 micrograms once daily
    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
    2 inhalations once daily at the same time of day, ideally in the morning between 6 am and 10 am.

    Number of subjects in period 1 [1]
    		Placebo Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms
    Started
    168
    166
    176
    Completed
    161
    159
    169
    Not completed
    7
    7
    7
         Adverse event, serious fatal
    2
    1
    -
         Consent withdrawn by subject
    -
    -
    3
         Adverse event, non-fatal
    4
    4
    3
         Reason not explained above
    1
    1
    1
         Lost to follow-up
    -
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients randomised to receive matching placebo

    Reporting group title
    Tiotropium Respimat 2.5 Micrograms
    Reporting group description
    		 Patients randomised to receive Tiotropium Respimat 2.5 micrograms once daily

    Reporting group title
    Tiotropium Respimat 5 Micrograms
    Reporting group description
    		 Patients randomised to receive Tiotropium Respimat 5.0 micrograms once daily

    Reporting group values
    		 Placebo Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms Total
    Number of subjects
    		 168 166 176 510
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 20.4 ( 11.6 ) 21.5 ( 12 ) 20.7 ( 11.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 72 81 82 235
        Male
    		 96 85 94 275
    Age, Customized
    Units: Subjects
        <= 11 years
    		 44 42 52 138
        >= 12 years
    		 124 124 124 372
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 0 1 2 3
        Black/African American
    		 0 3 2 5
        White
    		 127 124 132 383
        Missing
    		 39 35 37 111
        American Indian / Alaskan native
    		 2 3 3 8
    Alcohol history
    Units: Subjects
        Drinks no alcohol
    		 130 112 132 374
        Drinks alcohol but should not interfere with trial
    		 38 54 43 135
        Drinks alcohol but could interfere with trial
    		 0 0 1 1
    Smoking history
    Units: Subjects
        Never smoked
    		 159 157 167 483
        Ex-smoker
    		 7 5 7 19
        Currently smokes
    		 2 4 2 8
    Height
    Units: centimeters
        arithmetic mean (standard deviation)
    		 157.4 ( 17.2 ) 157.7 ( 17 ) 155.7 ( 18.2 ) -
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    		 52.1 ( 19 ) 51 ( 17.3 ) 50.4 ( 18.2 ) -
    Body Mass Index
    Units: kilogram/square meter
        arithmetic mean (standard deviation)
    		 20.3 ( 4.4 ) 19.9 ( 4 ) 20 ( 4.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients randomised to receive matching placebo

    Reporting group title
    Tiotropium Respimat 2.5 Micrograms
    Reporting group description
    		 Patients randomised to receive Tiotropium Respimat 2.5 micrograms once daily

    Reporting group title
    Tiotropium Respimat 5 Micrograms
    Reporting group description
    		 Patients randomised to receive Tiotropium Respimat 5.0 micrograms once daily

    Primary: Percent Predicted FEV1 AUC0-4 Response at the End of Week 12

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    End point title
    		 Percent Predicted FEV1 AUC0-4 Response at the End of Week 12
    End point description
    Change from baseline in percent predicted Forced Expiratory Volume in one second (FEV1) Area Under the Curve from 0 to 4 hours (AUC0-4). Calculated as percent predicted at week 12 minus percent predicted at baseline.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms
    Number of subjects analysed
    163 [1]
    158 [2]
    169 [3]
    Units: Percentage change
        least squares mean (standard error)
    -1.74 ( 0.65 )
    1.2 ( 0.66 )
    1.65 ( 0.63 )
    Notes
    [1] - FAS - only patients with endpoint values at week 12 were analysed
    [2] - FAS - only patients with endpoint values at week 12 were analysed
    [3] - FAS - only patients with endpoint values at week 12 were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Comparison of Tiotropium 2.5 microgram dose versus placebo adjusted for baseline, center, visit and age group. Analysis based on mixed effects model with repeated measures using unstructured covariance matrix.
    Comparison groups
    Placebo v Tiotropium Respimat 2.5 Micrograms
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.19
         upper limit
    		 4.7
    Notes
    [4] - Hierarchical testing was applied. Comparison of 2.5 dose to be performed only if superiority of tiotropium 5.0 dose compared to placebo was shown for both primary endpoints.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Comparison of Tiotropium 5.0 microgram dose versus placebo adjusted for baseline, center, visit and age group. Analysis based on mixed effects model with repeated measures using unstructured covariance matrix.
    Comparison groups
    Placebo v Tiotropium Respimat 5 Micrograms
    Number of subjects included in analysis
    332
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.67
         upper limit
    		 5.12
    Notes
    [5] - Hierarchical testing was applied. Comparison of 2.5 dose to be performed only if superiority of tiotropium 5.0 dose compared to placebo was shown for both primary endpoints.

    Primary: Percent Predicted FEV1 Trough Response at the End of Week 12

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    End point title
    		 Percent Predicted FEV1 Trough Response at the End of Week 12
    End point description
    Change from baseline in percent predicted trough Forced Expiratory Volume in one second. Calculated as percent predicted at week 12 minus percent predicted at baseline.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms
    Number of subjects analysed
    163 [6]
    158 [7]
    169 [8]
    Units: Percentage change
        least squares mean (standard error)
    -1.44 ( 0.71 )
    0.81 ( 0.71 )
    0.78 ( 0.69 )
    Notes
    [6] - FAS - only patients with endpoint values at week 12 were analysed
    [7] - FAS - only patients with endpoint values at week 12 were analysed
    [8] - FAS - only patients with endpoint values at week 12 were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Comparison of Tiotropium 2.5 microgram dose versus placebo adjusted for baseline, center, visit and age group. Analysis based on mixed effects model with repeated measures using unstructured covariance matrix
    Comparison groups
    Tiotropium Respimat 2.5 Micrograms v Placebo
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0184 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 4.11
    Notes
    [9] - Hierarchical testing was applied. Comparison of 2.5 dose to be performed only if superiority of tiotropium 5.0 dose compared to placebo was shown for both primary endpoints.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Comparison of Tiotropium 5.0 microgram dose versus placebo adjusted for baseline, center, visit and age group. Analysis based on mixed effects model with repeated measures using unstructured covariance matrix
    Comparison groups
    Placebo v Tiotropium Respimat 5 Micrograms
    Number of subjects included in analysis
    332
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0179 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 4.06
    Notes
    [10] - Hierarchical testing was applied. Comparison of 2.5 dose to be performed only if superiority of tiotropium 5.0 dose compared to placebo was shown for both primary endpoints.

    Secondary: Percent Predicted FVC AUC0-4 Response at the End of Week 12

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    End point title
    		 Percent Predicted FVC AUC0-4 Response at the End of Week 12
    End point description
    Change from baseline in percent predicted Forced Vital Capacity (FVC) Area Under the Curve from 0 to 4 hours (AUC0-4). Calculated as percent predicted at week 12 minus percent predicted at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms
    Number of subjects analysed
    149 [11]
    150 [12]
    158 [13]
    Units: Percentage change
        least squares mean (standard error)
    -1.3 ( 0.74 )
    0.53 ( 0.74 )
    1.81 ( 0.72 )
    Notes
    [11] - FAS - only patients with endpoint values at week 12 were analysed
    [12] - FAS - only patients with endpoint values at week 12 were analysed
    [13] - FAS - only patients with endpoint values at week 12 were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Comparison of Tiotropium 2.5 microgram dose versus placebo adjusted for baseline, center, visit and age group. Analysis based on mixed effects model with repeated measures using unstructured covariance matrix.
    Comparison groups
    Tiotropium Respimat 2.5 Micrograms v Placebo
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0756
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 3.86
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Comparison of Tiotropium 5.0 microgram dose versus placebo adjusted for baseline, center, visit and age group
    Comparison groups
    Placebo v Tiotropium Respimat 5 Micrograms
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0023
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.12
         upper limit
    		 5.12

    Secondary: Percent Predicted FVC Trough Response at the End of Week 12

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    End point title
    		 Percent Predicted FVC Trough Response at the End of Week 12
    End point description
    Change from baseline in percent predicted trough Forced Vital Capacity (FVC). Calculated as percent predicted at week 12 minus percent predicted at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms
    Number of subjects analysed
    149 [14]
    150 [15]
    158 [16]
    Units: Percentage change
        least squares mean (standard error)
    -0.39 ( 0.73 )
    0.47 ( 0.72 )
    0.81 ( 0.7 )
    Notes
    [14] - FAS - only patients with endpoint values at week 12 were analysed
    [15] - FAS - only patients with endpoint values at week 12 were analysed
    [16] - FAS - only patients with endpoint values at week 12 were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Comparison of Tiotropium 2.5 microgram dose versus placebo adjusted for baseline, center, visit and age group. Analysis based on mixed effects model with repeated measures using unstructured covariance matrix.
    Comparison groups
    Tiotropium Respimat 2.5 Micrograms v Placebo
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3857
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.08
         upper limit
    		 2.79
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Comparison of Tiotropium 5.0 microgram dose versus placebo adjusted for baseline, center, visit and age group. Analysis based on mixed effects model with repeated measures using unstructured covariance matrix
    Comparison groups
    Placebo v Tiotropium Respimat 5 Micrograms
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2199
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.72
         upper limit
    		 3.11

    Secondary: Pre-bronchodilator FEF25-75 Percent Predicted at the End of Week 12

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    End point title
    		 Pre-bronchodilator FEF25-75 Percent Predicted at the End of Week 12
    End point description
    Forced Expiratory Flow at 25-75% of vital capacity (FEF25-75). Calculated as percent predicted at week 12 minus percent predicted at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms
    Number of subjects analysed
    150 [17]
    152 [18]
    158 [19]
    Units: Percentage change
        least squares mean (standard error)
    -1.4 ( 1.57 )
    2.78 ( 1.55 )
    3.94 ( 1.52 )
    Notes
    [17] - FAS - only patients with endpoint values at week 12 were analysed
    [18] - FAS - only patients with endpoint values at week 12 were analysed
    [19] - FAS - only patients with endpoint values at week 12 were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Comparison of Tiotropium 2.5 microgram dose versus placebo. Analysis based on mixed effects model with repeated measures with fixed effects of treatment, visit, treatment-by-visit interaction, age group, baseline, baseline-by-visit interaction, and random effect of centre.
    Comparison groups
    Placebo v Tiotropium Respimat 2.5 Micrograms
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0363
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 8.11
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Comparison of Tiotropium 5.0 microgram dose versus placebo. Analysis based on mixed effects model with repeated measures with fixed effects of treatment, visit, treatment−by−visit interaction,age group, baseline, baseline−by−visit interaction, and random effect of centre.
    Comparison groups
    Placebo v Tiotropium Respimat 5 Micrograms
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0073
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.45
         upper limit
    		 9.23

    Secondary: Change From Baseline in Residual Volume/Total Lung Capacity (RV/TLC) at the End of Week 12

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    End point title
    		 Change From Baseline in Residual Volume/Total Lung Capacity (RV/TLC) at the End of Week 12
    End point description
    Change from baseline in static lung hyperinflation as measured by RV/TLC. Calculated as percent predicted at week 12 minus percent predicted at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms
    Number of subjects analysed
    53 [20]
    54 [21]
    54 [22]
    Units: Percentage change
        least squares mean (standard error)
    -0.01 ( 0.03 )
    0 ( 0.03 )
    0.04 ( 0.03 )
    Notes
    [20] - FAS - only patients with endpoint values at week 12 were analysed
    [21] - FAS - only patients with endpoint values at week 12 were analysed
    [22] - FAS - only patients with endpoint values at week 12 were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Comparison of Tiotropium 2.5 microgram dose versus placebo. Analysis based on mixed effects model adjusted for baseline, center, visit and age group.
    Comparison groups
    Placebo v Tiotropium Respimat 2.5 Micrograms
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7414
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.08
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Comparison of Tiotropium 5.0 microgram dose versus placebo. Analysis based on mixed effects model adjusted for baseline, center, visit and age group.
    Comparison groups
    Placebo v Tiotropium Respimat 5 Micrograms
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1418
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.12

    Secondary: Respiratory and Systemic Symptoms Questionnaire (RSSQ)

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    End point title
    		 Respiratory and Systemic Symptoms Questionnaire (RSSQ)
    End point description
    The RSSQ questionnaire is used to determine the presence or absence of an exacerbation during the recall period. This questionnaire consists of 12 symptoms and 3 physical findings. The definition of an exacerbation requires the patient to report at least 4 of 12 symptoms plus at least one of the following: findings on chest exam (e.g., crackles), greater than a 10% decrease in FEV1 or necessity of a chest x-ray.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms
    Number of subjects analysed
    167 [23]
    166 [24]
    175 [25]
    Units: Participants
        At least one pulmonary exacerbation
    16
    13
    12
        No pulmonary exacerbation
    151
    153
    163
    Notes
    [23] - FAS - only patients with endpoint values at week 12 were analysed
    [24] - FAS - only patients with endpoint values at week 12 were analysed
    [25] - FAS - only patients with endpoint values at week 12 were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Comparison of Tiotropium 2.5 microgram dose versus placebo. Treatment and age group were covariates for the logistic regression analysis.
    Comparison groups
    Placebo v Tiotropium Respimat 2.5 Micrograms
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8515
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.72
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Comparison of Tiotropium 5.0 microgram dose versus placebo. Treatment and age group were covariates for the logistic regression analysis.
    Comparison groups
    Placebo v Tiotropium Respimat 5 Micrograms
    Number of subjects included in analysis
    342
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5565
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 1.59

    Secondary: Change From Baseline in CFQ Scores - Adult Group

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    End point title
    		 Change From Baseline in CFQ Scores - Adult Group
    End point description
    The Cystic Fibrosis questionnaire (CFQ) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adults with CF. This validation questionnaire consists of 50 items on generic and disease-specific scales. The scores range from 0 to 100, with higher scores indicating better health.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms
    Number of subjects analysed
    168 [26]
    166 [27]
    176 [28]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Physical (N=99, 102, 105)
    -2.5 ( 14.8 )
    0 ( 14.1 )
    -2.9 ( 11.4 )
        Role (N=94, 100, 103)
    0.7 ( 12 )
    -2.7 ( 12 )
    -2.1 ( 15.1 )
        Vitality (N=99, 101, 105)
    -2.3 ( 15 )
    -1.8 ( 16.4 )
    -3.3 ( 17.7 )
        Emotion (N=99, 101, 105)
    -1.1 ( 11.5 )
    -1.3 ( 13.5 )
    0.1 ( 12.1 )
        Social (N=99, 101, 106)
    -1.1 ( 12.3 )
    -1 ( 10.7 )
    -0.8 ( 11.1 )
        Body (N=99,101, 106)
    0.4 ( 18.4 )
    -0.9 ( 15.3 )
    1.7 ( 16.4 )
        Eat (N=99,101,106)
    1.5 ( 9.5 )
    0.2 ( 10.3 )
    0 ( 16.4 )
        Treat (N=99, 101, 106)
    0.9 ( 15.5 )
    -1.4 ( 14.1 )
    -1.7 ( 12.7 )
        Health (N=99, 101, 106)
    -1.9 ( 15.1 )
    -3.2 ( 18.3 )
    -0.6 ( 18.1 )
        Weight (N=95, 101, 103)
    1.4 ( 22.2 )
    -3.3 ( 28.9 )
    0 ( 26 )
        Respirat (N=93, 101, 103)
    -1.3 ( 14.8 )
    -3.7 ( 15.8 )
    -1.8 ( 14.3 )
        Digest (N=93, 101, 103)
    0.8 ( 14.9 )
    -1.3 ( 13.7 )
    0.3 ( 14.9 )
    Notes
    [26] - FAS - only patients with endpoint values at week 12 were analysed
    [27] - FAS - only patients with endpoint values at week 12 were analysed
    [28] - FAS - only patients with endpoint values at week 12 were analysed
    No statistical analyses for this end point

    Secondary: Change From Baseline in CFQ Scores - Adolescents Group

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    End point title
    		 Change From Baseline in CFQ Scores - Adolescents Group
    End point description
    The Cystic Fibrosis questionnaire (CFQ) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adolescents (age 6-13) with CF. This validation questionnaire consists of 50 items on generic and disease-specific scales. The scores range from 0 to 100, with higher scores indicating better health.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms
    Number of subjects analysed
    168 [29]
    166 [30]
    176 [31]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Physical (N=46, 42, 54)
    1.1 ( 18 )
    3.2 ( 14.8 )
    -1.9 ( 15 )
        School (N=46, 42, 55)
    1.1 ( 14.3 )
    -1.6 ( 10.9 )
    -1.1 ( 13.5 )
        Body (N=46, 42, 55)
    2.8 ( 13.9 )
    -0.3 ( 16.1 )
    -0.1 ( 15.7 )
        School2 (N=46, 42, 55)
    1.2 ( 18.8 )
    4.2 ( 19.2 )
    2.4 ( 20.9 )
        Eat (N=46, 42, 55)
    -1.4 ( 19.7 )
    -2.4 ( 17.3 )
    1.6 ( 22.8 )
        Treat (N=46, 42, 55)
    0.2 ( 16.5 )
    -1.9 ( 20.1 )
    5.7 ( 19.5 )
        Respirat (N=46, 42, 55)
    -1.4 ( 15.2 )
    1.2 ( 16.7 )
    -3 ( 20.2 )
        Digest (N=46, 42, 55)
    -5.1 ( 26.3 )
    2.4 ( 26.9 )
    -3 ( 35.3 )
    Notes
    [29] - FAS - only patients with endpoint values at week 12 were analysed
    [30] - FAS - only patients with endpoint values at week 12 were analysed
    [31] - FAS - only patients with endpoint values at week 12 were analysed
    No statistical analyses for this end point

    Secondary: Change From Baseline in CFQ Scores - Parent Questionnaire

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    End point title
    		 Change From Baseline in CFQ Scores - Parent Questionnaire
    End point description
    The Cystic Fibrosis questionnaire (CFQ) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adolescents with CF - parent questionnaire. This validation questionnaire consists of 50 items on generic and disease-specific scales. The scores range from 0 to 100, with higher scores indicating better health.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms
    Number of subjects analysed
    168 [32]
    166 [33]
    176 [34]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Physical (N=46, 45, 53)
    -0.1 ( 15.4 )
    4.9 ( 15.9 )
    0.2 ( 12.7 )
        Emotion (N=46, 45, 52)
    -0.3 ( 11.2 )
    0 ( 16 )
    -0.1 ( 15.7 )
        Vitality (N=46, 44, 53)
    -0.1 ( 12.3 )
    3.3 ( 13.1 )
    -1.5 ( 14.9 )
        School (N=46, 45, 52)
    -4.8 ( 19.5 )
    2.2 ( 26.3 )
    0.4 ( 17 )
        Eat (N=46, 43, 49)
    -2.2 ( 23.7 )
    -0.8 ( 21.2 )
    3.4 ( 15.9 )
        Body (N=46, 45, 52)
    -3.9 ( 18.6 )
    -1.7 ( 21.7 )
    -3.2 ( 22.6 )
        Treat (N=46, 45, 52)
    -2.4 ( 18.6 )
    2.5 ( 16.4 )
    -0.2 ( 21.4 )
        Health (N=46, 45, 52)
    -2.7 ( 21.4 )
    3.5 ( 23.1 )
    -3 ( 20.7 )
        Respirat (N=45, 43, 50)
    -2.8 ( 16.4 )
    -2.2 ( 18.8 )
    -6 ( 14.2 )
        Digest (N=46, 43, 50)
    -0.7 ( 15.6 )
    -1.8 ( 17 )
    1.1 ( 16.8 )
        Weight (N=45, 45, 49)
    -5.2 ( 35.5 )
    1.5 ( 30.1 )
    4.1 ( 31.6 )
    Notes
    [32] - FAS - only patients with endpoint values at week 12 were analysed
    [33] - FAS - only patients with endpoint values at week 12 were analysed
    [34] - FAS - only patients with endpoint values at week 12 were analysed
    No statistical analyses for this end point

    Secondary: Amount of Tiotropium Eliminated in Urine From 0 to 4 Hours at Steady State (Ae0-4,ss)

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    End point title
    		 Amount of Tiotropium Eliminated in Urine From 0 to 4 Hours at Steady State (Ae0-4,ss) [35]
    End point description
    Ae0-4,ss represents the amount of tiotropium that is eliminated in urine from time 0 to 4 hours at steady state
    End point type
    Secondary
    End point timeframe
    pre-dose, and 5 minutes (min), 20 min, 1 hour (h), and 2 h post-dose
    Notes
    [35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In this case, the amount of tiotropium that is eliminated in urine from time 0 to 4 hours is analyzed and hence, only tiotropium arms have been included in the analysis.
    End point values
    		 Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms
    Number of subjects analysed
    102 [36]
    99 [37]
    Units: ng
        geometric mean (geometric coefficient of variation)
    114 ( 73 )
    245 ( 67.5 )
    Notes
    [36] - FAS - only patients with endpoint values at week 12 were analysed
    [37] - FAS - only patients with endpoint values at week 12 were analysed
    No statistical analyses for this end point

    Secondary: Maximum Measured Concentration at Steady State (Cmax,ss)

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    End point title
    		 Maximum Measured Concentration at Steady State (Cmax,ss) [38]
    End point description
    Cmax,ss represents the maximum measured concentration of tiotropium in plasma at steady state.
    End point type
    Secondary
    End point timeframe
    pre-dose, and 5 minutes (min), 20 min, 1 hour (h), and 2 h post-dose
    Notes
    [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In this case, the maximum measured concentration of tiotropium in plasma is analyzed and hence, only tiotropium arms have been included in the analysis.
    End point values
    		 Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms
    Number of subjects analysed
    49 [39]
    59 [40]
    Units: pg/mL
        geometric mean (geometric coefficient of variation)
    6.49 ( 58.5 )
    9.95 ( 66.6 )
    Notes
    [39] - FAS - only patients with endpoint values at week 12 were analysed
    [40] - FAS - only patients with endpoint values at week 12 were analysed
    No statistical analyses for this end point

    Secondary: Time From Dosing to the Maximum Concentration (Tmax,ss)

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    End point title
    		 Time From Dosing to the Maximum Concentration (Tmax,ss) [41]
    End point description
    Tmax,ss represents the time from dosing to the maximum concentration of tiotropium in plasma
    End point type
    Secondary
    End point timeframe
    pre-dose, and 5 minutes (min), 20 min, 1 hour (h), and 2 h post-dose
    Notes
    [41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In this case, the time from dosing to the maximum concentration of tiotropium in plasma is analyzed and hence, only tiotropium arms have been included in the analysis.
    End point values
    		 Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms
    Number of subjects analysed
    49 [42]
    59 [43]
    Units: hours
        median (full range (min-max))
    0.083 (0.033 to 0.433)
    0.083 (0.033 to 0.333)
    Notes
    [42] - FAS - only patients with endpoint values at week 12 were analysed
    [43] - FAS - only patients with endpoint values at week 12 were analysed.
    No statistical analyses for this end point

    Secondary: Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation

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    End point title
    		 Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation
    End point description
    Clinical Relevant Abnormalities for Vital Signs and Laboratory evaluation. Any new or clinically relevant worsening of baseline conditions was reported as Adverse Event. This analysis was conducted on the treated set which includes all randomized patients who received at least one dose of treatment.
    End point type
    Secondary
    End point timeframe
    From first drug administration until 30 days after last drug administration (up to 121 days)
    End point values
    		 Placebo Tiotropium Respimat 2.5 Micrograms Tiotropium Respimat 5 Micrograms
    Number of subjects analysed
    168 [44]
    166 [45]
    176 [46]
    Units: Participants
        Blood chloride decreased
    0
    0
    1
        Blood glucose increased
    1
    1
    0
        Blood pressure increased
    2
    1
    0
        Blood sodium decreased
    0
    0
    1
        Eosinophil count increased
    0
    1
    0
        Hepatic enzyme increased
    2
    0
    0
        Oxygen saturation decreased
    0
    0
    1
        Vitamin K decreased
    1
    0
    0
        White blood cell count increased
    0
    1
    0
    Notes
    [44] - Participants in the treated set were included.
    [45] - Participants in the treated set were included.
    [46] - Participants in the treated set were included.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration until 30 days after the last drug administration up to 121 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients randomised to receive matching placebo

    Reporting group title
    Tio R 2.5
    Reporting group description
    		 Patients randomised to receive Tiotropium Respimat 2.5 micrograms once daily

    Reporting group title
    Tio R 5.0
    Reporting group description
    		 Patients randomised to receive Tiotropium Respimat 5.0 micrograms once daily

    Serious adverse events
    		 Placebo Tio R 2.5 Tio R 5.0
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 168 (12.50%)
    28 / 166 (16.87%)
    21 / 176 (11.93%)
         number of deaths (all causes)
    2
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Surgical and medical procedures
    Antibiotic prophylaxis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    0 / 176 (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
    General disorders and administration site conditions
    Application site hypersensitivity
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (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
    Infusion related reaction
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (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
    Multi-organ failure
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (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
    Acute respiratory failure
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (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
    Haemoptysis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (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
    Lung disorder
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 166 (0.00%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (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 disorder
         subjects affected / exposed
    0 / 168 (0.00%)
    2 / 166 (1.20%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sputum increased
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (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
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (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
    Investigations
    Pulmonary function test decreased
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    0 / 176 (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
    Congenital, familial and genetic disorders
    Cystic fibrosis
         subjects affected / exposed
    5 / 168 (2.98%)
    8 / 166 (4.82%)
    8 / 176 (4.55%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 9
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystic fibrosis lung
         subjects affected / exposed
    7 / 168 (4.17%)
    4 / 166 (2.41%)
    4 / 176 (2.27%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Aplastic anaemia
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    0 / 176 (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
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (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
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 166 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 166 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (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
    Cholelithiasis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    0 / 176 (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
    Renal and urinary disorders
    Renal disorder
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    0 / 176 (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
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 168 (1.19%)
    2 / 166 (1.20%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 166 (0.60%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    0 / 176 (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
    Chronic sinusitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    0 / 176 (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
    Lung infection
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (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
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 166 (0.60%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (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
    Overgrowth bacterial
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    0 / 176 (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
    Pleurisy viral
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (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
    Pneumonia
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (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
    Pseudomonas infection
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    0 / 176 (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
    Sepsis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 166 (0.00%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Stenotrophomonas infection
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 166 (0.60%)
    0 / 176 (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
    Metabolism and nutrition disorders
    Hyperlipasaemia
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 166 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         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 R 2.5 Tio R 5.0
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    97 / 168 (57.74%)
    88 / 166 (53.01%)
    110 / 176 (62.50%)
    Congenital, familial and genetic disorders
    Cystic fibrosis
         subjects affected / exposed
    12 / 168 (7.14%)
    15 / 166 (9.04%)
    19 / 176 (10.80%)
         occurrences all number
    13
    20
    23
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 168 (10.71%)
    7 / 166 (4.22%)
    14 / 176 (7.95%)
         occurrences all number
    20
    13
    19
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    17 / 168 (10.12%)
    9 / 166 (5.42%)
    18 / 176 (10.23%)
         occurrences all number
    20
    10
    20
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 168 (5.95%)
    13 / 166 (7.83%)
    9 / 176 (5.11%)
         occurrences all number
    11
    14
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    34 / 168 (20.24%)
    34 / 166 (20.48%)
    46 / 176 (26.14%)
         occurrences all number
    45
    47
    65
    Dyspnoea
         subjects affected / exposed
    9 / 168 (5.36%)
    8 / 166 (4.82%)
    6 / 176 (3.41%)
         occurrences all number
    9
    9
    7
    Haemoptysis
         subjects affected / exposed
    7 / 168 (4.17%)
    12 / 166 (7.23%)
    11 / 176 (6.25%)
         occurrences all number
    8
    13
    14
    Nasal congestion
         subjects affected / exposed
    4 / 168 (2.38%)
    9 / 166 (5.42%)
    10 / 176 (5.68%)
         occurrences all number
    4
    9
    12
    Oropharyngeal pain
         subjects affected / exposed
    13 / 168 (7.74%)
    5 / 166 (3.01%)
    11 / 176 (6.25%)
         occurrences all number
    14
    5
    12
    Rhinorrhoea
         subjects affected / exposed
    9 / 168 (5.36%)
    6 / 166 (3.61%)
    9 / 176 (5.11%)
         occurrences all number
    10
    8
    9
    Sputum increased
         subjects affected / exposed
    8 / 168 (4.76%)
    11 / 166 (6.63%)
    13 / 176 (7.39%)
         occurrences all number
    9
    12
    13
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 168 (5.36%)
    5 / 166 (3.01%)
    4 / 176 (2.27%)
         occurrences all number
    12
    5
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    8 / 168 (4.76%)
    4 / 166 (2.41%)
    10 / 176 (5.68%)
         occurrences all number
    10
    5
    13
    Nasopharyngitis
         subjects affected / exposed
    14 / 168 (8.33%)
    11 / 166 (6.63%)
    14 / 176 (7.95%)
         occurrences all number
    15
    12
    16
    Sinusitis
         subjects affected / exposed
    6 / 168 (3.57%)
    3 / 166 (1.81%)
    9 / 176 (5.11%)
         occurrences all number
    7
    3
    10
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 168 (3.57%)
    8 / 166 (4.82%)
    11 / 176 (6.25%)
         occurrences all number
    7
    10
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Aug 2008
    1.Added a second (co-primary) endpoint. 2.Implemented administration of age-specific CFQs. The change from baseline in CFQ at the end of Week 12 was added as a secondary endpoint. 3.Restricted the collection of blood for pharmacokinetic (PK) evaluation to two subpopulations, and specified the timing of sample collection by subpopulation. This was also added as a PK endpoint. 4.Clarified Exclusion Criterion 7 5.Specified the contents of each patient treatment box 6.Required a 12-h washout of LABAs on PFT testing days 7.Permitted the use of LABA/long-acting corticosteroid fixed dose combination products 8.Allowed rescheduling of Visit 6 to comply with the permitted on-treatment TOBI regimen 9.Added instructions for urine collection for the PK analyses
    07 May 2009
    1.Specified that PFTs and body plethysmography should be conducted within ±10 min of the specified time. 2.Implemented new Inclusion Criterion 5c:pre-bronchodilator FEV1 at Visit 2 must have been within 15% of the value at Visit 1 3.Added an optional pre-bronchodilator forced expiratory maneuver to document the degree of reversibility.

    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.
    A "Missing" category is unavailable for the countrywise and age group breakdown of enrolled patients. Hence, 7 patients with a missing country have been added to "United States" and 7 patients with a missing age group to "Adults (18-64 years)".
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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