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    Clinical Trial Results:
    A randomised, double-blind, placebo-controlled parallel-group trial to confirm the efficacy after 12 weeks and the safety of tiotropium 5 mcg administered once daily via the Respimat® device in patients with cystic fibrosis

    Summary
    EudraCT number
    2010-019802-17
    Trial protocol
    PT   HU   FR   SK   DE   GB   BE   CZ   IT   AT   IE   ES  
    Global end of trial date
    07 Mar 2012

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

    Trial information

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    Trial identification
    Sponsor protocol code
    205.438
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01179347
    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-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
    23 Mar 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Mar 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this confirmatory study was to investigate the efficacy (over 12 weeks) and long-term safety (over at least 6 months [24 weeks]) of tiotropium solution for inhalation (5 mcg) delivered by the Respimat® inhaler in comparison to placebo (i.e. on top of usual care) in patients with cystic fibrosis (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. Rescue medication was not provided because the study drug was administered on top of usual maintenance therapy.
    Background therapy
    Patients maintained their background therapy , including inhaled corticosteroids (ICS) as long as the dose had been stabilised for at least 2 weeks prior to study start and remained stable for the first 12 weeks of the study.
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Sep 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    14 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 32
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    Czech Republic: 22
    Country: Number of subjects enrolled
    France: 79
    Country: Number of subjects enrolled
    Germany: 52
    Country: Number of subjects enrolled
    Hungary: 25
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Israel: 22
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Portugal: 16
    Country: Number of subjects enrolled
    Russian Federation: 39
    Country: Number of subjects enrolled
    Slovakia: 26
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Switzerland: 13
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    United States: 112
    Worldwide total number of subjects
    567
    EEA total number of subjects
    332
    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)
    2
    Children (2-11 years)
    186
    Adolescents (12-17 years)
    117
    Adults (18-64 years)
    259
    From 65 to 84 years
    3
    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 randomised to trial treatment if any one of the specific entry criteria were violated.

    Period 1
    Period 1 title
    Double-blind period (12 weeks)
    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
    Matching Placebo once daily (qd) delivered by the Respimat® inhaler as add-on therapy to usual care in patients with cystic fibrosis.
    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 puffs once daily delivered by the Respimat® inhaler.

    Arm title
    Tio R5 qd
    Arm description
    Tiotropium 5 mcg qd delivered by the Respimat® inhaler as add-on therapy to usual care in patients with cystic fibrosis.
    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 puffs once daily for a total dose of 5 mcg delivered by the Respimat® inhaler.

    Number of subjects in period 1 [1]
    Placebo Tio R5 qd
    Started
    155
    308
    Completed
    147
    294
    Not completed
    8
    14
         Consent withdrawn by subject
    1
    2
         Reason other than those stated above
    2
    4
         Adverse event, non-fatal
    2
    6
         Lost to follow-up
    1
    2
         Protocol deviation
    2
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one of the trial medication.
    Period 2
    Period 2 title
    Open-label period (12 to 60 weeks)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Tiotropium 5 mcg qd delivered by the Respimat® inhaler as add-on therapy to usual care in patients with cystic fibrosis. All patients randomised to Placebo in period 1 switched to experimental treatment in period 2.
    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 puffs once daily for a total dose of 5 mcg delivered by the Respimat® inhaler.

    Arm title
    Tio R5 qd
    Arm description
    Tiotropium 5 mcg qd delivered by the Respimat® inhaler as add-on therapy to usual care in patients with cystic fibrosis. All patients randomised to Tiotropium in period 1 continue experimental treatment in period 2.
    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 puffs once daily for a total dose of 5 mcg delivered by the Respimat® inhaler.

    Number of subjects in period 2
    Placebo Tio R5 qd
    Started
    147
    294
    Completed
    132
    278
    Not completed
    15
    16
         Consent withdrawn by subject
    1
    1
         Reason other than those stated above
    7
    4
         Adverse event, non-fatal
    5
    9
         Lost to follow-up
    1
    -
         Protocol deviation
    1
    -
         Lack of efficacy
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching Placebo once daily (qd) delivered by the Respimat® inhaler as add-on therapy to usual care in patients with cystic fibrosis.

    Reporting group title
    Tio R5 qd
    Reporting group description
    Tiotropium 5 mcg qd delivered by the Respimat® inhaler as add-on therapy to usual care in patients with cystic fibrosis.

    Reporting group values
    Placebo Tio R5 qd Total
    Number of subjects
    155 308 463
    Age categorical
    Units: Subjects
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    20.6 ( 13.6 ) 19.3 ( 12 ) -
    Gender, Male/Female
    Units: participants
        Female
    65 139 204
        Male
    90 169 259

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching Placebo once daily (qd) delivered by the Respimat® inhaler as add-on therapy to usual care in patients with cystic fibrosis.

    Reporting group title
    Tio R5 qd
    Reporting group description
    Tiotropium 5 mcg qd delivered by the Respimat® inhaler as add-on therapy to usual care in patients with cystic fibrosis.
    Reporting group title
    Placebo
    Reporting group description
    Tiotropium 5 mcg qd delivered by the Respimat® inhaler as add-on therapy to usual care in patients with cystic fibrosis. All patients randomised to Placebo in period 1 switched to experimental treatment in period 2.

    Reporting group title
    Tio R5 qd
    Reporting group description
    Tiotropium 5 mcg qd delivered by the Respimat® inhaler as add-on therapy to usual care in patients with cystic fibrosis. All patients randomised to Tiotropium in period 1 continue experimental treatment in period 2.

    Primary: Forced expiratory volume in 1 second (FEV1) area under the curve 0-4 hours (AUC0-4h) response

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    End point title
    Forced expiratory volume in 1 second (FEV1) area under the curve 0-4 hours (AUC0-4h) response
    End point description
    Mixed Model Repeated Measurement (MMRM) results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (<= 11, >=12), baseline and baseline-by-visit interaction. FEV1 AUC0-4h was normalised for time and was calculated using the trapezoidal rule divided by the observation time (4 h). The full analysis set (FAS) was defined as all patients in the treated set who had at least 1 baseline pulmonary function test (PFT) measurement and at least 1 post-baseline on-treatment PFT measurement. No patients <5 years of age were included in the FAS.
    End point type
    Primary
    End point timeframe
    30 minutes (min) before first dosing of study drug (defined as baseline), at 1 hour (h), 2 h , 3 h, and 4 h post dosing at day 1 and at 30 min before dosing, at 1 hour, 2 h , 3 h, and 4 h post dosing after 12 weeks.
    End point values
    Placebo Tio R5 qd
    Number of subjects analysed
    146 [1]
    292 [2]
    Units: Percent of predicted
        arithmetic mean (standard error)
    0.87 ( 0.8 )
    2.51 ( 0.57 )
    Notes
    [1] - Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance.
    [2] - Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hierarchical testing procedure was applied for both co-primary endpoints to maintain the overall alpha level. If and only if statistical superiority of the Tio R5 qd compared to Placebo in FEV1 AUC0-4h was demonstrated at the 1 sided alpha level of 0.025, confirmatory comparison in the second co-primary endpoint, at the same alpha level of 0.025 could be done .
    Comparison groups
    Placebo v Tio R5 qd
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.092 [4]
    Method
    Mixed model repeated measures (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    1.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.27
         upper limit
    3.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.97
    Notes
    [3] - Tio R5 qd minus Placebo
    [4] - Two-sided p-value.

    Primary: Trough (pre-dose) FEV1 response

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    End point title
    Trough (pre-dose) FEV1 response
    End point description
    MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Trough FEV1 was defined as the pre-dose FEV1 measured just prior to the administration of randomised treatment. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (<= 11, >=12), baseline and baseline-by-visit interaction.
    End point type
    Primary
    End point timeframe
    Baseline and 12 weeks
    End point values
    Placebo Tio R5 qd
    Number of subjects analysed
    144 [5]
    287 [6]
    Units: Percent of predicted
        arithmetic mean (standard error)
    0.72 ( 0.8 )
    2.12 ( 0.58 )
    Notes
    [5] - Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance.
    [6] - Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hierarchical testing for co-primary endpoints, confirmatory only if previous hypotheses had been successful.
    Comparison groups
    Placebo v Tio R5 qd
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.15 [8]
    Method
    Mixed model repeated measures (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    3.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.97
    Notes
    [7] - Tio R5 qd minus Placebo
    [8] - Two-sided p-value.

    Secondary: Forced vital capacity (FVC) area under the curve 0-4 hours (AUC0-4h) response

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    End point title
    Forced vital capacity (FVC) area under the curve 0-4 hours (AUC0-4h) response
    End point description
    MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (<= 11, >=12), baseline and baseline-by-visit interaction. FVC AUC0-4h was normalised for time and was calculated using the trapezoidal rule divided by the observation time (4 h).
    End point type
    Secondary
    End point timeframe
    30 minutes (min) before first dosing of study drug (defined as baseline), at 1 hour (h), 2 h , 3 h, and 4 h post dosing at day 1 and at 30 min before dosing, at 1 hour, 2 h , 3 h, and 4 h post dosing after 12 weeks.
    End point values
    Placebo Tio R5 qd
    Number of subjects analysed
    137 [9]
    282 [10]
    Units: Percent of predicted
        arithmetic mean (standard error)
    0.17 ( 0.75 )
    1.27 ( 0.53 )
    Notes
    [9] - Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance.
    [10] - Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed effects model with repeated measures analysis for comparing Tiotropium 5 mcg versus placebo with fixed effects of treatment, visit, treatment-by-visit interaction, age group (≤11; ≥12), baseline, baseline-by-visit interaction.
    Comparison groups
    Placebo v Tio R5 qd
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.23 [12]
    Method
    Mixed model repeated measures (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    1.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.68
         upper limit
    2.86
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9
    Notes
    [11] - Tio R5 qd minus Placebo
    [12] - Two-sided p-value.

    Secondary: Trough (pre-dose) FVC response

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    End point title
    Trough (pre-dose) FVC response
    End point description
    MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Trough FCV was defined as the pre-dose FVC measured just prior to the administration of randomised treatment. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (<= 11, >=12), baseline and baseline-by-visit interaction.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    Placebo Tio R5 qd
    Number of subjects analysed
    135 [13]
    277 [14]
    Units: Percent of predicted
        arithmetic mean (standard error)
    0.3 ( 0.77 )
    1.51 ( 0.55 )
    Notes
    [13] - Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance.
    [14] - Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed effects model with repeated measures analysis for comparing Tiotropium 5 mcg versus placebo with fixed effects of treatment, visit, treatment-by-visit interaction, age group (≤11; ≥12), baseline, baseline-by-visit interaction.
    Comparison groups
    Placebo v Tio R5 qd
    Number of subjects included in analysis
    412
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.19 [16]
    Method
    Mixed model repeated measures (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.62
         upper limit
    3.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.93
    Notes
    [15] - Tio R5 qd minus Placebo
    [16] - Two-sided p-value.

    Secondary: Pre-bronchodilator Forced expiratory flow between 25 percent and 75 percent of the FVC (FEF25−75) response

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    End point title
    Pre-bronchodilator Forced expiratory flow between 25 percent and 75 percent of the FVC (FEF25−75) response
    End point description
    MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. FEF25−75 is also known as maximum mid-expiratory flow and was measured before bronchodilator (salbutamol) use. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (<= 11, >=12), baseline and baseline-by-visit interaction.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    Placebo Tio R5 qd
    Number of subjects analysed
    135 [17]
    277 [18]
    Units: Percent of predicted
        arithmetic mean (standard error)
    2.15 ( 1.48 )
    3.02 ( 1.05 )
    Notes
    [17] - Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance.
    [18] - Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed effects model with repeated measures analysis for comparing Tiotrpium 5 mcg versus placebo with fixed effects of treatment, visit, treatment-by-visit interaction, age group (<=11; >=12), baseline, baseline-by-visit interaction.
    Comparison groups
    Placebo v Tio R5 qd
    Number of subjects included in analysis
    412
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    = 0.62 [20]
    Method
    Mixed model repeated measures (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.59
         upper limit
    4.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.76
    Notes
    [19] - Tio R5 qd minus Placebo.
    [20] - Two-sided p-value.

    Secondary: Percentage of participants with at least 1 pulmonary exacerbation during double-blind treatment

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    End point title
    Percentage of participants with at least 1 pulmonary exacerbation during double-blind treatment
    End point description
    Selected questions from the Respiratory and Systemic Symptoms Questionnaire (RSSQ), the investigator assessment of physical findings and pulmonary function, and the use of intravenous antibiotics as a concomitant therapy were used to determine if a cystic fibrosis-related pulmonary exacerbation had occurred.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    Placebo Tio R5 qd
    Number of subjects analysed
    102 [21]
    214 [22]
    Units: Percentage of Participants
        number (not applicable)
    7.8
    8.9
    Notes
    [21] - FAS reduced to patients having RSSQ information on day 29, 57 or 85.
    [22] - FAS reduced to patients having RSSQ information on day 29, 57 or 85.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Logistic regression with treatment, age group, baseline weight and baseline FEV1 percent predicted as covariates was used for the analysis of the proportion of patients with at least 1 pulmonary exacerbation.
    Comparison groups
    Placebo v Tio R5 qd
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    = 0.84 [24]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.092
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.453
         upper limit
    2.633
    Notes
    [23] - Tio R5 qd versus Placebo.
    [24] - Two-sided p-value.

    Secondary: Change from Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score

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    End point title
    Change from Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score
    End point description
    Different format of CFQ-R are used depending of the patients' age. Adolescent and adult format of CFQ-R is used for patients of 14 years and older, for younger children a parent version and a children format is used. In case parent and children questionnaires were filled out, the children questionnaire is taken into account. Scores were calculated for each domain of the CFQ-R which are presented separately. A score of 100 corresponds to the highest quality of life possible, whereas a score of 0 corresponds to the lowest quality of life possible. Increasing score indicates better health.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    Placebo Tio R5 qd
    Number of subjects analysed
    130 [25]
    255 [26]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Adolescents: Physical (N=83, N=162)
    -0.85 ( 14.4 )
    -0.15 ( 12.95 )
        Adolescents: Role (N=78, N=157)
    0.85 ( 12.99 )
    -0.42 ( 13.3 )
        Adolescents: Vitality (N=82, N=161)
    -1.22 ( 18.06 )
    0.05 ( 14.08 )
        Adolescents: Emotion (N=82, N=161)
    -1.54 ( 12.05 )
    -0.99 ( 12.96 )
        Adolescents: Social (N=82, N=159)
    -1.69 ( 10.09 )
    0.7 ( 10.19 )
        Adolescents: Body Image (N=82, N=159)
    0.14 ( 16.14 )
    3.14 ( 15.11 )
        Adolescents: Eating (N=82, N=161)
    -1.49 ( 14.89 )
    1.38 ( 10.74 )
        Adolescents: Treatment burden (N=82, N=160)
    0.95 ( 14.73 )
    0.56 ( 14.84 )
        Adolescents: Health perceptions (N=82, N=159)
    -0.81 ( 13.83 )
    0.77 ( 16.68 )
        Adolescents: Weight (N=80, N=160)
    -2.08 ( 29.22 )
    3.75 ( 26.96 )
        Adolescents: Respiratory (N=80, N=159)
    0.97 ( 13.83 )
    -0.77 ( 15.19 )
        Adolescents: Digestion (N=80, N=159)
    -0.83 ( 17.03 )
    0.49 ( 12.4 )
        Children: Physical (N=47, N=93)
    -2.84 ( 15.67 )
    1.43 ( 15.19 )
        Children: Social (N=46, N=93)
    2.8 ( 15.73 )
    1.59 ( 15.7 )
        Children: Body Image (N=46, N=93)
    -1.21 ( 18.48 )
    4.66 ( 25.71 )
        Children: Emotion (N=47, N=93)
    -1.24 ( 12.83 )
    1.12 ( 12.18 )
        Children: Eating (N=47, N=93)
    2.84 ( 19.03 )
    0.72 ( 20.18 )
        Children: Treatment burden (N=46, N=93)
    0.72 ( 15.43 )
    -0.48 ( 19.1 )
        Children: Respiratory (N=46, N=93)
    -0.91 ( 15.34 )
    -1.61 ( 16.81 )
        Children: Digestion (N=46, N=92)
    2.17 ( 22.66 )
    -1.09 ( 29.84 )
    Notes
    [25] - FAS reduced to patients having CFQ-R information at baseline and at week 12.
    [26] - FAS reduced to patients having CFQ-R information at baseline and at week 12.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First administration of trial medication until 30 days after last administration of trial drug, for AE analyses over open-label period and over the study. Over the double-blind period, 30 days of wash-out is only used for premature discontinued patients.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Placebo Over the Double-Blind Period
    Reporting group description
    Matching Placebo once daily (qd) delivered by the Respimat® inhaler as add-on therapy to usual care in patients with cystic fibrosis over the double-blind period (period 1).

    Reporting group title
    Tio 5mcg Over the Double-Blind Period
    Reporting group description
    Tiotropium 5 mcg qd delivered by the Respimat® inhaler as add-on therapy to usual care in patients with cystic fibrosis over the double-blind period (period 1).

    Reporting group title
    Placebo Over the Open-Label Period
    Reporting group description
    All placebo patients in period 1 switched to Tiotropium in the open-label period. Tiotropium 5 mcg qd delivered by the Respimat® inhaler as add-on therapy to usual care in patients with cystic fibrosis over the study.

    Reporting group title
    Tio 5mcg Over the Study
    Reporting group description
    Tiotropium 5 mcg qd delivered by the Respimat® inhaler as add-on therapy to usual care in patients with cystic fibrosis over the study.

    Serious adverse events
    Placebo Over the Double-Blind Period Tio 5mcg Over the Double-Blind Period Placebo Over the Open-Label Period Tio 5mcg Over the Study
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 155 (8.39%)
    36 / 308 (11.69%)
    24 / 147 (16.33%)
    62 / 308 (20.13%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Antibiotic prophylaxis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central venous catheter removal
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central venous catheterisation
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    4 / 308 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    2 / 155 (1.29%)
    5 / 308 (1.62%)
    2 / 147 (1.36%)
    9 / 308 (2.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    1 / 2
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sputum increased
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Bacterial test positive
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Forced expiratory volume decreased
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary function test decreased
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus lesion
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cystic fibrosis
         subjects affected / exposed
    2 / 155 (1.29%)
    6 / 308 (1.95%)
    7 / 147 (4.76%)
    11 / 308 (3.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
    0 / 11
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystic fibrosis lung
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 308 (0.65%)
    3 / 147 (2.04%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystic fibrosis related diabetes
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    1 / 147 (0.68%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    1 / 155 (0.65%)
    2 / 308 (0.65%)
    0 / 147 (0.00%)
    3 / 308 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth impacted
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urethral stenosis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspergillosis
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 308 (0.65%)
    3 / 147 (2.04%)
    6 / 308 (1.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    2 / 155 (1.29%)
    4 / 308 (1.30%)
    3 / 147 (2.04%)
    10 / 308 (3.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 4
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    1 / 147 (0.68%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 155 (0.00%)
    5 / 308 (1.62%)
    1 / 147 (0.68%)
    6 / 308 (1.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 308 (0.00%)
    1 / 147 (0.68%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stenotrophomonas infection
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 308 (0.32%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 308 (0.00%)
    0 / 147 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Over the Double-Blind Period Tio 5mcg Over the Double-Blind Period Placebo Over the Open-Label Period Tio 5mcg Over the Study
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 155 (32.90%)
    124 / 308 (40.26%)
    72 / 147 (48.98%)
    194 / 308 (62.99%)
    Congenital, familial and genetic disorders
    Cystic fibrosis
         subjects affected / exposed
    4 / 155 (2.58%)
    11 / 308 (3.57%)
    7 / 147 (4.76%)
    20 / 308 (6.49%)
         occurrences all number
    5
    13
    10
    37
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 155 (3.23%)
    11 / 308 (3.57%)
    8 / 147 (5.44%)
    22 / 308 (7.14%)
         occurrences all number
    7
    13
    12
    27
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    10 / 155 (6.45%)
    15 / 308 (4.87%)
    13 / 147 (8.84%)
    28 / 308 (9.09%)
         occurrences all number
    13
    17
    20
    35
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 155 (3.23%)
    11 / 308 (3.57%)
    5 / 147 (3.40%)
    19 / 308 (6.17%)
         occurrences all number
    5
    13
    5
    27
    Nausea
         subjects affected / exposed
    1 / 155 (0.65%)
    6 / 308 (1.95%)
    8 / 147 (5.44%)
    10 / 308 (3.25%)
         occurrences all number
    1
    6
    8
    16
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 155 (12.90%)
    55 / 308 (17.86%)
    30 / 147 (20.41%)
    84 / 308 (27.27%)
         occurrences all number
    21
    69
    43
    132
    Lung disorder
         subjects affected / exposed
    5 / 155 (3.23%)
    11 / 308 (3.57%)
    8 / 147 (5.44%)
    24 / 308 (7.79%)
         occurrences all number
    6
    12
    16
    32
    Oropharyngeal pain
         subjects affected / exposed
    2 / 155 (1.29%)
    6 / 308 (1.95%)
    9 / 147 (6.12%)
    16 / 308 (5.19%)
         occurrences all number
    2
    6
    9
    18
    Sputum increased
         subjects affected / exposed
    5 / 155 (3.23%)
    13 / 308 (4.22%)
    6 / 147 (4.08%)
    24 / 308 (7.79%)
         occurrences all number
    6
    14
    10
    36
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 155 (2.58%)
    12 / 308 (3.90%)
    10 / 147 (6.80%)
    26 / 308 (8.44%)
         occurrences all number
    4
    16
    14
    42
    Nasopharyngitis
         subjects affected / exposed
    4 / 155 (2.58%)
    14 / 308 (4.55%)
    11 / 147 (7.48%)
    25 / 308 (8.12%)
         occurrences all number
    4
    14
    14
    32
    Pharyngitis
         subjects affected / exposed
    2 / 155 (1.29%)
    4 / 308 (1.30%)
    1 / 147 (0.68%)
    18 / 308 (5.84%)
         occurrences all number
    2
    4
    1
    19
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 155 (2.58%)
    11 / 308 (3.57%)
    7 / 147 (4.76%)
    24 / 308 (7.79%)
         occurrences all number
    4
    12
    8
    27

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Nov 2010
    1. Introduction of a pre-dose urine sample at Visit 5. 2. Elimination of a physical examination at Visit 13. 3. The introduction of an interactive voice and web system instead of only an IVRS. 4. Changes made to clarify inconsistencies within the text and between text and flowcharts, or to provide further description and explanation for investigations.
    25 Nov 2011
    Added a new open-label tiotropium treatment period to allow for the assessment of ECGs

    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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    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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