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    Clinical Trial Results:
    Efficacy and safety of 2 doses of tiotropium via respimat in adult patients with mild persistent asthma

    Summary
    EudraCT number
    		 2010-023112-14
    Trial protocol
    		 LV   HU   EE   SK   AT   IT   PL  
    Global end of trial date
    19 Apr 2012

    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

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    205.442
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim Pharma GmbH & Co. KG
    Sponsor organisation address
    Binger Strasse 173 , Ingelheim am Rhein , Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure , Boehringer Ingelheim Pharma GmbH & Co. KG, +1 800 243 0127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure , Boehringer Ingelheim Pharma GmbH & Co. KG, +1 800 243 0127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 May 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Apr 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Apr 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy and safety of 2 doses pf tiotropium inhalation solution in comparison to placebo delivered by respimat inhaler in adult patients with uncontrolled, mild, persistent asthma.
    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 allowed for all patients as required.
    Background therapy
    		 Low-dose inhaled corticosteroid
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Mar 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 22
    Country: Number of subjects enrolled
    Austria: 40
    Country: Number of subjects enrolled
    Croatia: 37
    Country: Number of subjects enrolled
    Estonia: 21
    Country: Number of subjects enrolled
    Guatemala: 66
    Country: Number of subjects enrolled
    Hungary: 120
    Country: Number of subjects enrolled
    India: 95
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 57
    Country: Number of subjects enrolled
    Latvia: 58
    Country: Number of subjects enrolled
    Poland: 50
    Country: Number of subjects enrolled
    Slovakia: 104
    Worldwide total number of subjects
    686
    EEA total number of subjects
    446
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    653
    From 65 to 84 years
    33
    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 had to meet all inclusion/exclusion criteria. Subjects were not randomised to trial treatment if any one of the specific entry criteria were violated. Rescue medication, open-label salbutamol/albuterol was administered as needed.

    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, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Patients treated with matching placebo. One patient was randomised to placebo but not treated.
    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
    Oral inhalation via the Respimat inhaler once daily in the evening

    Arm title
    		 Tio R2.5
    Arm description
    		 Patients treated with tiotropium inhalation solution 2.5 micrograms qd.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium 2.5 micrograms
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Patients treated with tiotropium inhalation solution 2.5 microgram once daily in the evening

    Arm title
    		 Tio R5
    Arm description
    		 Patients treated with tiotropium inhalation solution 5 micrograms qd.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium 5 micrograms
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Patients treated with tiotropium inhalation solution 5 microgram once daily in the evening

    Number of subjects in period 1 [1]
    		Placebo Tio R2.5 Tio R5
    Started
    155
    154
    155
    Completed
    154
    149
    152
    Not completed
    1
    5
    3
         Consent withdrawn by subject
    1
    2
    -
         Adverse event, non-fatal
    -
    2
    1
         Reasons other than listed above
    -
    1
    1
         Protocol deviation
    -
    -
    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 treated with matching placebo. One patient was randomised to placebo but not treated.

    Reporting group title
    Tio R2.5
    Reporting group description
    		 Patients treated with tiotropium inhalation solution 2.5 micrograms qd.

    Reporting group title
    Tio R5
    Reporting group description
    		 Patients treated with tiotropium inhalation solution 5 micrograms qd.

    Reporting group values
    		 Placebo Tio R2.5 Tio R5 Total
    Number of subjects
    		 155 154 155 464
    Age categorical
    Units: Subjects
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 42.8 ± 12.1 43.8 ± 14 41.9 ± 13 -
    Gender, Male/Female
    Units: Participants
        Female
    		 103 82 96 281
        Male
    		 52 72 59 183

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients treated with matching placebo. One patient was randomised to placebo but not treated.

    Reporting group title
    Tio R2.5
    Reporting group description
    		 Patients treated with tiotropium inhalation solution 2.5 micrograms qd.

    Reporting group title
    Tio R5
    Reporting group description
    		 Patients treated with tiotropium inhalation solution 5 micrograms qd.

    Primary: Peak Forced Expiratory Volume in 1 second (FEV1) response within 3 hours post dosing (0-3h) after a treatment period of 12 weeks.

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    End point title
    		 Peak Forced Expiratory Volume in 1 second (FEV1) response within 3 hours post dosing (0-3h) after a treatment period of 12 weeks.
    End point description
    Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 12 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit. FAS= Full analysis set that is defined as all patients in the treated set who received at least one dose of randomised trial medication.
    End point type
    Primary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo Tio R2.5 Tio R5
    Number of subjects analysed
    154 [1]
    151 [2]
    152 [3]
    Units: Liter
        least squares mean (standard error)
    0.134 ± 0.026
    0.293 ± 0.026
    0.262 ± 0.026
    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
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit. Differences calculated as Tio R5- Placebo
    Comparison groups
    Placebo v Tio R5
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.128
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.057
         upper limit
    		 0.199
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.036
    Notes
    [4] - Step-wise testing for the two treatment groups for the primary endpoint, confirmatory only if previous hypotheses had been successful, significance level of alpha=0.025 (one-sided) for primary endpoint.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit. Differences calculated as Tio R2.5- Placebo
    Comparison groups
    Placebo v Tio R2.5
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.159
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.088
         upper limit
    		 0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.036
    Notes
    [5] - Step-wise testing for the two treatment groups for the primary endpoint, confirmatory only if previous hypotheses had been successful, significance level of alpha=0.025 (one-sided) for the primary endpoint.

    Secondary: Trough FEV1 response determined after a treatment period of 12 weeks.

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    End point title
    		 Trough FEV1 response determined after a treatment period of 12 weeks.
    End point description
    The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 12 weeks and the trough FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo Tio R2.5 Tio R5
    Number of subjects analysed
    154 [6]
    151 [7]
    152 [8]
    Units: Liter
        least squares mean (standard error)
    0.015 ± 0.026
    0.125 ± 0.026
    0.137 ± 0.027
    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
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit. Differences calculated as Tio R5- Placebo
    Comparison groups
    Placebo v Tio R5
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.122
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.049
         upper limit
    		 0.194
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.037
    Notes
    [9] - p-values serve an exploratory function only
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit. Differences calculated as Tio R2.5- Placebo
    Comparison groups
    Placebo v Tio R2.5
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0028 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.038
         upper limit
    		 0.182
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.037
    Notes
    [10] - p-values serve an exploratory function only

    Secondary: Peak (within 3 hours post-dosing) Forced Vital Capacity (FVC) response at the end of the 12-week treatment period.

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    End point title
    		 Peak (within 3 hours post-dosing) Forced Vital Capacity (FVC) response at the end of the 12-week treatment period.
    End point description
    Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 12 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo Tio R2.5 Tio R5
    Number of subjects analysed
    154 [11]
    151 [12]
    152 [13]
    Units: Liter
        least squares mean (standard error)
    0.126 ± 0.03
    0.231 ± 0.03
    0.183 ± 0.03
    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
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit. Differences calculated as Tio R5- Placebo
    Comparison groups
    Placebo v Tio R5
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1714 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.057
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.025
         upper limit
    		 0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.042
    Notes
    [14] - p-values serve an exploratory function only
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit. Differences calculated as Tio R2.5- Placebo
    Comparison groups
    Placebo v Tio R2.5
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0119 [15]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.106
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.023
         upper limit
    		 0.188
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.042
    Notes
    [15] - p-values serve an exploratory function only

    Secondary: FEV1 Area Under the Curve (AUC0-3h) response at the end of the 12-week treatment period.

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    End point title
    		 FEV1 Area Under the Curve (AUC0-3h) response at the end of the 12-week treatment period.
    End point description
    The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 12 weeks. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit baseline*visit.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo Tio R2.5 Tio R5
    Number of subjects analysed
    154 [16]
    151 [17]
    152 [18]
    Units: Liter
        least squares mean (standard error)
    0.048 ± 0.024
    0.198 ± 0.024
    0.174 ± 0.025
    Notes
    [16] - FAS- only patients with endpoint values at week 12 were analysed
    [17] - FAS-only patients with endpoint values at week 12 were analysed
    [18] - FAS- only patients with endpoint values at week 12 were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit. Differences calculated as Tio R5- Placebo
    Comparison groups
    Placebo v Tio R5
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003 [19]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.125
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.058
         upper limit
    		 0.192
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.034
    Notes
    [19] - p-values serve an exploratory function only
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit. Differences calculated as Tio R2.5- Placebo
    Comparison groups
    Placebo v Tio R2.5
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [20]
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (net)
    Point estimate
    0.149
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.082
         upper limit
    		 0.216
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.034
    Notes
    [20] - p-values serve an exploratory function only

    Secondary: FVC (AUC0-3h) response at the end of the 12-week treatment period.

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    End point title
    		 FVC (AUC0-3h) response at the end of the 12-week treatment period.
    End point description
    The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 12 weeks. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit baseline*visit.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo Tio R2.5 Tio R5
    Number of subjects analysed
    154 [21]
    151 [22]
    152 [23]
    Units: Liter
        least squares mean (standard error)
    0 ± 0.028
    0.101 ± 0.028
    0.061 ± 0.028
    Notes
    [21] - FAS-only patients with endpoint values at week 12 were analysed
    [22] - FAS-only patients with endpoint values at week 12 were analysed
    [23] - FAS- only patients with endpoint values at week 12 were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit. Differences calculated as Tio R5- Placebo
    Comparison groups
    Placebo v Tio R5
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1182 [24]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.061
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.016
         upper limit
    		 0.138
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.039
    Notes
    [24] - p-values serve an exploratory function only
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit. Differences calculated as Tio R2.5- Placebo
    Comparison groups
    Placebo v Tio R2.5
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0102 [25]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.101
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.024
         upper limit
    		 0.178
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.039
    Notes
    [25] - p-values serve an exploratory function only

    Secondary: Asthma Control Questionnaire (ACQ) responder after 12 weeks of treatment

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    End point title
    		 Asthma Control Questionnaire (ACQ) responder after 12 weeks of treatment
    End point description
    For the ACQ, the total score was calculated as the mean of the responses to 6 self administered questions and one question which was completed by clinical staff based upon pre-bronchodilator FEV1. The score ranges from 0 (no impairment) to 6 (maximum impairment). Response was categorised as: responder (change from baseline <= -0.5), no change (-0.5 <change from baseline < 0.5) and worsening (change from baseline >= 0.5).
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Tio R2.5 Tio R5
    Number of subjects analysed
    154 [26]
    149 [27]
    152 [28]
    Units: Number of patients
        Responder
    91
    91
    90
        No change
    61
    48
    57
        Worsening
    2
    10
    5
    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: Time to first severe asthma exacerbation during the 12-week treatment.

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    End point title
    		 Time to first severe asthma exacerbation during the 12-week treatment.
    End point description
    Severe asthma exacerbations are defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days. Since only 4 of the 155 patients in the placebo group, 6 of the 154 patients in the Tio R2.5 group and 1 in the Tio R5 group had severe exacerbations, the median times were not calculable (99999)
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Tio R2.5 Tio R5
    Number of subjects analysed
    155 [29]
    154 [30]
    155 [31]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    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
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Since the percent patients with event is less than 50% the median is not calculable, but Hazard Ratio is still estimable from the Cox model. Parameter estimates of Cox proportional hazard model with only treatment fitted as an effect in the model. Hazard Ratio (HR) below 1 favors tiotropium.
    Comparison groups
    Placebo v Tio R5
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2155 [32]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 2.24
    Notes
    [32] - Significance level of alpha=0.05 (two-sided). P-values serve an exploratory function only.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Since the percent patients with event is less than 50% the median is not calculable, but Hazard Ratio is still estimable from the Cox model. Parameter estimates of Cox proportional hazard model with only treatment fitted as an effect in the model. Hazard Ratio (HR) below 1 favors tiotropium.
    Comparison groups
    Placebo v Tio R2.5
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5071 [33]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 5.44
    Notes
    [33] - Significance level of alpha=0.05 (two-sided). P-values serve an exploratory function only.

    Secondary: Time to first asthma exacerbation during the 12-week treatment.

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    End point title
    		 Time to first asthma exacerbation during the 12-week treatment.
    End point description
    An asthma exacerbation was defined as an episode of progressive increase in 1 or more asthma symptom that were outside the patient's usual range of day-to-day asthma symptoms and lasted for at least 2 consecutive days or as a decrease in a patient's best morning PEF of 30% or more from a patient's mean morning PEF for at least 2 consecutive days that may or may not have been accompanied by symptoms. Since 22 of the 155 patients in the placebo group, 21 of the 154 patients in Toio R2.5 group and 13 of the 155 patients in the Tio R5 group reported at least one asthma exacerbation, the median times were not calculable (99999)
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Tio R2.5 Tio R5
    Number of subjects analysed
    155 [34]
    154 [35]
    155 [36]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    99999 (87 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [34] - FAS-only patients with endpoint values at week 12 were analysed
    [35] - FAS-only patients with endpoint values at week 12 were analysed
    [36] - FAS-only patients with endpoint values at week 12 were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Since only 22 of the 155 patients in the placebo group, 21 of the 154 patients in the Tio R2.5 group and 13 of the 155 patients in the Tio R5 group had asthma exacerbations, the median times were not calculable (99999). The Hazard Ratio is still estimable from the Cox model. Hazard Ratio (HR) below 1 favors tiotropium.
    Comparison groups
    Placebo v Tio R2.5
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8974 [37]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.75
    Notes
    [37] - Significance level of alpha=0.05 (two-sided). P-values serve an exploratory function only.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Since only 22 of the 155 patients in the placebo group, 21 of the 154 patients in the Tio R2.5 group and 13 of the 155 patients in the Tio R5 group had asthma exacerbations, the median times were not calculable (99999) Hazard Ratio (HR) below 1 favors tiotropium.
    Comparison groups
    Placebo v Tio R5
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1217 [38]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.16
    Notes
    [38] - Significance level of alpha=0.05 (two-sided). P-values serve an exploratory function only.

    Secondary: Use of rescue medication during 24h period

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    End point title
    		 Use of rescue medication during 24h period
    End point description
    Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during 24 h period), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5. The mean was adjusted for treatment, centre, week, baseline, treatment*week and baseline*week.
    End point type
    Secondary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Placebo Tio R2.5 Tio R5
    Number of subjects analysed
    153 [39]
    150 [40]
    152 [41]
    Units: puffs of rescue medication
        arithmetic mean (standard error)
    -0.815 ± 0.093
    -0.594 ± 0.093
    -0.848 ± 0.093
    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
    [41] - FAS-only patients with endpoint values at week 12 were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, centre, week, baseline, treatment*week and baseline*week. Differences calculated as Tio R2.5- Placebo
    Comparison groups
    Tio R2.5 v Placebo
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0872 [42]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.222
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.032
         upper limit
    		 0.476
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.129
    Notes
    [42] - p-values serve an exploratory function only
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, centre, week, baseline, treatment*week and baseline*week. Differences calculated as Tio R5- Placebo
    Comparison groups
    Tio R5 v Placebo
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7995 [43]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.033
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.287
         upper limit
    		 0.221
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.129
    Notes
    [43] - p-values serve an exploratory function only

    Secondary: Use of rescue medication during daytime

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    End point title
    		 Use of rescue medication during daytime
    End point description
    Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during daytime), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5. The mean was adjusted for treatment, centre, week, baseline, treatment*week and baseline*week.
    End point type
    Secondary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Placebo Tio R2.5 Tio R5
    Number of subjects analysed
    153 [44]
    149 [45]
    152 [46]
    Units: puffs of rescue medication
        arithmetic mean (standard error)
    -0.428 ± 0.055
    -0.331 ± 0.055
    -0.436 ± 0.055
    Notes
    [44] - FAS-only patients with endpoint values at week 12 were analysed
    [45] - FAS-only patients with endpoint values at week 12 were analysed
    [46] - FAS-only patients with endpoint values at week 12 were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, centre, week, baseline, treatment*week and baseline*week. Differences calculated as Tio R2.5- Placebo
    Comparison groups
    Tio R2.5 v Placebo
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2038 [47]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.097
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.053
         upper limit
    		 0.247
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.076
    Notes
    [47] - p-values serve an exploratory function only
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, centre, week, baseline, treatment*week and baseline*week. Differences calculated as Tio R5- Placebo
    Comparison groups
    Tio R5 v Placebo
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9104 [48]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.009
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.158
         upper limit
    		 0.141
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.076
    Notes
    [48] - p-values serve an exploratory function only

    Secondary: Use of rescue medication during nighttime

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    End point title
    		 Use of rescue medication during nighttime
    End point description
    Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during nighttime), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5. The mean was adjusted for treatment, centre, week, baseline, treatment*week and baseline*week.
    End point type
    Secondary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Placebo Tio R2.5 Tio R5
    Number of subjects analysed
    152 [49]
    150 [50]
    152 [51]
    Units: puffs of rescue medication
        arithmetic mean (standard error)
    -0.376 ± 0.049
    -0.245 ± 0.049
    -0.386 ± 0.049
    Notes
    [49] - FAS-only patients with endpoint values at week 12 were analysed
    [50] - FAS-only patients with endpoint values at week 12 were analysed
    [51] - FAS-only patients with endpoint values at week 12 were analysed
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, centre, week, baseline, treatment*week and baseline*week. Differences calculated as Tio R2.5- Placebo
    Comparison groups
    Tio R2.5 v Placebo
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0559 [52]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.131
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.003
         upper limit
    		 0.265
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.068
    Notes
    [52] - p-values serve an exploratory function only
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, centre, week, baseline, treatment*week and baseline*week. Differences calculated as Tio R5- Placebo
    Comparison groups
    Tio R5 v Placebo
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8795 [53]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.144
         upper limit
    		 0.123
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.068
    Notes
    [53] - p-values serve an exploratory function only

    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 157 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients treated with matching placebo.

    Reporting group title
    Tio R2.5
    Reporting group description
    		 Patients treated with tiotropium inhalation solution 2.5 micrograms qd.

    Reporting group title
    Tio R5
    Reporting group description
    		 Patients treated with tiotropium inhalation solution 5 micrograms qd.

    Serious adverse events
    		 Placebo Tio R2.5 Tio R5
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    1 / 155 (0.65%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer in situ
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Tio R2.5 Tio R5
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 155 (16.13%)
    30 / 154 (19.48%)
    21 / 155 (13.55%)
    Investigations
    Peak expiratory flow rate decreased
         subjects affected / exposed
    6 / 155 (3.87%)
    9 / 154 (5.84%)
    6 / 155 (3.87%)
         occurrences all number
    10
    14
    16
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    19 / 155 (12.26%)
    24 / 154 (15.58%)
    17 / 155 (10.97%)
         occurrences all number
    36
    30
    26

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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