Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   35495   clinical trials with a EudraCT protocol, of which   5837   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Randomised, double-blind, placebo-controlled, 6 treatment, 4 period, incomplete cross-over trial to characterise the 24-hour lung function profiles of tiotropium + olodaterol fixed dose combination (2.5/5 µg, 5/5 µg), tiotropium (2.5 µg, 5 µg) and olodaterol (5 µg) (oral inhalation, delivered by the Respimat® Inhaler) after 6 weeks once daily treatment in patients with Chronic Obstructive Pulmonary Disease (COPD)

    Summary
    EudraCT number
    2011-004710-42
    Trial protocol
    DE   NL   DK   BE   HU  
    Global end of trial date
    12 Aug 2013

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

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    1237.20
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01559116
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173 , 55216 Ingelheim am Rhein , Germany,
    Public contact
    Clinical Trial Information Disclosure , QRPE Processes and Systems Coordination , +1 800 243 0127 , clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Clinical Trial Information Disclosure , QRPE Processes and Systems Coordination , +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
    27 Sep 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jul 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial is to determine the 24-hour FEV1-time profile of tiotropium + olodaterol FDC (2.5/5 μg, 5/5 μg), administered once daily by the RESPIMAT Inhaler, after 6 weeks of treatment.
    Protection of trial subjects
    An independent DMC was formed to ensure patient safety and was to make recommendations to the sponsor with regard to the continuation and potential modification or termination of the trial. All patients were informed that they were free to withdraw their consent at any time during the study without penalty or prejudice. The patients were informed that their personal trial related data would be considered confidential and used by BI in accordance with the local data protection laws.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Mar 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 40
    Country: Number of subjects enrolled
    Belgium: 27
    Country: Number of subjects enrolled
    Denmark: 23
    Country: Number of subjects enrolled
    Germany: 94
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    United States: 47
    Worldwide total number of subjects
    259
    EEA total number of subjects
    205
    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)
    172
    From 65 to 84 years
    87
    85 years and over
    0

    Subject disposition

    Close Top of page
    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 implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the entry criteria were violated.

    Period 1
    Period 1 title
    Overall trial
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst

    Arms
    Arm title
    All subjects
    Arm description
    All enrolled subject were included.
    Arm type
    all treatments combined subjects

    Investigational medicinal product name
    Tiotropium (Tio), Olodaterol (Olo), Tio+Olo, placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Randomised, double-blind, placebo-controlled, 6 treatment, 4 period, incomplete cross-over trial to characterise the 24-hour lung function profiles of tiotropium + olodaterol fixed dose combination (2.5/5 μg, 5/5 μg), tiotropium (2.5 μg, 5 μg) and olodaterol (5 μg) (oral inhalation, delivered by the Respimat® Inhaler) after 6 weeks once daily treatment in patients with Chronic Obstructive Pulmonary Disease (COPD)

    Number of subjects in period 1 [1]
    All subjects
    Started
    219
    Completed
    193
    Not completed
    26
         'Other than stated above '
    9
         Protocol deviation
    1
         Lack of efficacy
    1
         Adverse event, non-fatal
    10
         Consent withdrawn by subject
    4
         Lost to follow-up
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one of the trial medication. Thus, even though 259 subjects were enrolled in the trail, 40 subjects were not treated. Therefore only 219 subjects were reported in the baseline period.
    Period 2
    Period 2 title
    Overall trial (treatment period)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Placebo
    Arm description
    2 inhalations once daily (a.m. dosing) for 6 weeks
    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 placebo inhalations once daily (a.m. dosing) for 6 weeks

    Arm title
    Olo 5 μg
    Arm description
    2 inhalations once daily (a.m. dosing) for 6 weeks. Olodaterol (Olo): one dose (5 μg) only
    Arm type
    Active comparator

    Investigational medicinal product name
    Olodaterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations once daily (a.m. dosing) for 6 weeks. Olodaterol: one dose only

    Arm title
    Tio 2.5 μg
    Arm description
    2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium (Tio): low dose
    Arm type
    Active comparator

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium: low dose

    Arm title
    Tio 5 μg
    Arm description
    2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium (Tio): high dose
    Arm type
    Active comparator

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium: high dose

    Arm title
    T+O 2.5/5 μg
    Arm description
    2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium + Olodaterol (T+O) fixed dose combination (FDC) low dose: low dose + one dose only
    Arm type
    Experimental

    Investigational medicinal product name
    Tiotropium, Olodaterol FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium + Olodaterol (T+O) fixed dose combination (FDC) low dose: low dose + one dose only.

    Arm title
    T+O 5/5 μg
    Arm description
    2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium+Olodaterol (T+O) fixed dose combination (FDC) high dose: high dose + one dose only
    Arm type
    Experimental

    Investigational medicinal product name
    Tio, Olo FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium+Olodaterol fixed dose combination (FDC) high dose: high dose + one dose only

    Number of subjects in period 2
    Placebo Olo 5 μg Tio 2.5 μg Tio 5 μg T+O 2.5/5 μg T+O 5/5 μg
    Started
    138
    138
    137
    138
    136
    139
    Completed
    130
    136
    135
    135
    135
    138
    Not completed
    8
    2
    2
    3
    1
    1
         'Other than stated above '
    -
    -
    1
    2
    -
    1
         Lack of efficacy
    1
    -
    -
    -
    -
    -
         Adverse event, non-fatal
    6
    2
    1
    1
    -
    -
         Consent withdrawn by subject
    -
    -
    -
    -
    1
    -
         Lost to follow-up
    1
    -
    -
    -
    -
    -

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one of the trial medication. Therefore 219 subjects were in baseline characteristic reporting group.

    Reporting group values
    Overall trial Total
    Number of subjects
    219 219
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    61.1 ± 7.7 -
    Gender categorical
    Units: Subjects
        Female
    90 90
        Male
    129 129

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    All subjects
    Reporting group description
    All enrolled subject were included.
    Reporting group title
    Placebo
    Reporting group description
    2 inhalations once daily (a.m. dosing) for 6 weeks

    Reporting group title
    Olo 5 μg
    Reporting group description
    2 inhalations once daily (a.m. dosing) for 6 weeks. Olodaterol (Olo): one dose (5 μg) only

    Reporting group title
    Tio 2.5 μg
    Reporting group description
    2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium (Tio): low dose

    Reporting group title
    Tio 5 μg
    Reporting group description
    2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium (Tio): high dose

    Reporting group title
    T+O 2.5/5 μg
    Reporting group description
    2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium + Olodaterol (T+O) fixed dose combination (FDC) low dose: low dose + one dose only

    Reporting group title
    T+O 5/5 μg
    Reporting group description
    2 inhalations once daily (a.m. dosing) for 6 weeks. Tiotropium+Olodaterol (T+O) fixed dose combination (FDC) high dose: high dose + one dose only

    Primary: Forced Expiratory Volume in 1 Second (FEV1) AUC0-24h Response [L] After 6 Weeks Treatment.

    Close Top of page
    End point title
    Forced Expiratory Volume in 1 Second (FEV1) AUC0-24h Response [L] After 6 Weeks Treatment.
    End point description
    Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 0 to 24 h post-dose, using the trapezoidal rule, divided by the duration (24 h) to report in litres. Response was defined as the change from patient baseline. Full Analysis Set (FAS): included all randomised patients who received at least 1 dose of study medication, had a period baseline measurement, and at least 1 evaluable postbaseline measurement for the primary endpoint at any Week 6 visit. Pulmonary function test (PFT) time schedule: At Visits 2, 4, 6, 8: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2 and 3 h post-dose. At Visits 3, 5, 7, 9: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min post-dose.
    End point type
    Primary
    End point timeframe
    Day 1 and week 6 (details in description)
    End point values
    Placebo Olo 5 μg Tio 2.5 μg Tio 5 μg T+O 2.5/5 μg T+O 5/5 μg
    Number of subjects analysed
    132 [1]
    136 [2]
    136 [3]
    135 [4]
    135 [5]
    138 [6]
    Units: litre(s)
        least squares mean (standard error)
    -0.037 ± 0.014
    0.129 ± 0.013
    0.117 ± 0.013
    0.133 ± 0.014
    0.241 ± 0.014
    0.244 ± 0.013
    Notes
    [1] - Full analysis set (FAS): definition in description
    [2] - FAS
    [3] - FAS
    [4] - FAS
    [5] - FAS
    [6] - FAS
    Statistical analysis title
    T+O 5/5 vs placebo
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Placebo.
    Comparison groups
    Placebo v T+O 5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.252
         upper limit
    0.309
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Notes
    [7] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.115
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.087
         upper limit
    0.143
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Notes
    [8] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.082
         upper limit
    0.139
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Notes
    [9] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs placebo
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Placebo.
    Comparison groups
    Placebo v T+O 2.5/5 μg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.277
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.249
         upper limit
    0.306
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [10] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.111
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.083
         upper limit
    0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Notes
    [11] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.
    Comparison groups
    Tio 2.5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.124
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.096
         upper limit
    0.152
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Notes
    [12] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.107
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.079
         upper limit
    0.136
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Notes
    [13] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus T+O 2.5/5.
    Comparison groups
    T+O 2.5/5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [14]
    P-value
    = 0.8238
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.003
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.025
         upper limit
    0.031
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Notes
    [14] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Tio 2.5
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Tio 2.5.
    Comparison groups
    Tio 2.5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.127
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.099
         upper limit
    0.155
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Notes
    [15] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number.
    Statistical analysis title
    Tio 5 vs Olo 5
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as Tio 5 minus Olo 5.
    Comparison groups
    Olo 5 μg v Tio 5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [16]
    P-value
    = 0.7722
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.004
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.024
         upper limit
    0.032
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Notes
    [16] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    Tio 2.5 vs Olo 5
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as Tio 2.5 minus Olo 5.
    Comparison groups
    Olo 5 μg v Tio 2.5 μg
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    = 0.3842
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.012
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.041
         upper limit
    0.016
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Notes
    [17] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (272) does not reflect the actual number.
    Statistical analysis title
    Tio 5 vs Tio 2.5
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as Tio 5 minus Tio 2.5.
    Comparison groups
    Tio 2.5 μg v Tio 5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [18]
    P-value
    = 0.2487
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.017
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.012
         upper limit
    0.045
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Notes
    [18] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    Olo 5 vs placebo
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as Olo 5 minus Placebo.
    Comparison groups
    Placebo v Olo 5 μg
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.166
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.137
         upper limit
    0.194
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [19] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (268) does not reflect the actual number.
    Statistical analysis title
    Tio 2.5 vs placebo
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as Tio 2.5 minus Placebo.
    Comparison groups
    Tio 2.5 μg v Placebo
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority [20]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.153
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.125
         upper limit
    0.182
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [20] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (268) does not reflect the actual number.
    Statistical analysis title
    Tio 5 vs placebo
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as Tio 5 minus Placebo.
    Comparison groups
    Placebo v Tio 5 μg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority [21]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.141
         upper limit
    0.198
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Notes
    [21] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number.

    Secondary: FEV1 AUC0-12h Response [L] After 6 Weeks Treatment

    Close Top of page
    End point title
    FEV1 AUC0-12h Response [L] After 6 Weeks Treatment
    End point description
    This is a key secondary endpoint. Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 0 to 12 h post-dose, using the trapezoidal rule, divided by the duration (12h) to report in litres. Response was defined as the change from patient baseline. PFT time schedule: At Visits 2, 4, 6, 8: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2 and 3 h post-dose At Visits 3, 5, 7, 9: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min post-dose.
    End point type
    Secondary
    End point timeframe
    baseline and after 6 weeks (details in description)
    End point values
    Placebo Olo 5 μg Tio 2.5 μg Tio 5 μg T+O 2.5/5 μg T+O 5/5 μg
    Number of subjects analysed
    132 [22]
    136 [23]
    136 [24]
    135 [25]
    135 [26]
    138 [27]
    Units: litre(s)
        least squares mean (standard error)
    -0.013 ± 0.015
    0.179 ± 0.015
    0.171 ± 0.015
    0.186 ± 0.015
    0.31 ± 0.015
    0.305 ± 0.015
    Notes
    [22] - FAS
    [23] - FAS
    [24] - FAS
    [25] - FAS
    [26] - FAS
    [27] - FAS
    Statistical analysis title
    T+O 5/5 vs placebo
    Statistical analysis description
    The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Placebo.
    Comparison groups
    Placebo v T+O 5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [28]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.319
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.289
         upper limit
    0.349
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [28] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Olo 5
    Comparison groups
    Olo 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority [29]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.126
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.096
         upper limit
    0.156
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [29] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [30]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.119
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.089
         upper limit
    0.149
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [30] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Placebo.
    Comparison groups
    Placebo v T+O 2.5/5 μg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority [31]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.323
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.293
         upper limit
    0.354
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [31] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [32]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.131
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.101
         upper limit
    0.161
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [32] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.
    Comparison groups
    Tio 2.5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [33]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.139
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.109
         upper limit
    0.169
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [33] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [34]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.124
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.093
         upper limit
    0.154
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [34] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.

    Secondary: FEV1 AUC12-24h Response [L] After 6 Weeks Treatment

    Close Top of page
    End point title
    FEV1 AUC12-24h Response [L] After 6 Weeks Treatment
    End point description
    This is a key secondary endpoint. Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 12 to 24 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Response was defined as the change from patient baseline. PFT time schedule: At Visits 2, 4, 6, 8: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2 and 3 h post-dose. At Visits 3, 5, 7, 9: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min post-dose.
    End point type
    Secondary
    End point timeframe
    baseline and after 6 weeks (details in description)
    End point values
    Placebo Olo 5 μg Tio 2.5 μg Tio 5 μg T+O 2.5/5 μg T+O 5/5 μg
    Number of subjects analysed
    132 [35]
    136 [36]
    136 [37]
    135 [38]
    135 [39]
    138 [40]
    Units: litre(s)
        least squares mean (standard error)
    -0.06 ± 0.014
    0.079 ± 0.013
    0.062 ± 0.013
    0.081 ± 0.014
    0.172 ± 0.014
    0.182 ± 0.013
    Notes
    [35] - FAS
    [36] - FAS
    [37] - FAS
    [38] - FAS
    [39] - FAS
    [40] - FAS
    Statistical analysis title
    T+O 5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Placebo.
    Comparison groups
    Placebo v T+O 5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [41]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.243
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.212
         upper limit
    0.273
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [41] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority [42]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.103
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.074
         upper limit
    0.133
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [42] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [43]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.102
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.072
         upper limit
    0.132
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [43] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.
    Comparison groups
    Placebo v T+O 2.5/5 μg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority [44]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.232
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.201
         upper limit
    0.262
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [44] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [45]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.093
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.063
         upper limit
    0.123
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [45] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.
    Comparison groups
    Tio 2.5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [46]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.08
         upper limit
    0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [46] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [47]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.091
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.061
         upper limit
    0.121
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Notes
    [47] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.

    Secondary: Trough FEV1 Response [L] After 6 Weeks Treatment

    Close Top of page
    End point title
    Trough FEV1 Response [L] After 6 Weeks Treatment
    End point description
    The trough was defined as the mean of the 23 h and 23 h50 min measurements at Visits 3, 5, 7, 9 and Response was defined as the change from patient baseline. PFT time schedule: At Visits 2, 4, 6, 8: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2 and 3 h post-dose. At Visits 3, 5, 7, 9: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min post-dose.
    End point type
    Secondary
    End point timeframe
    baseline and after 6 weeks (details in description)
    End point values
    Placebo Olo 5 μg Tio 2.5 μg Tio 5 μg T+O 2.5/5 μg T+O 5/5 μg
    Number of subjects analysed
    132 [48]
    136 [49]
    136 [50]
    135 [51]
    135 [52]
    138 [53]
    Units: litre(s)
        least squares mean (standard error)
    -0.006 ± 0.015
    0.109 ± 0.015
    0.095 ± 0.015
    0.122 ± 0.015
    0.196 ± 0.015
    0.201 ± 0.015
    Notes
    [48] - FAS
    [49] - FAS
    [50] - FAS
    [51] - FAS
    [52] - FAS
    [53] - FAS
    Statistical analysis title
    T+O 5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Placebo.
    Comparison groups
    Placebo v T+O 5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [54]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.207
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.173
         upper limit
    0.241
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.017
    Notes
    [54] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority [55]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.092
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.059
         upper limit
    0.126
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.017
    Notes
    [55] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [56]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.079
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.045
         upper limit
    0.113
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.017
    Notes
    [56] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.
    Comparison groups
    Placebo v T+O 2.5/5 μg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority [57]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.201
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.167
         upper limit
    0.235
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.017
    Notes
    [57] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [58]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.086
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.052
         upper limit
    0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.017
    Notes
    [58] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.
    Comparison groups
    Tio 2.5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [59]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.101
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.067
         upper limit
    0.135
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.017
    Notes
    [59] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [60]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.073
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.039
         upper limit
    0.107
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.017
    Notes
    [60] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.

    Secondary: Peak(0-3h) FEV1 Response [L] After 6 Weeks Treatment

    Close Top of page
    End point title
    Peak(0-3h) FEV1 Response [L] After 6 Weeks Treatment
    End point description
    The peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline. PFT time schedule: At Visits 2, 4, 6, 8: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2 and 3 h post-dose. At Visits 3, 5, 7, 9: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min post-dose.
    End point type
    Secondary
    End point timeframe
    baseline and after 6 weeks (details in description)
    End point values
    Placebo Olo 5 μg Tio 2.5 μg Tio 5 μg T+O 2.5/5 μg T+O 5/5 μg
    Number of subjects analysed
    135 [61]
    138 [62]
    136 [63]
    137 [64]
    135 [65]
    138 [66]
    Units: litre(s)
        least squares mean (standard error)
    0.072 ± 0.017
    0.291 ± 0.016
    0.29 ± 0.016
    0.3 ± 0.016
    0.422 ± 0.016
    0.411 ± 0.016
    Notes
    [61] - FAS
    [62] - FAS
    [63] - FAS
    [64] - FAS
    [65] - FAS
    [66] - FAS
    Statistical analysis title
    T+O 5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Placebo.
    Comparison groups
    Placebo v T+O 5/5 μg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [67]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.338
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.305
         upper limit
    0.371
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.017
    Notes
    [67] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    superiority [68]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.087
         upper limit
    0.153
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.017
    Notes
    [68] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (276) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    superiority [69]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.111
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.078
         upper limit
    0.143
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.017
    Notes
    [69] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (275) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.
    Comparison groups
    Placebo v T+O 2.5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [70]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.317
         upper limit
    0.383
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.017
    Notes
    [70] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [71]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.131
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.098
         upper limit
    0.164
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.017
    Notes
    [71] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.
    Comparison groups
    Tio 2.5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [72]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.132
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.099
         upper limit
    0.165
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.017
    Notes
    [72] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority [73]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.122
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.089
         upper limit
    0.155
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.017
    Notes
    [73] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (272) does not reflect the actual number.

    Secondary: FVC AUC0-24h Response [L] After 6 Weeks Treatment

    Close Top of page
    End point title
    FVC AUC0-24h Response [L] After 6 Weeks Treatment
    End point description
    Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. Response was defined as the change from patient baseline. PFT time schedule: At Visits 2, 4, 6, 8: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2 and 3 h post-dose. At Visits 3, 5, 7, 9: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min post-dose.
    End point type
    Secondary
    End point timeframe
    baseline and after 6 weeks (details in description)
    End point values
    Placebo Olo 5 μg Tio 2.5 μg Tio 5 μg T+O 2.5/5 μg T+O 5/5 μg
    Number of subjects analysed
    132 [74]
    136 [75]
    136 [76]
    135 [77]
    135 [78]
    138 [79]
    Units: litre(s)
        least squares mean (standard error)
    -0.065 ± 0.023
    0.158 ± 0.022
    0.172 ± 0.022
    0.191 ± 0.022
    0.331 ± 0.022
    0.368 ± 0.022
    Notes
    [74] - FAS
    [75] - FAS
    [76] - FAS
    [77] - FAS
    [78] - FAS
    [79] - FAS
    Statistical analysis title
    T+O 5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Placebo.
    Comparison groups
    Placebo v T+O 5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [80]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.433
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.389
         upper limit
    0.477
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.022
    Notes
    [80] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority [81]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.166
         upper limit
    0.253
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.022
    Notes
    [81] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [82]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.177
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.133
         upper limit
    0.221
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.022
    Notes
    [82] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.
    Comparison groups
    Placebo v T+O 2.5/5 μg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority [83]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.396
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.352
         upper limit
    0.441
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.023
    Notes
    [83] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [84]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.173
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.129
         upper limit
    0.217
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.022
    Notes
    [84] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.
    Comparison groups
    Tio 2.5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [85]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.159
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.115
         upper limit
    0.203
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.022
    Notes
    [85] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [86]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.096
         upper limit
    0.184
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.022
    Notes
    [86] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.

    Secondary: FVC AUC0-12h Response [L] After 6 Weeks Treatment

    Close Top of page
    End point title
    FVC AUC0-12h Response [L] After 6 Weeks Treatment
    End point description
    Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Response was defined as the change from patient baseline. PFT time schedule: At Visits 2, 4, 6, 8: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2 and 3 h post-dose. At Visits 3, 5, 7, 9: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min post-dose.
    End point type
    Secondary
    End point timeframe
    baseline and after 6 weeks (details in description)
    End point values
    Placebo Olo 5 μg Tio 2.5 μg Tio 5 μg T+O 2.5/5 μg T+O 5/5 μg
    Number of subjects analysed
    132 [87]
    136 [88]
    136 [89]
    135 [90]
    135 [91]
    138 [92]
    Units: litre(s)
        least squares mean (standard error)
    -0.023 ± 0.024
    0.24 ± 0.024
    0.249 ± 0.024
    0.261 ± 0.024
    0.42 ± 0.024
    0.44 ± 0.024
    Notes
    [87] - FAS
    [88] - FAS
    [89] - FAS
    [90] - FAS
    [91] - FAS
    [92] - FAS
    Statistical analysis title
    T+O 5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Placebo.
    Comparison groups
    Placebo v T+O 5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [93]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.463
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.417
         upper limit
    0.509
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    Notes
    [93] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority [94]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.154
         upper limit
    0.246
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.023
    Notes
    [94] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [95]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.179
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.133
         upper limit
    0.225
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.023
    Notes
    [95] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.
    Comparison groups
    Placebo v T+O 2.5/5 μg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority [96]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.443
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.396
         upper limit
    0.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    Notes
    [96] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [97]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.181
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.134
         upper limit
    0.227
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    Notes
    [97] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.
    Comparison groups
    Tio 2.5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [98]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.171
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.125
         upper limit
    0.218
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    Notes
    [98] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [99]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.159
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.113
         upper limit
    0.206
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    Notes
    [99] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.

    Secondary: FVC AUC12-24h Response [L] After 6 Weeks Treatment

    Close Top of page
    End point title
    FVC AUC12-24h Response [L] After 6 Weeks Treatment
    End point description
    Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 12 to 24 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Response was defined as the change from patient baseline. PFT time schedule: At Visits 2, 4, 6, 8: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2 and 3 h post-dose. At Visits 3, 5, 7, 9: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min post-dose.
    End point type
    Secondary
    End point timeframe
    baseline and after 6 weeks (details in description)
    End point values
    Placebo Olo 5 μg Tio 2.5 μg Tio 5 μg T+O 2.5/5 μg T+O 5/5 μg
    Number of subjects analysed
    132 [100]
    136 [101]
    136 [102]
    135 [103]
    135 [104]
    138 [105]
    Units: litre(s)
        least squares mean (standard error)
    -0.108 ± 0.023
    0.077 ± 0.023
    0.095 ± 0.023
    0.122 ± 0.023
    0.243 ± 0.023
    0.296 ± 0.023
    Notes
    [100] - FAS
    [101] - FAS
    [102] - FAS
    [103] - FAS
    [104] - FAS
    [105] - FAS
    Statistical analysis title
    T+O 5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Placebo.
    Comparison groups
    Placebo v T+O 5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [106]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.404
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.355
         upper limit
    0.453
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Notes
    [106] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority [107]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.219
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.17
         upper limit
    0.267
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Notes
    [107] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [108]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.174
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.126
         upper limit
    0.223
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Notes
    [108] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.
    Comparison groups
    Placebo v T+O 2.5/5 μg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority [109]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.351
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.301
         upper limit
    0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Notes
    [109] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [110]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.166
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.117
         upper limit
    0.214
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Notes
    [110] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.
    Comparison groups
    Tio 2.5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [111]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.148
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.099
         upper limit
    0.197
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Notes
    [111] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [112]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.121
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.072
         upper limit
    0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Notes
    [112] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.

    Secondary: Trough FVC Response [L] After 6 Weeks Treatment

    Close Top of page
    End point title
    Trough FVC Response [L] After 6 Weeks Treatment
    End point description
    The trough was defined as the mean of the 23 h and 23 h50 min measurements at visits 3, 5, 7, 9 and response was defined as the change from patient baseline. PFT time schedule: At Visits 2, 4, 6, 8: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2 and 3 h post-dose. At Visits 3, 5, 7, 9: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min post-dose.
    End point type
    Secondary
    End point timeframe
    baseline and after 6 weeks (details in description)
    End point values
    Placebo Olo 5 μg Tio 2.5 μg Tio 5 μg T+O 2.5/5 μg T+O 5/5 μg
    Number of subjects analysed
    132 [113]
    136 [114]
    136 [115]
    135 [116]
    135 [117]
    138 [118]
    Units: litre(s)
        least squares mean (standard error)
    -0.025 ± 0.026
    0.134 ± 0.026
    0.115 ± 0.026
    0.183 ± 0.026
    0.282 ± 0.026
    0.304 ± 0.026
    Notes
    [113] - FAS
    [114] - FAS
    [115] - FAS
    [116] - FAS
    [117] - FAS
    [118] - FAS
    Statistical analysis title
    T+O 5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Placebo.
    Comparison groups
    Placebo v T+O 5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [119]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.329
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.274
         upper limit
    0.385
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [119] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority [120]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.115
         upper limit
    0.225
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [120] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (274) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [121]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.121
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.066
         upper limit
    0.176
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [121] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.
    Comparison groups
    Placebo v T+O 2.5/5 μg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority [122]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.307
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.251
         upper limit
    0.363
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.029
    Notes
    [122] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (267) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [123]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.147
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.092
         upper limit
    0.203
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [123] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.
    Comparison groups
    Tio 2.5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [124]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.166
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.111
         upper limit
    0.222
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [124] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [125]
    P-value
    = 0.0005
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.099
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.043
         upper limit
    0.154
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [125] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.

    Secondary: Peak (0-3h) FVC Response [L] After 6 Weeks Treatment

    Close Top of page
    End point title
    Peak (0-3h) FVC Response [L] After 6 Weeks Treatment
    End point description
    Peak (0-3h) Forced Vital Capacity (FVC) responses. Peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline. PFT time schedule: At Visits 2, 4, 6, 8: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2 and 3 h post-dose. At Visits 3, 5, 7, 9: pre-dose PFT: 30 mins prior to inhalation of dose of study medication; post-dose PFT: 30 min, 1, 2, 3, 4, 6, 8, 10, 12, 22, 23 h and 23h 50 min post-dose.
    End point type
    Secondary
    End point timeframe
    baseline and after 6 weeks (details in description)
    End point values
    Placebo Olo 5 μg Tio 2.5 μg Tio 5 μg T+O 2.5/5 μg T+O 5/5 μg
    Number of subjects analysed
    135 [126]
    138 [127]
    136 [128]
    137 [129]
    135 [130]
    138 [131]
    Units: litre(s)
        least squares mean (standard error)
    0.159 ± 0.029
    0.463 ± 0.029
    0.45 ± 0.029
    0.47 ± 0.029
    0.612 ± 0.029
    0.621 ± 0.028
    Notes
    [126] - FAS
    [127] - FAS
    [128] - FAS
    [129] - FAS
    [130] - FAS
    [131] - FAS
    Statistical analysis title
    T+O 5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Placebo.
    Comparison groups
    Placebo v T+O 5/5 μg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [132]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.462
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.408
         upper limit
    0.516
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [132] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    superiority [133]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.159
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.105
         upper limit
    0.212
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027
    Notes
    [133] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (276) does not reflect the actual number.
    Statistical analysis title
    T+O 5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 5/5 μg
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    superiority [134]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.151
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.098
         upper limit
    0.205
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027
    Notes
    [134] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (275) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs placebo
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus placebo.
    Comparison groups
    Placebo v T+O 2.5/5 μg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [135]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.452
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.398
         upper limit
    0.507
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [135] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (270) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Olo 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Olo 5.
    Comparison groups
    Olo 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [136]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.149
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.095
         upper limit
    0.203
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [136] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (273) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 2.5.
    Comparison groups
    Tio 2.5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority [137]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.161
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.107
         upper limit
    0.216
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [137] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (271) does not reflect the actual number.
    Statistical analysis title
    T+O 2.5/5 vs Tio 5
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The adjusted mean difference is calculated as T+O 2.5/5 minus Tio 5.
    Comparison groups
    Tio 5 μg v T+O 2.5/5 μg
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority [138]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.142
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.087
         upper limit
    0.196
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [138] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (272) does not reflect the actual number.

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From drug administration until 21 days after the last administration, up to 92 days.
    Adverse event reporting additional description
    AE additional description
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo matching Tiotropium+Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 Oral inhalations once daily in the morning for 6 weeks.

    Reporting group title
    Olodaterol (5 µg)
    Reporting group description
    Olodaterol solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.

    Reporting group title
    Tiotropium (2.5 µg)
    Reporting group description
    Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.

    Reporting group title
    Tiotropium (5 µg)
    Reporting group description
    Tiotropium solution for inhalation - RESPIMAT : 2 oral inhalations once daily in the morning for 6 weeks.

    Reporting group title
    Tiotropium+Olodaterol FDC (2.5/5 µg)
    Reporting group description
    Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.

    Reporting group title
    Tiotropium+Olodaterol FDC (5/5 µg)
    Reporting group description
    Tiotropium + Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT: 2 oral inhalations once daily in the morning for 6 weeks.

    Serious adverse events
    Placebo Olodaterol (5 µg) Tiotropium (2.5 µg) Tiotropium (5 µg) Tiotropium+Olodaterol FDC (2.5/5 µg) Tiotropium+Olodaterol FDC (5/5 µg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 138 (2.90%)
    8 / 138 (5.80%)
    5 / 137 (3.65%)
    3 / 138 (2.17%)
    4 / 136 (2.94%)
    1 / 139 (0.72%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Arterial disorder
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 138 (0.72%)
    0 / 137 (0.00%)
    0 / 138 (0.00%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    0 / 138 (0.00%)
    2 / 138 (1.45%)
    0 / 137 (0.00%)
    0 / 138 (0.00%)
    1 / 136 (0.74%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery aneurysm
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 138 (0.72%)
    0 / 137 (0.00%)
    0 / 138 (0.00%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 138 (0.00%)
    1 / 137 (0.73%)
    0 / 138 (0.00%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 138 (0.00%)
    1 / 137 (0.73%)
    0 / 138 (0.00%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 138 (0.00%)
    1 / 137 (0.73%)
    0 / 138 (0.00%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 138 (0.00%)
    0 / 137 (0.00%)
    0 / 138 (0.00%)
    1 / 136 (0.74%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 138 (0.72%)
    0 / 137 (0.00%)
    1 / 138 (0.72%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Food allergy
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 138 (0.00%)
    0 / 137 (0.00%)
    1 / 138 (0.72%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 138 (0.00%)
    0 / 137 (0.00%)
    1 / 138 (0.72%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Impaired healing
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 138 (0.72%)
    0 / 137 (0.00%)
    0 / 138 (0.00%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 138 (0.00%)
    0 / 137 (0.00%)
    0 / 138 (0.00%)
    1 / 136 (0.74%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 138 (0.00%)
    0 / 137 (0.00%)
    0 / 138 (0.00%)
    1 / 136 (0.74%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 138 (0.00%)
    0 / 137 (0.00%)
    1 / 138 (0.72%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Comminuted fracture
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 138 (0.72%)
    0 / 137 (0.00%)
    0 / 138 (0.00%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial tachycardia
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 138 (0.00%)
    1 / 137 (0.73%)
    0 / 138 (0.00%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 138 (0.72%)
    1 / 137 (0.73%)
    0 / 138 (0.00%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 138 (0.00%)
    0 / 137 (0.00%)
    0 / 138 (0.00%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 138 (0.00%)
    0 / 137 (0.00%)
    1 / 138 (0.72%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 138 (1.45%)
    2 / 138 (1.45%)
    0 / 137 (0.00%)
    0 / 138 (0.00%)
    0 / 136 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 138 (0.72%)
    0 / 137 (0.00%)
    0 / 138 (0.00%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 138 (0.00%)
    0 / 137 (0.00%)
    1 / 138 (0.72%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 138 (0.00%)
    0 / 137 (0.00%)
    1 / 138 (0.72%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 138 (0.72%)
    1 / 138 (0.72%)
    0 / 137 (0.00%)
    0 / 138 (0.00%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 138 (0.00%)
    0 / 137 (0.00%)
    0 / 138 (0.00%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal infarct
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 138 (0.72%)
    0 / 137 (0.00%)
    0 / 138 (0.00%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 138 (0.00%)
    0 / 137 (0.00%)
    1 / 138 (0.72%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 138 (0.72%)
    0 / 137 (0.00%)
    1 / 138 (0.72%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 138 (1.45%)
    0 / 138 (0.00%)
    1 / 137 (0.73%)
    1 / 138 (0.72%)
    0 / 136 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salpingitis
         subjects affected / exposed
    0 / 138 (0.00%)
    0 / 138 (0.00%)
    0 / 137 (0.00%)
    0 / 138 (0.00%)
    1 / 136 (0.74%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Olodaterol (5 µg) Tiotropium (2.5 µg) Tiotropium (5 µg) Tiotropium+Olodaterol FDC (2.5/5 µg) Tiotropium+Olodaterol FDC (5/5 µg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 138 (30.43%)
    21 / 138 (15.22%)
    30 / 137 (21.90%)
    29 / 138 (21.01%)
    23 / 136 (16.91%)
    25 / 139 (17.99%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    15 / 138 (10.87%)
    5 / 138 (3.62%)
    13 / 137 (9.49%)
    12 / 138 (8.70%)
    8 / 136 (5.88%)
    9 / 139 (6.47%)
         occurrences all number
    16
    5
    14
    12
    8
    9
    Cough
         subjects affected / exposed
    7 / 138 (5.07%)
    2 / 138 (1.45%)
    3 / 137 (2.19%)
    6 / 138 (4.35%)
    2 / 136 (1.47%)
    7 / 139 (5.04%)
         occurrences all number
    7
    3
    3
    6
    2
    7
    Dyspnoea
         subjects affected / exposed
    9 / 138 (6.52%)
    3 / 138 (2.17%)
    4 / 137 (2.92%)
    3 / 138 (2.17%)
    1 / 136 (0.74%)
    2 / 139 (1.44%)
         occurrences all number
    9
    3
    4
    3
    1
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    14 / 138 (10.14%)
    12 / 138 (8.70%)
    12 / 137 (8.76%)
    12 / 138 (8.70%)
    12 / 136 (8.82%)
    9 / 139 (6.47%)
         occurrences all number
    14
    12
    12
    12
    12
    10

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Mar 2012
    Additional guidance was provided regarding individual withdrawal criteria, and regarding medication restrictions. It was specified that adjudication was to be carried out for all SAEs (rather than only fatal events), and that clinically significant laboratory values were to be entered as AEs. Modifications were introduced regarding the time points of vital sign acquisition and regarding the pre-dose time window for PFT measurements. Administrative changes, corrections, and further clarifications were introduced.

    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
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2019 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA