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    Clinical Trial Results:
    A randomised, double-blind, cross-over study to evaluate the effect of 6 weeks treatment of orally inhaled tiotropium + olodaterol fixed dose combination (5/5 μg) compared with tiotropium (5 μg), both delivered by the Respimat® Inhaler, on breathlessness during the three minute Constant Speed Shuttle Test (3min CSST) in patients with Chronic Obstructive Pulmonary Disease (COPD).

    Summary
    EudraCT number
    		 2015-002974-20
    Trial protocol
    		 BE   NL  
    Global end of trial date
    14 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Aug 2018
    First version publication date
    29 Aug 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1237.28
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02853123
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, 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
    29 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the effect of tiotropium + olodaterol fixed dose combination (FDC) compared to tiotropium monotherapy on the intensity of breathlessness during the 3minute (min) Constant Speed Shuttle Test (CSST).
    Protection of trial subjects
    Only participants that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All participants were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all participants was adhered to throughout the trial conduct. Rescue medication was allowed for all participants as required. The terms and conditions of the insurance coverage were available to the investigator and the patients in the investigator site file (ISF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Oct 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 31
    Country: Number of subjects enrolled
    Belgium: 26
    Country: Number of subjects enrolled
    Germany: 45
    Country: Number of subjects enrolled
    Netherlands: 28
    Worldwide total number of subjects
    130
    EEA total number of subjects
    99
    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)
    59
    From 65 to 84 years
    71
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A randomized, double-blind, active-controlled, 2-period crossover, Phase IV study to evaluate the effects of tiotropium+olodaterol fixed dose combination compared with tiotropium on the intensity of breathlessness in patients with Chronic Obstructive Pulmonary Disease. Total of 130 patients were enrolled, 106 patients were entered and randomized.

    Pre-assignment
    Screening details
    		 All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which then ensured that all patients met all inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any specific entry criteria were violated.

    Period 1
    Period 1 title
    Period 1 (Overall trial by sequence)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    This is Randomised and controlled trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tiotropium 5 microgram (μg)/ Tiotropium + Olodaterol 5/5 μg
    Arm description
    		 Patients inhaled 2 puffs from the Respimat® Inhaler of the Tiotropium (Tio) inhalation solution (2.5 μg per actuation) once a day, in the morning for a period of 6 weeks in period 1 followed by a 3 week washout period. In period 2, patients inhaled 2 puffs from the Respimat® Inhaler of the Tiotropium + Olodaterol (Tio+Olo) fixed dose combination (FDC) inhalation solution (2.5/2.5 μg per actuation) once a day, in the morning for a period of 6 weeks.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium + Olodaterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 puffs from the Respimat® Inhaler of the Tiotropium + Olodaterol Fixed Dose Combination (FDC) inhalation solution (2.5/2.5 μg per actuation) once a day, in the morning for a period of 6 weeks

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 puffs from the Respimat® Inhaler of the Tiotropium inhalation solution (2.5 μg per actuation) once a day, in the morning for a period of 6 weeks

    Arm title
    		 Tiotropium + Olodaterol 5/5 μg/Tiotropium 5 μg
    Arm description
    		 Patients inhaled 2 puffs from the Respimat® Inhaler of the Tiotropium + Olodaterol (Tio+Olo) fixed dose combination (FDC) inhalation solution (2.5/2.5 μg per actuation) once a day, in the morning for a period of 6 weeks in period 1 followed by a 3 week washout period. In period 2, patients inhaled 2 puffs from the Respimat® Inhaler of the Tiotropium (Tio) inhalation solution (2.5 μg per actuation) once a day, in the morning for a period of 6 weeks.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 puffs from the Respimat® Inhaler of the Tiotropium inhalation solution (2.5 μg per actuation) once a day, in the morning for a period of 6 weeks

    Investigational medicinal product name
    Tiotropium + Olodaterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 puffs from the Respimat® Inhaler of the Tiotropium + Olodaterol Fixed Dose Combination (FDC) inhalation solution (2.5/2.5 μg per actuation) once a day, in the morning for a period of 6 weeks

    Number of subjects in period 1 [1]
    		Tiotropium 5 microgram (μg)/ Tiotropium + Olodaterol 5/5 μg Tiotropium + Olodaterol 5/5 μg/Tiotropium 5 μg
    Started
    52
    54
    Completed
    51
    48
    Not completed
    1
    6
         Adverse event, non-fatal
    1
    3
         Worsening COPD
    -
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.
    Period 2
    Period 2 title
    Period 2 (Treatment period)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    This is Randomised and controlled trial.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Tiotropium 5 microgram (μg)
    Arm description
    		 Patients inhaled 2 puffs from the Respimat® Inhaler of the Tiotropium (Tio) inhalation solution (2.5 μg per actuation) once a day, in the morning for a period of 6 weeks.
    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 puffs from the Respimat® Inhaler of the Tiotropium inhalation solution (2.5 μg per actuation) once a day, in the morning for a period of 6 weeks

    Arm title
    		 Tiotropium + Olodaterol 5/5 μg
    Arm description
    		 Patients inhaled 2 puffs from the Respimat® Inhaler of the Tiotropium + Olodaterol (Tio+Olo) fixed dose combination (FDC) inhalation solution (2.5/2.5 μg per actuation) once a day, in the morning for a period of 6 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium + Olodaterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Patients inhaled 2 puffs from the Respimat® Inhaler of the Tiotropium + Olodaterol Fixed Doce Combination (FDC) inhalation solution (2.5/2.5 μg per actuation) once a day, in the morning for a period of 6 weeks

    Number of subjects in period 2
    		Tiotropium 5 microgram (μg) Tiotropium + Olodaterol 5/5 μg
    Started
    100
    105
    Completed
    100
    102
    Not completed
    0
    3
         Adverse event, non-fatal
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Period 1 (Overall trial by sequence)
    Reporting group description
    		 This patient set was nested within the randomized set (RS) and included all patients who were dispensed study medication and were documented to have taken any dose of study medication.

    Reporting group values
    		 Period 1 (Overall trial by sequence) Total
    Number of subjects
    		 106
    Age categorical
    Units: Subjects
    Age Continuous
    The age data are presented by years. Treated set (TS): This patient set was nested within the RS and included all patients who were dispensed study medication and were documented to have taken any dose of study medication.
    Units: years
        arithmetic mean (standard deviation)
    		 63.6 ( 7.2 ) -
    Sex: Female, Male
    The sex data are presented by count of participants. TS
    Units: Subjects
        Male
    		 66 66
        Female
    		 40 40
    Race (NIH/OMB)
    The race data are presented by count of participants. Ethnicity was not captured in this trial.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 0 0
        White
    		 105 105
        More than one race
    		 0 0
        Unknown or Not Reported
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    Tiotropium 5 microgram (μg)/ Tiotropium + Olodaterol 5/5 μg
    Reporting group description
    		 Patients inhaled 2 puffs from the Respimat® Inhaler of the Tiotropium (Tio) inhalation solution (2.5 μg per actuation) once a day, in the morning for a period of 6 weeks in period 1 followed by a 3 week washout period. In period 2, patients inhaled 2 puffs from the Respimat® Inhaler of the Tiotropium + Olodaterol (Tio+Olo) fixed dose combination (FDC) inhalation solution (2.5/2.5 μg per actuation) once a day, in the morning for a period of 6 weeks.

    Reporting group title
    Tiotropium + Olodaterol 5/5 μg/Tiotropium 5 μg
    Reporting group description
    		 Patients inhaled 2 puffs from the Respimat® Inhaler of the Tiotropium + Olodaterol (Tio+Olo) fixed dose combination (FDC) inhalation solution (2.5/2.5 μg per actuation) once a day, in the morning for a period of 6 weeks in period 1 followed by a 3 week washout period. In period 2, patients inhaled 2 puffs from the Respimat® Inhaler of the Tiotropium (Tio) inhalation solution (2.5 μg per actuation) once a day, in the morning for a period of 6 weeks.
    Reporting group title
    Tiotropium 5 microgram (μg)
    Reporting group description
    		 Patients inhaled 2 puffs from the Respimat® Inhaler of the Tiotropium (Tio) inhalation solution (2.5 μg per actuation) once a day, in the morning for a period of 6 weeks.

    Reporting group title
    Tiotropium + Olodaterol 5/5 μg
    Reporting group description
    		 Patients inhaled 2 puffs from the Respimat® Inhaler of the Tiotropium + Olodaterol (Tio+Olo) fixed dose combination (FDC) inhalation solution (2.5/2.5 μg per actuation) once a day, in the morning for a period of 6 weeks.

    Primary: Change from baseline in intensity of breathlessness measured using the Modified Borg Scale at the end of the 3 minute Constant Speed Shuttle Test after 6 weeks of treatment.

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    End point title
    		 Change from baseline in intensity of breathlessness measured using the Modified Borg Scale at the end of the 3 minute Constant Speed Shuttle Test after 6 weeks of treatment.
    End point description
    At 3 min or end of exercise (if 3 min not achieved), patients were asked to estimate the intensity of breathing discomfort that they were experiencing by matching their subjective estimate to descriptive phrases that best described the intensity of each sensation using the Modified Borg Scale (MBS-S). Measure type is actually Adjusted Mean Change from Baseline. Full analysis set (FAS): This patient set was nested within the Treated set (TS) and included patients who had baseline measurement and at least one post-baseline measurement for the primary endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and week 6
    End point values
    		 Tiotropium 5 microgram (μg) Tiotropium + Olodaterol 5/5 μg
    Number of subjects analysed
    100 [1]
    101 [2]
    Units: Unit on Scale
        least squares mean (standard error)
    -0.968 ( 0.137 )
    -1.325 ( 0.136 )
    Notes
    [1] - FAS
    [2] - FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within−patient variation.
    Comparison groups
    Tiotropium 5 microgram (μg) v Tiotropium + Olodaterol 5/5 μg
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0217 [4]
    Method
    		 Mixed Effect Model Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.357
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.661
         upper limit
    		 -0.053
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.153
    Notes
    [3] - Mean difference means the treatment difference vs. Tiotropium (i.e. Tiotropium/Olodaterol - Tiotropium). 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 (201) does not reflect the actual number. The number of subjects in FAS is 105.
    [4] - Kenward−Roger approximation of denominator was used for degrees of freedom.

    Secondary: Change from baseline after 6 weeks of treatment for inspiratory capacity measured prior to exercise

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    End point title
    		 Change from baseline after 6 weeks of treatment for inspiratory capacity measured prior to exercise
    End point description
    Inspiratory Capacity (IC) is a standard measurement for the assessment of lung function. IC measurements were performed prior to the 3min Constant Speed Shuttle Test (CSST) (at rest). Measure type is actually Adjusted Mean Change from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and week 6
    End point values
    		 Tiotropium 5 microgram (μg) Tiotropium + Olodaterol 5/5 μg
    Number of subjects analysed
    100 [5]
    101 [6]
    Units: Litre (L)
        least squares mean (standard error)
    0.279 ( 0.040 )
    0.464 ( 0.039 )
    Notes
    [5] - FAS
    [6] - FAS
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    IC measured prior to exercise, the adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within−patient variation.
    Comparison groups
    Tiotropium 5 microgram (μg) v Tiotropium + Olodaterol 5/5 μg
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed Effect Model Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.185
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.106
         upper limit
    		 0.265
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04
    Notes
    [7] - Mean difference means the treatment difference vs. Tiotropium (i.e. Tiotropium/Olodaterol - Tiotropium). 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 (201) does not reflect the actual number. The number of subjects in FAS is 105.
    [8] - Kenward−Roger approximation of denominator was used for degrees of freedom.

    Secondary: Change from baseline after 6 weeks of treatment for inspiratory capacity measured at the end of exercise

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    End point title
    		 Change from baseline after 6 weeks of treatment for inspiratory capacity measured at the end of exercise
    End point description
    Inspiratory Capacity (IC) is a standard measurement for the assessment of lung function. IC measurements were performed at the end of the 3min Constant Speed Shuttle Test (CSST). Measure type is actually Adjusted Mean Change from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and week 6
    End point values
    		 Tiotropium 5 microgram (μg) Tiotropium + Olodaterol 5/5 μg
    Number of subjects analysed
    98 [9]
    100 [10]
    Units: Litre (L)
        least squares mean (standard error)
    0.256 ( 0.034 )
    0.322 ( 0.034 )
    Notes
    [9] - FAS
    [10] - FAS
    Statistical analysis title
    		 Statistical Annalysis 3
    Statistical analysis description
    IC measured end of exercise, the adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within−patient variation
    Comparison groups
    Tiotropium 5 microgram (μg) v Tiotropium + Olodaterol 5/5 μg
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0852 [12]
    Method
    		 Mixed Effect Model Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.066
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.009
         upper limit
    		 0.141
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.038
    Notes
    [11] - Mean difference means the treatment difference vs. Tiotropium (i.e. Tiotropium/Olodaterol - Tiotropium). 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 (198) does not reflect the actual number. The number of subjects in FAS is 105.
    [12] - Kenward−Roger approximation of denominator was used for degrees of freedom.

    Secondary: Change from baseline after 6 weeks of treatment for 1 hour post-dose Forced Expiratory Volume in 1st second

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    End point title
    		 Change from baseline after 6 weeks of treatment for 1 hour post-dose Forced Expiratory Volume in 1st second
    End point description
    Forced Expiratory Volume in 1st second (FEV1) is a standard measurement for the assessment of lung function. The best of 3 efforts was defined as the highest FEV1, each obtained on any of 3 manoeuvres meeting the American Thoracic Society (ATS) criteria (to a maximum of 5 attempts). Measure type is actually Adjusted Mean Change from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and week 6
    End point values
    		 Tiotropium 5 microgram (μg) Tiotropium + Olodaterol 5/5 μg
    Number of subjects analysed
    99 [13]
    103 [14]
    Units: Litre (L)
        least squares mean (standard error)
    0.163 ( 0.021 )
    0.318 ( 0.021 )
    Notes
    [13] - FAS
    [14] - FAS
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    The adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within−patient variation.
    Comparison groups
    Tiotropium 5 microgram (μg) v Tiotropium + Olodaterol 5/5 μg
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 < 0.0001 [16]
    Method
    		 Mixed Effect Model Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.155
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.117
         upper limit
    		 0.194
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02
    Notes
    [15] - Mean difference means the treatment difference vs. Tiotropium (i.e. Tiotropium/Olodaterol - Tiotropium). 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 (202) does not reflect the actual number. The number of subjects in FAS is 105.
    [16] - Kenward−Roger approximation of denominator was used for degrees of freedom.

    Secondary: Change from baseline after 6 weeks of treatment for 1 hour post-dose Forced Vital Capacity

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    End point title
    		 Change from baseline after 6 weeks of treatment for 1 hour post-dose Forced Vital Capacity
    End point description
    Forced Vital Capacity (FVC) is a standard measurement for the assessment of lung function. The best of 3 efforts was defined as the highest FVC, each obtained on any of 3 manoeuvres meeting the American Thoracic Society (ATS) criteria (to a maximum of 5 attempts). Measure type is actually Adjusted Mean Change from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and week 6
    End point values
    		 Tiotropium 5 microgram (μg) Tiotropium + Olodaterol 5/5 μg
    Number of subjects analysed
    99 [17]
    103 [18]
    Units: Litre (L)
        least squares mean (standard error)
    0.258 ( 0.040 )
    0.459 ( 0.039 )
    Notes
    [17] - FAS
    [18] - FAS
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    The adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within−patient variation.
    Comparison groups
    Tiotropium 5 microgram (μg) v Tiotropium + Olodaterol 5/5 μg
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 < 0.0001 [20]
    Method
    		 Mixed Effect Model Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.201
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.134
         upper limit
    		 0.267
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.034
    Notes
    [19] - Mean difference means the treatment difference vs. Tiotropium (i.e. Tiotropium/Olodaterol - Tiotropium). 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 (202) does not reflect the actual number. The number of subjects in FAS is 105.
    [20] - Kenward−Roger approximation of denominator was used for degrees of freedom.

    Secondary: Change from baseline after 6 weeks of treatment for intensity of breathlessness (MBS-S) at 1, 2 and 2.5 minute (min) during the 3 min Constant Speed Shuttle Test

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    End point title
    		 Change from baseline after 6 weeks of treatment for intensity of breathlessness (MBS-S) at 1, 2 and 2.5 minute (min) during the 3 min Constant Speed Shuttle Test
    End point description
    At 1, 2 and 2.5 min during exercise, patients were asked to estimate the intensity of breathing discomfort that they were experiencing by matching their subjective estimate to descriptive phrases that best described the intensity of each sensation using the Modified Borg Scale (MBS-S). Measure type is actually Adjusted Mean Change from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and week 6
    End point values
    		 Tiotropium 5 microgram (μg) Tiotropium + Olodaterol 5/5 μg
    Number of subjects analysed
    100 [21]
    101 [22]
    Units: Unit on Scale
    least squares mean (standard error)
        1 min
    -0.685 ( 0.081 )
    -0.793 ( 0.081 )
        2 min
    -0.839 ( 0.102 )
    -1.079 ( 0.101 )
        2.5 min
    -0.846 ( 0.127 )
    -1.164 ( 0.126 )
    Notes
    [21] - FAS
    [22] - FAS
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    1 min, the adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within−patient variation.
    Comparison groups
    Tiotropium 5 microgram (μg) v Tiotropium + Olodaterol 5/5 μg
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.2645 [24]
    Method
    		 Mixed Effect Model Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.108
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.083
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.096
    Notes
    [23] - Mean difference means the treatment difference vs. Tiotropium (i.e. Tiotropium/Olodaterol - Tiotropium). 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 (201) does not reflect the actual number. The number of subjects in FAS is 105.
    [24] - Kenward−Roger approximation of denominator was used for degrees of freedom.
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    2 min, the adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within−patient variation.
    Comparison groups
    Tiotropium 5 microgram (μg) v Tiotropium + Olodaterol 5/5 μg
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.0267 [26]
    Method
    		 Mixed Effect Model Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.452
         upper limit
    		 -0.028
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.107
    Notes
    [25] - Mean difference means the treatment difference vs. Tiotropium (i.e. Tiotropium/Olodaterol - Tiotropium). 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 (201) does not reflect the actual number. The number of subjects in FAS is 105.
    [26] - Kenward−Roger approximation of denominator was used for degrees of freedom.
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    2.5 min, the adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within−patient variation.
    Comparison groups
    Tiotropium 5 microgram (μg) v Tiotropium + Olodaterol 5/5 μg
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.0258 [28]
    Method
    		 Mixed Effect Model Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.318
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.596
         upper limit
    		 -0.039
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.14
    Notes
    [27] - Mean difference means the treatment difference vs. Tiotropium (i.e. Tiotropium/Olodaterol - Tiotropium). 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 (201) does not reflect the actual number. The number of subjects in FAS is 105.
    [28] - Kenward−Roger approximation of denominator was used for degrees of freedom.

    Secondary: Change from baseline after 6 weeks of treatment for Chronic Respiratory Questionnaire - Self Administered Individualized dyspnoea domain score

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    End point title
    		 Change from baseline after 6 weeks of treatment for Chronic Respiratory Questionnaire - Self Administered Individualized dyspnoea domain score
    End point description
    Patients completed the Chronic Respiratory Questionnaire - Self Administered Individualized (CRQ-SAI) questionnaire, which contained a dyspnoea domain individualized to each patient. The patients were asked to select the 5 activities among 26 activities associated with breathlessness that they performed frequently and were most important to them. Measure type is actually Adjusted Mean Change from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and week 6
    End point values
    		 Tiotropium 5 microgram (μg) Tiotropium + Olodaterol 5/5 μg
    Number of subjects analysed
    93 [29]
    96 [30]
    Units: Unit on Scale
        least squares mean (standard error)
    0.640 ( 0.091 )
    0.610 ( 0.089 )
    Notes
    [29] - FAS
    [30] - FAS
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    The adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within−patient variation.
    Comparison groups
    Tiotropium 5 microgram (μg) v Tiotropium + Olodaterol 5/5 μg
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.8025 [32]
    Method
    		 Mixed Effect Model Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.268
         upper limit
    		 0.208
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [31] - Mean difference means the treatment difference vs. Tiotropium (i.e. Tiotropium/Olodaterol - Tiotropium). 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 (189) does not reflect the actual number. The number of subjects in FAS is 105.
    [32] - Kenward−Roger approximation of denominator was used for degrees of freedom.

    Secondary: Change from baseline after 6 weeks of treatment for Chronic Respiratory Questionnaire - Self Administered Standardized dyspnoea domain score

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    End point title
    		 Change from baseline after 6 weeks of treatment for Chronic Respiratory Questionnaire - Self Administered Standardized dyspnoea domain score
    End point description
    The Chronic Respiratory Questionnaire - Self Administered Standardized (CRQ-SAS) is a questionnaire that assesses the patients’ perception of their COPD and measures the impact of COPD on their life and contains 20 standardized questions. The first part of the questionnaire contains 5 standardized activities and the patients had to indicate how much shortness of breath they had experienced while performing each of the activities. Measure type is actually Adjusted Mean Change from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and week 6
    End point values
    		 Tiotropium 5 microgram (μg) Tiotropium + Olodaterol 5/5 μg
    Number of subjects analysed
    100 [33]
    102 [34]
    Units: Unit on Scale
        least squares mean (standard error)
    0.325 ( 0.088 )
    0.415 ( 0.087 )
    Notes
    [33] - FAS
    [34] - FAS
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    The adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within−patient variation.
    Comparison groups
    Tiotropium 5 microgram (μg) v Tiotropium + Olodaterol 5/5 μg
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 = 0.3634 [36]
    Method
    		 Mixed Effect Model Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.106
         upper limit
    		 0.286
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.099
    Notes
    [35] - Mean difference means the treatment difference vs. Tiotropium (i.e. Tiotropium/Olodaterol - Tiotropium). 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 (202) does not reflect the actual number. The number of subjects in FAS is 105.
    [36] - Kenward−Roger approximation of denominator was used for degrees of freedom.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first drug administration until 21 days after last drug administration, up to 18 weeks.
    Adverse event reporting additional description
    Treated set (TS) (This patient set was nested within the Randomised set (RS) and included all patients who were dispensed study medication and were documented to have taken any dose of study medication.) was used for patient safety analyses.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Tiotropium 5 microgram (μg)
    Reporting group description
    		 Patients inhaled 2 puffs from the Respimat® Inhaler of the Tiotropium (Tio) inhalation solution (2.5 μg per actuation) once a day, in the morning for a period of 6 weeks.

    Reporting group title
    Total subjects
    Reporting group description
    		 This patient set was nested within the randomized set (RS) and included all patients who were dispensed study medication and were documented to have taken any dose of study medication.

    Reporting group title
    Tiotropium + Olodaterol 5/5 μg
    Reporting group description
    		 Patients inhaled 2 puffs from the Respimat® Inhaler of the Tiotropium + Olodaterol (Tio+Olo) fixed dose combination (FDC) inhalation solution (2.5/2.5 μg per actuation) once a day, in the morning for a period of 6 weeks.

    Serious adverse events
    		 Tiotropium 5 microgram (μg) Total subjects Tiotropium + Olodaterol 5/5 μg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 100 (1.00%)
    6 / 106 (5.66%)
    5 / 105 (4.76%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon neoplasm
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 106 (0.94%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 106 (0.94%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 106 (0.94%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 106 (0.94%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 106 (0.94%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 106 (0.94%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 106 (0.94%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 106 (0.94%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tiotropium 5 microgram (μg) Total subjects Tiotropium + Olodaterol 5/5 μg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 100 (21.00%)
    44 / 106 (41.51%)
    31 / 105 (29.52%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    10 / 100 (10.00%)
    22 / 106 (20.75%)
    14 / 105 (13.33%)
         occurrences all number
    12
    30
    18
    Cough
         subjects affected / exposed
    2 / 100 (2.00%)
    6 / 106 (5.66%)
    5 / 105 (4.76%)
         occurrences all number
    2
    7
    5
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    13 / 100 (13.00%)
    23 / 106 (21.70%)
    14 / 105 (13.33%)
         occurrences all number
    13
    27
    14

    More information

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

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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