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    Clinical Trial Results:
    A randomised, double-blind, parallel group study to assess the efficacy and safety of 52 weeks of once daily treatment of orally inhaled tiotropium plus olodaterol fixed dose combination (2.5 μg / 5 μg; 5 μg / 5 μg) (delivered by the Respimat® Inhaler) compared with the individual components (2.5 μg and 5 μg tiotropium, 5 μg olodaterol) (delivered by the Respimat® Inhaler) in patients with Chronic Obstructive Pulmonary Disease (COPD)

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    2009-010669-22
    Trial protocol
    NO   SE   ES   SK   BE   DE   HU   IE   AT   GB  
    Global end of trial date
    11 Nov 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    01 Jul 2016
    First version publication date
    01 Aug 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Data correction due to a system error in EudraCT- Results

    Trial information

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    Trial identification
    Sponsor protocol code
    1237.6
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01431287
    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, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 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
    09 Dec 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Apr 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess the efficacy and safety of 52 weeks once daily treatment with orally inhaled tiotropium + olodaterol fixed dose combination (2.5 µg / 5 µg; 5 µg / 5 µg) (delivered by the Respimat® Inhaler) compared with the individual components (2.5 and 5 μg tiotropium, 5 µg olodaterol) (delivered by the Respimat® Inhaler) in patients with Chronic Obstructive Pulmonary Disease (COPD).
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time without the need to provide a reason. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Sep 2011
    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
    Slovakia: 22
    Country: Number of subjects enrolled
    South Africa: 122
    Country: Number of subjects enrolled
    Spain: 131
    Country: Number of subjects enrolled
    Sweden: 106
    Country: Number of subjects enrolled
    Taiwan: 87
    Country: Number of subjects enrolled
    Turkey: 128
    Country: Number of subjects enrolled
    United Kingdom: 65
    Country: Number of subjects enrolled
    United States: 643
    Country: Number of subjects enrolled
    Austria: 108
    Country: Number of subjects enrolled
    Belgium: 101
    Country: Number of subjects enrolled
    Brazil: 178
    Country: Number of subjects enrolled
    Canada: 140
    Country: Number of subjects enrolled
    China: 362
    Country: Number of subjects enrolled
    Colombia: 76
    Country: Number of subjects enrolled
    Croatia: 26
    Country: Number of subjects enrolled
    Germany: 346
    Country: Number of subjects enrolled
    Hungary: 68
    Country: Number of subjects enrolled
    India: 94
    Country: Number of subjects enrolled
    Ireland: 29
    Country: Number of subjects enrolled
    Japan: 318
    Country: Number of subjects enrolled
    Norway: 129
    Country: Number of subjects enrolled
    Romania: 72
    Country: Number of subjects enrolled
    Russian Federation: 68
    Country: Number of subjects enrolled
    Serbia: 99
    Worldwide total number of subjects
    3518
    EEA total number of subjects
    1203
    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)
    1804
    From 65 to 84 years
    1706
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    A "Missing" category is unavailable for the age group breakdown of enrolled patients. Hence, 17 subjects with a missing data for age group have been added to age-category "18-64 years".

    Pre-assignment
    Screening details
    All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all strictly implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Olodaterol (Olo) 5 µg
    Arm description
    Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
    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
    5 μg Once daily with orally inhalation

    Arm title
    Tiotropium (Tio) 2.5 µg
    Arm description
    Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
    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
    2.5 µg once daily with oral inhalation

    Arm title
    Tiotropium (Tio) 5 µg
    Arm description
    Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning. One patient who was randomised to the Tiotropium 5 ug arm was not treated. Consequently, number of subjects that started is 507 but only 506 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.
    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
    5 µg once daily with oral inhalation

    Arm title
    Tio + Olo (T+O) 2.5/5 µg
    Arm description
    Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
    Arm type
    Experimental

    Investigational medicinal product name
    Olodaterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    5 µg once daily with oral inhalation

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2.5 µg once daily with oral inhalation

    Arm title
    Tio + Olo (T+O) 5/5 µg
    Arm description
    Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
    Arm type
    Experimental

    Investigational medicinal product name
    Olodaterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    5 µg once daily with oral inhalation

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    5 µg once daily with oral inhalation

    Number of subjects in period 1 [1]
    Olodaterol (Olo) 5 µg Tiotropium (Tio) 2.5 µg Tiotropium (Tio) 5 µg Tio + Olo (T+O) 2.5/5 µg Tio + Olo (T+O) 5/5 µg
    Started
    510
    507
    506
    508
    507
    Completed
    412
    409
    410
    445
    430
    Not completed
    98
    98
    96
    63
    77
         Protocol deviation
    6
    6
    5
    6
    5
         Adverse event, serious fatal
    8
    4
    8
    6
    8
         Adverse event, non-fatal
    51
    53
    45
    27
    33
         not specified
    4
    2
    2
    2
    1
         Consent withdrawn by subject
    29
    30
    34
    19
    29
         Lost to follow-up
    -
    3
    2
    3
    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 the patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Olodaterol (Olo) 5 µg
    Reporting group description
    Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

    Reporting group title
    Tiotropium (Tio) 2.5 µg
    Reporting group description
    Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

    Reporting group title
    Tiotropium (Tio) 5 µg
    Reporting group description
    Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning. One patient who was randomised to the Tiotropium 5 ug arm was not treated. Consequently, number of subjects that started is 507 but only 506 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

    Reporting group title
    Tio + Olo (T+O) 2.5/5 µg
    Reporting group description
    Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

    Reporting group title
    Tio + Olo (T+O) 5/5 µg
    Reporting group description
    Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

    Reporting group values
    Olodaterol (Olo) 5 µg Tiotropium (Tio) 2.5 µg Tiotropium (Tio) 5 µg Tio + Olo (T+O) 2.5/5 µg Tio + Olo (T+O) 5/5 µg Total
    Number of subjects
    510 507 506 508 507 2538
    Age categorical
    Units: Subjects
    Age continuous
    Treated Set (TS): This patient set included all patients in the randomised set who were dispensed study medication and were documented to have taken any dose of study medication.
    Units: years
        arithmetic mean (standard deviation)
    64.7 ± 8.3 63.9 ± 8.7 63.5 ± 8.7 64.1 ± 7.6 62.7 ± 8.4 -
    Gender categorical
    Treated Set (TS): This patient set included all patients in the randomised set who were dispensed study medication and were documented to have taken any dose of study medication.
    Units: Subjects
        Female
    132 146 134 140 158 710
        Male
    378 361 372 368 349 1828

    End points

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    End points reporting groups
    Reporting group title
    Olodaterol (Olo) 5 µg
    Reporting group description
    Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

    Reporting group title
    Tiotropium (Tio) 2.5 µg
    Reporting group description
    Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

    Reporting group title
    Tiotropium (Tio) 5 µg
    Reporting group description
    Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning. One patient who was randomised to the Tiotropium 5 ug arm was not treated. Consequently, number of subjects that started is 507 but only 506 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

    Reporting group title
    Tio + Olo (T+O) 2.5/5 µg
    Reporting group description
    Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

    Reporting group title
    Tio + Olo (T+O) 5/5 µg
    Reporting group description
    Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

    Primary: Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169.

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    End point title
    Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169.
    End point description
    Area under the FEV-time curve from 0 to 3h post-dose(FEV1 AUC(0-3h)) was calculated using trapezoidal rule,divided by duration(3h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of 2 pre-dose measurements performed 1h & at 10 min prior to first dose at visit 2(day1). The adjusted means(SE) were obtained by fitting MMRM model with fixed effects of treatment,planned test day,treatment-by-test day interaction,baseline & baseline-by-test day interaction,patient as random effect,& spatial power covariance structure for within-patient errors & Kenward-Roger approximation for denominator degrees of freedom.The Full analysis set(FAS) included all randomized patients, dispensed study medication,documented to have taken any dose of study medication & who had non-missing baseline & at least one non-missing post-baseline measurement for at least one primary or key secondary efficacy endpoints.
    End point type
    Primary
    End point timeframe
    1 hour (h) and at 10 minutes (min) prior to dose on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169
    End point values
    Olodaterol (Olo) 5 µg Tiotropium (Tio) 2.5 µg Tiotropium (Tio) 5 µg Tio + Olo (T+O) 2.5/5 µg Tio + Olo (T+O) 5/5 µg
    Number of subjects analysed
    507 [1]
    504 [2]
    500 [3]
    506 [4]
    502 [5]
    Units: litre(s)
        least squares mean (standard error)
    0.136 ± 0.009
    0.125 ± 0.009
    0.165 ± 0.009
    0.256 ± 0.009
    0.268 ± 0.009
    Notes
    [1] - Number of FAS (full analysis set) patients actually contributing to the model.
    [2] - Number of FAS (full analysis set) patients actually contributing to the model.
    [3] - Number of FAS (full analysis set) patients actually contributing to the model.
    [4] - Number of FAS (full analysis set) patients actually contributing to the model.
    [5] - Number of FAS (full analysis set) patients actually contributing to the model.
    Statistical analysis title
    T+O 5/5 vs Olo 5
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1009
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.108
         upper limit
    0.157
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 5
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.078
         upper limit
    0.127
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Statistical analysis title
    T+O 2.5/5 vs Olo 5
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1013
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.096
         upper limit
    0.145
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1010
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.106
         upper limit
    0.155
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Statistical analysis title
    T+O 2.5/5 vs Tio 5
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.066
         upper limit
    0.115
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    1008
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3394
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.012
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.013
         upper limit
    0.036
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Statistical analysis title
    T+O 5/5 vs Tio 2.5
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.143
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.118
         upper limit
    0.167
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Olo 5
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0173
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.005
         upper limit
    0.054
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Statistical analysis title
    Tio 2.5 vs Olo 5
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1011
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.421
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.035
         upper limit
    0.014
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Tio 2.5
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1004
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0014
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.015
         upper limit
    0.064
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012

    Primary: Trough FEV1 response on day 170

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    End point title
    Trough FEV1 response on day 170
    End point description
    Trough FEV1 defined as the FEV1 value at the end of the dosing interval (24h)&calculated as mean of 2 FEV1 measurements performed at 23h &at 23h 50 min after inhalation of study medication at clinic visit on the previous day.Trough FEV1 response was defined as trough FEV1 minus baseline FEV1.Baseline was defined as mean of 2 pre-dose measurements performed 1h&at 10 min prior to administration of first dose at visit2(day 1).The adjusted means (SE) obtained by fitting mixed effect model repeated measures(MMRM) including fixed effects of treatment,planned test day,treatment-by-test day interaction,baseline&baseline-by-test day interaction,patient as random effect,&spatial power covariance structure for within-patient errors&Kenward- Roger approximation for denominator degrees of freedom.Since it is possible for patient to meet the data criterion for only a subset of the primary endpoints,it is possible that number of patients used in the FAS analysis for different endpoint will vary.
    End point type
    Primary
    End point timeframe
    1 hours(h) and at 10 min prior to dose on the first day of randomized treatment (baseline) and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170
    End point values
    Olodaterol (Olo) 5 µg Tiotropium (Tio) 2.5 µg Tiotropium (Tio) 5 µg Tio + Olo (T+O) 2.5/5 µg Tio + Olo (T+O) 5/5 µg
    Number of subjects analysed
    503 [6]
    499 [7]
    498 [8]
    500 [9]
    497 [10]
    Units: litre(s)
        least squares mean (standard error)
    0.057 ± 0.009
    0.062 ± 0.009
    0.096 ± 0.009
    0.125 ± 0.009
    0.145 ± 0.009
    Notes
    [6] - Number of FAS (full analysis set) patients actually contributing to the model.
    [7] - Number of FAS (full analysis set) patients actually contributing to the model.
    [8] - Number of FAS (full analysis set) patients actually contributing to the model.
    [9] - Number of FAS (full analysis set) patients actually contributing to the model.
    [10] - Number of FAS (full analysis set) patients actually contributing to the model.
    Statistical analysis title
    T+O 5/5 vs Olo 5
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1000
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.088
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.063
         upper limit
    0.113
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 5
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    995
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.024
         upper limit
    0.075
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Olo 5
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Olodaterol (Olo) 5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    1003
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.067
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.042
         upper limit
    0.092
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    999
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.062
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.037
         upper limit
    0.087
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 5
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    998
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0231
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.029
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.004
         upper limit
    0.054
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1073
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.021
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.004
         upper limit
    0.046
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 2.5
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    996
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.083
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.058
         upper limit
    0.108
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Olo 5
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1001
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0029
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.038
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.013
         upper limit
    0.063
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 2.5 vs Olo 5
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6939
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.005
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.02
         upper limit
    0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Tio 2.5
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0097
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.033
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.008
         upper limit
    0.058
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013

    Secondary: FEV1 AUC (0-3h) response on Day 1, Day 85, and Day 365

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    End point title
    FEV1 AUC (0-3h) response on Day 1, Day 85, and Day 365
    End point description
    FEV1 AUC(0-3h) was calculated as the area under the FEV1-time curve from 0 to 3 h post-dose using the trapezoidal rule,divided by the duration (3 h) to report in litres.FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1.Baseline was defined as the mean of 2 pre-dose measurements performed 1 h & at 10 min prior to administration of the first dose of randomised treatment at Day1.The adjusted means (SE) were obtained by fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment,planned test day, treatment-by-test day interaction,baseline & baseline-by-test day interaction, patient as random effect, & spatial power covariance structure for within−patient errors and Kenward-Roger approximation for denominator degrees of freedom.Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints,it is possible that the number of patients used in the FAS analysis for different endpoint will vary.
    End point type
    Secondary
    End point timeframe
    1 hour (h) and at 10 minutes (min) prior to dose on the first day of randomized treatment and on Days 85 and 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment and on Days 85 and 365.
    End point values
    Olodaterol (Olo) 5 µg Tiotropium (Tio) 2.5 µg Tiotropium (Tio) 5 µg Tio + Olo (T+O) 2.5/5 µg Tio + Olo (T+O) 5/5 µg
    Number of subjects analysed
    507 [11]
    504 [12]
    500 [13]
    506 [14]
    502 [15]
    Units: litre(s)
    least squares mean (standard error)
        Day 1
    0.196 ± 0.009
    0.135 ± 0.009
    0.164 ± 0.009
    0.228 ± 0.009
    0.229 ± 0.009
        Day 85
    0.153 ± 0.009
    0.165 ± 0.009
    0.187 ± 0.009
    0.272 ± 0.009
    0.297 ± 0.009
        Day 365
    0.105 ± 0.01
    0.105 ± 0.01
    0.124 ± 0.01
    0.223 ± 0.009
    0.237 ± 0.01
    Notes
    [11] - Number of FAS (full analysis set) patients actually contributing to the model.
    [12] - Number of FAS (full analysis set) patients actually contributing to the model.
    [13] - Number of FAS (full analysis set) patients actually contributing to the model.
    [14] - Number of FAS (full analysis set) patients actually contributing to the model.
    [15] - Number of FAS (full analysis set) patients actually contributing to the model.
    Statistical analysis title
    T+O 5/5 vs Olo 5 on Day 1
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1009
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0095
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.033
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.008
         upper limit
    0.058
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 5 on Day 1
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.065
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.04
         upper limit
    0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 on Day 1
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1013
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0112
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.033
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.007
         upper limit
    0.058
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 on Day 1
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1010
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.068
         upper limit
    0.119
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 on Day 1
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.064
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.039
         upper limit
    0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 on Day 1
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    1008
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9514
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.001
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.024
         upper limit
    0.026
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 on Day 1
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.094
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.069
         upper limit
    0.119
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Olo 5 on Day 1
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0131
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.032
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.057
         upper limit
    -0.007
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 2.5 vs Olo 5 on Day 1
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1011
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.061
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.086
         upper limit
    -0.036
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Tio 2.5 on Day 1
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1004
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0243
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.029
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.004
         upper limit
    0.054
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Olo 5 on Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1009
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.145
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.119
         upper limit
    0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 5 on Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.085
         upper limit
    0.136
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 on Day 85
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1013
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.094
         upper limit
    0.144
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 on Day 85
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1010
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.106
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.081
         upper limit
    0.132
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 on Day 85
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.085
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.059
         upper limit
    0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 on Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    1008
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.047
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.026
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0.051
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 on Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.107
         upper limit
    0.158
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Olo 5 on Day 85
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0083
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.034
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.009
         upper limit
    0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 2.5 vs Olo 5 on Day 85
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1011
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3329
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.013
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.013
         upper limit
    0.038
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Tio 2.5 on Day 85
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1004
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0958
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.022
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.004
         upper limit
    0.047
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Olo 5 on Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1009
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.105
         upper limit
    0.158
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Statistical analysis title
    T+O 5/5 vs Tio 5 on Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.112
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.086
         upper limit
    0.139
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 on Day 365
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1013
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.118
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.092
         upper limit
    0.144
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 on Day 365
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1010
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.118
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.092
         upper limit
    0.144
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 on Day 365
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.098
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.072
         upper limit
    0.125
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 on Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    1008
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3008
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.014
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.012
         upper limit
    0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 on Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.105
         upper limit
    0.158
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Statistical analysis title
    Tio 5 vs Olo 5 on Day 365
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1484
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.007
         upper limit
    0.046
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Statistical analysis title
    Tio 2.5 vs Olo 5 on Day 365
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1011
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9981
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.026
         upper limit
    0.027
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Statistical analysis title
    Tio 5 vs Tio 2.5 on Day 365
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1004
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.148
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.007
         upper limit
    0.046
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013

    Secondary: Trough FEV1 response on Days 15, 43, 85, 169 and 365

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    End point title
    Trough FEV1 response on Days 15, 43, 85, 169 and 365
    End point description
    Trough FEV1 defined as the FEV1 value at the end of the dosing interval (24 hours),calculated as mean of the pre-dose measurements.Trough FEV1 response was defined as trough FEV1 minus baseline FEV1.Baseline was defined as mean of 2 pre-dose measurements performed 1h&at 10 min prior to administration of the first dose of randomised treatment at Day1.The adjusted means (SE) were obtained by MMRM model including fixed effects of treatment,planned test day, treatment-by-test day interaction,baseline &baseline-by-test day interaction,patient as random effect,&spatial power covariance structure for within-patient errors &Kenward-Roger approximation for denominator degrees of freedom.Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints,it is possible that number of patients used in the FAS analysis for different endpoint will vary.
    End point type
    Secondary
    End point timeframe
    1 hour (h) and at 10 minutes (min) prior to dose on the first day of randomized treatment and on Days 85, 169 and 365 and 10 minutes (min) prior to randomized treatment on days 15 and 43.
    End point values
    Olodaterol (Olo) 5 µg Tiotropium (Tio) 2.5 µg Tiotropium (Tio) 5 µg Tio + Olo (T+O) 2.5/5 µg Tio + Olo (T+O) 5/5 µg
    Number of subjects analysed
    503 [16]
    499 [17]
    498 [18]
    500 [19]
    497 [20]
    Units: litre(s)
    least squares mean (standard error)
        Day 15
    0.083 ± 0.009
    0.085 ± 0.009
    0.112 ± 0.009
    0.147 ± 0.009
    0.148 ± 0.009
        Day 43
    0.07 ± 0.009
    0.085 ± 0.009
    0.103 ± 0.009
    0.146 ± 0.009
    0.15 ± 0.009
        Day 85
    0.047 ± 0.009
    0.081 ± 0.009
    0.088 ± 0.009
    0.129 ± 0.009
    0.147 ± 0.009
        Day 169
    0.034 ± 0.009
    0.041 ± 0.009
    0.068 ± 0.009
    0.111 ± 0.009
    0.119 ± 0.009
        Day 365
    0.011 ± 0.009
    0.022 ± 0.009
    0.04 ± 0.009
    0.077 ± 0.009
    0.093 ± 0.009
    Notes
    [16] - Number of FAS (full analysis set) patients actually contributing to the model.
    [17] - Number of FAS (full analysis set) patients actually contributing to the model.
    [18] - Number of FAS (full analysis set) patients actually contributing to the model.
    [19] - Number of FAS (full analysis set) patients actually contributing to the model.
    [20] - Number of FAS (full analysis set) patients actually contributing to the model.
    Statistical analysis title
    T+O 5/5 vs Olo 5 on Day 15
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1000
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.065
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.04
         upper limit
    0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 5 on Day 15
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    995
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.036
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.011
         upper limit
    0.061
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 on Day 15
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1003
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.064
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.039
         upper limit
    0.089
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 on Day 15
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    999
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.063
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.037
         upper limit
    0.088
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 on Day 15
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    998
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0057
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.036
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.01
         upper limit
    0.061
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 on Day 15
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9633
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.001
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.025
         upper limit
    0.026
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 on Day 15
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    996
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.063
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.038
         upper limit
    0.088
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Olo 5 on Day 15
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1001
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.025
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.029
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.004
         upper limit
    0.054
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 2.5 vs Olo 5 on Day 15
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8949
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.002
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.023
         upper limit
    0.027
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Tio 2.5 on Day 15
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0351
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.027
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.002
         upper limit
    0.052
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Olo 5 on Day 43
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1000
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.055
         upper limit
    0.105
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 5 on Day 43
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    995
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.022
         upper limit
    0.073
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 on Day 43
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1003
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.076
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.051
         upper limit
    0.101
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 on Day 43
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    999
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.061
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.036
         upper limit
    0.086
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 on Day 43
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    998
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.044
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.018
         upper limit
    0.069
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 on Day 43
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7755
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.004
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.022
         upper limit
    0.029
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 on Day 43
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    996
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.065
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.039
         upper limit
    0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Olo 5 on Day 43
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1001
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0118
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.032
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.007
         upper limit
    0.058
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 2.5 vs Olo 5 on Day 43
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2416
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.015
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Tio 2.5 on Day 43
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1792
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.017
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.008
         upper limit
    0.043
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Olo 5 on Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1000
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.074
         upper limit
    0.125
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 5 on Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    995
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.059
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.033
         upper limit
    0.084
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 on Day 85
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1003
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.082
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.057
         upper limit
    0.107
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 on Day 85
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    999
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.048
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.023
         upper limit
    0.073
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 on Day 85
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    998
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0014
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.041
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.016
         upper limit
    0.067
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 on Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1747
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.018
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.008
         upper limit
    0.043
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 on Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    996
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.065
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.04
         upper limit
    0.091
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Olo 5 on Day 85
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1001
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0016
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.041
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.016
         upper limit
    0.066
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 2.5 vs Olo 5 on Day 85
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0081
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.034
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.009
         upper limit
    0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Tio 2.5 on Day 85
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.611
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.007
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.019
         upper limit
    0.032
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Olo 5 on Day 169
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1000
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.085
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.059
         upper limit
    0.111
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 5 on Day 169
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    995
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.025
         upper limit
    0.076
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 on Day 169
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1003
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.077
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.051
         upper limit
    0.102
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 on Day 169
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    999
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.069
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.044
         upper limit
    0.095
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 on Day 169
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    998
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0013
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.042
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.016
         upper limit
    0.068
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 on Day 169
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5274
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.008
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.017
         upper limit
    0.034
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 on Day 169
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    996
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.078
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.052
         upper limit
    0.103
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Olo 5 on Day 169
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1001
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0083
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.035
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.009
         upper limit
    0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 2.5 vs Olo 5 on Day 169
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5744
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.007
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.018
         upper limit
    0.033
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Tio 2.5 on Day 169
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0381
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.027
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.001
         upper limit
    0.053
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Olo 5 on Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1000
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.081
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.055
         upper limit
    0.108
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 5 on Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    995
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.053
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.027
         upper limit
    0.079
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 on Day 365
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1003
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.065
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.039
         upper limit
    0.091
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 on Day 365
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    999
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.055
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.029
         upper limit
    0.081
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 on Day 365
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    998
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0052
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.037
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.011
         upper limit
    0.063
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 on Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2273
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.016
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.042
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 on Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    996
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.071
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.045
         upper limit
    0.097
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Olo 5 on Day 365
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1001
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.033
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.028
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.002
         upper limit
    0.055
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 2.5 vs Olo 5 on Day 365
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4327
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.016
         upper limit
    0.037
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013
    Statistical analysis title
    Tio 5 vs Tio 2.5 on Day 365
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1764
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.018
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.008
         upper limit
    0.044
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013

    Secondary: Forced vital capacity (FVC) AUC (0-3h) response on Day 1, Day 85, Day

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    End point title
    Forced vital capacity (FVC) AUC (0-3h) response on Day 1, Day 85, Day
    End point description
    FVC AUC(0-3h) calculated as area under FVC-time curve from 0to3h post-dose using trapezoidal rule,divided by duration(3h) to report in litres.FVC AUC(0-3h) response defined as FVC AUC(0-3h) minus baseline FVC.Baseline was defined as mean of 2 pre-dose measurements performed 1h&at10 min prior to administration of first dose at visit2(day 1).The adjusted means (SE) were obtained by fitting MMRM model including fixed effects of treatment,planned test day,treatment-by-test day interaction,baseline&baseline-by-test day interaction,patient as random effect,&spatial power covariance structure for within-patient errors&Kenward-Roger approximation for denominator degrees of freedom. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints,it is possible that the number of patients used in the FAS analysis for different endpoints will vary.
    End point type
    Secondary
    End point timeframe
    1 hour (h) and at 10 minutes (min) prior to dose and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment and on each of the days specified in the title.
    End point values
    Olodaterol (Olo) 5 µg Tiotropium (Tio) 2.5 µg Tiotropium (Tio) 5 µg Tio + Olo (T+O) 2.5/5 µg Tio + Olo (T+O) 5/5 µg
    Number of subjects analysed
    507 [21]
    504 [22]
    500 [23]
    506 [24]
    502 [25]
    Units: litre(s)
    least squares mean (standard error)
        Day 1
    0.341 ± 0.018
    0.264 ± 0.018
    0.298 ± 0.018
    0.411 ± 0.018
    0.397 ± 0.018
        Day 85
    0.25 ± 0.018
    0.306 ± 0.018
    0.326 ± 0.018
    0.46 ± 0.018
    0.469 ± 0.018
        Day 169
    0.231 ± 0.018
    0.247 ± 0.018
    0.283 ± 0.018
    0.439 ± 0.018
    0.429 ± 0.018
        Day 365
    0.18 ± 0.019
    0.216 ± 0.018
    0.198 ± 0.019
    0.397 ± 0.018
    0.381 ± 0.019
    Notes
    [21] - Number of FAS (full analysis set) patients actually contributing to the model.
    [22] - Number of FAS (full analysis set) patients actually contributing to the model.
    [23] - Number of FAS (full analysis set) patients actually contributing to the model.
    [24] - Number of FAS (full analysis set) patients actually contributing to the model.
    [25] - Number of FAS (full analysis set) patients actually contributing to the model.
    Statistical analysis title
    T+O 5/5 vs Olo 5 Day 1
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1009
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0241
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.056
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.007
         upper limit
    0.105
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 5/5 vs Tio 5 Day 1
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.051
         upper limit
    0.148
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 Day 1
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1013
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0049
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.021
         upper limit
    0.119
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 Day 1
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1010
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.098
         upper limit
    0.196
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 Day 1
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.113
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.064
         upper limit
    0.162
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 Day 1
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    1008
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5831
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    -0.014
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.063
         upper limit
    0.035
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 Day 1
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.133
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.084
         upper limit
    0.182
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    Tio 5 vs Olo 5 Day 1
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0822
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    -0.043
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.092
         upper limit
    0.006
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    Tio 2.5 vs Olo 5 Day 1
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg.The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1011
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    -0.077
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.126
         upper limit
    -0.028
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    Tio 5 vs Tio 2.5 Day 1
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1004
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1774
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.034
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.015
         upper limit
    0.083
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 5/5 vs Olo 5 Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1009
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.169
         upper limit
    0.268
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 5/5 vs Tio 5 Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.143
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.094
         upper limit
    0.193
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 Day 85
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1013
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.209
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.16
         upper limit
    0.258
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 Day 85
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1010
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.104
         upper limit
    0.203
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 Day 85
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.134
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.084
         upper limit
    0.183
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    1008
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6974
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.04
         upper limit
    0.059
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.163
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.114
         upper limit
    0.213
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    Tio 5 vs Olo 5 Day 85
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0027
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.076
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.026
         upper limit
    0.125
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    Tio 2.5 vs Olo 5 Day 85
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg.The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1011
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0269
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.056
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.006
         upper limit
    0.105
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    Tio 5 vs Tio 2.5 Day 85
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1004
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4343
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.03
         upper limit
    0.069
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 5/5 vs Olo 5 Day 169
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1009
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.198
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.148
         upper limit
    0.248
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs Tio 5 Day 169
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.146
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.096
         upper limit
    0.197
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 Day 169
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1013
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.208
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.158
         upper limit
    0.258
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 Day 169
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1010
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.193
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.143
         upper limit
    0.242
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 Day 169
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.156
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.106
         upper limit
    0.206
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 Day 169
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    1008
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.698
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.06
         upper limit
    0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 Day 169
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.183
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.132
         upper limit
    0.233
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    Tio 5 vs Olo 5 Day 169
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0442
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.051
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.001
         upper limit
    0.102
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    Tio 2.5 vs Olo 5 Day 169
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1011
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5514
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.015
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.035
         upper limit
    0.065
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    Tio 5 vs Tio 2.5 Day 169
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1004
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1569
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.036
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.014
         upper limit
    0.086
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs Olo 5 Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1009
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.202
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.15
         upper limit
    0.253
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs Tio 5 Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.183
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.132
         upper limit
    0.234
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 Day 365
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1013
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.218
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.167
         upper limit
    0.269
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 Day 365
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1010
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.13
         upper limit
    0.232
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 Day 365
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.199
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.148
         upper limit
    0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    1008
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5373
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    -0.016
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.067
         upper limit
    0.035
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.165
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.114
         upper limit
    0.216
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    Tio 5 vs Olo 5 Day 365
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4763
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.019
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.033
         upper limit
    0.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    Tio 2.5 vs Olo 5 Day 365
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1011
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1613
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    0.037
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.015
         upper limit
    0.088
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    Tio 5 vs Tio 2.5 Day 365
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    1004
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4908
    Method
    Mixed models analysis
    Parameter type
    adjusted mean difference
    Point estimate
    -0.018
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.069
         upper limit
    0.033
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026

    Secondary: Trough FVC response on Day 15, Day 43, Day 85, Day 170, and Day 365

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    End point title
    Trough FVC response on Day 15, Day 43, Day 85, Day 170, and Day 365
    End point description
    Trough FVC defined as the FVC value at the end of the dosing interval (24 hours),calculated as mean of the pre-dose measurements. Trough FVC defined as FVC value at the end of the dosing interval (24 hours),calculated as mean of the pre-dose measurements.Trough FVC response defined as trough FVC minus baseline FVC. Baseline was defined as mean of 2 pre-dose measurements performed 1h&at 10min prior to administration of first dose at visit 2(day 1).The adjusted means (SE) were obtained by fitting MMRM including fixed effects of treatment,planned test day,treatment-by-test day interaction,baseline &baseline-by-test day interaction,patient as random effect,&spatial power covariance structure for within-patient errors &Kenward-Roger approximation for denominator degrees of freedom. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.
    End point type
    Secondary
    End point timeframe
    1 h and at 10 min prior to dose on the first day of randomized treatment (baseline), day 85, day 365, at 10 min pre-dose on day 15 and 43 and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170.
    End point values
    Olodaterol (Olo) 5 µg Tiotropium (Tio) 2.5 µg Tiotropium (Tio) 5 µg Tio + Olo (T+O) 2.5/5 µg Tio + Olo (T+O) 5/5 µg
    Number of subjects analysed
    503 [26]
    499 [27]
    498 [28]
    500 [29]
    497 [30]
    Units: litre(s)
    least squares mean (standard error)
        Day 15
    0.163 ± 0.018
    0.209 ± 0.018
    0.222 ± 0.018
    0.293 ± 0.018
    0.285 ± 0.018
        Day 43
    0.129 ± 0.018
    0.206 ± 0.018
    0.222 ± 0.018
    0.281 ± 0.018
    0.293 ± 0.018
        Day 85
    0.063 ± 0.018
    0.178 ± 0.018
    0.184 ± 0.018
    0.246 ± 0.018
    0.274 ± 0.019
        Day 170
    0.116 ± 0.018
    0.163 ± 0.018
    0.202 ± 0.018
    0.266 ± 0.018
    0.274 ± 0.018
        Day 365
    0.028 ± 0.019
    0.096 ± 0.019
    0.097 ± 0.019
    0.198 ± 0.019
    0.184 ± 0.019
    Notes
    [26] - Number of FAS (full analysis set) patients actually contributing to the model.
    [27] - Number of FAS (full analysis set) patients actually contributing to the model.
    [28] - Number of FAS (full analysis set) patients actually contributing to the model.
    [29] - Number of FAS (full analysis set) patients actually contributing to the model.
    [30] - Number of FAS (full analysis set) patients actually contributing to the model.
    Statistical analysis title
    T+O 5/5 vs Olo 5 Day 15
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1000
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.072
         upper limit
    0.173
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs Tio 5 Day 15
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    995
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0154
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.063
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.012
         upper limit
    0.113
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 Day 15
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1003
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.08
         upper limit
    0.181
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 Day 15
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    999
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0012
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.084
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.033
         upper limit
    0.134
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 Day 15
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    998
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0061
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.071
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.02
         upper limit
    0.121
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 Day 15
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7518
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.008
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.059
         upper limit
    0.042
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 Day 15
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    996
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0034
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.076
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.025
         upper limit
    0.126
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    Tio 5 vs Olo 5 Day 15
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1001
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0209
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.059
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.009
         upper limit
    0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    Tio 2.5 vs Olo 5 Day 15
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0708
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.004
         upper limit
    0.097
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    Tio 5 vs Tio 2.5 Day 15
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6148
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.013
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.038
         upper limit
    0.064
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs Olo 5 Day 43
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1000
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.164
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.114
         upper limit
    0.215
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs Tio 5 Day 43
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    995
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0064
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.071
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.02
         upper limit
    0.122
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 Day 43
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1003
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.152
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.102
         upper limit
    0.203
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 Day 43
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    999
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0035
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.075
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.025
         upper limit
    0.126
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 Day 43
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    998
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0233
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.059
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.008
         upper limit
    0.109
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 Day 43
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6413
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.012
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.039
         upper limit
    0.063
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 Day 43
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    996
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.088
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.037
         upper limit
    0.138
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    Tio 5 vs Olo 5 Day 43
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1001
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.094
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.043
         upper limit
    0.144
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    Tio 2.5 vs Olo 5 Day 43
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.077
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.026
         upper limit
    0.127
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    Tio 5 vs Tio 2.5 Day 43
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5159
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.017
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.034
         upper limit
    0.068
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs Olo 5 Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1000
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.159
         upper limit
    0.261
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs Tio 5 Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    995
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.089
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.038
         upper limit
    0.141
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 Day 85
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1003
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.183
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.132
         upper limit
    0.234
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 Day 85
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    999
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0094
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.068
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.017
         upper limit
    0.119
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 Day 85
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    998
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0174
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.062
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.011
         upper limit
    0.113
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2888
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.028
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.023
         upper limit
    0.079
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 Day 85
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    996
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.095
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.044
         upper limit
    0.146
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    Tio 5 vs Olo 5 Day 85
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1001
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.07
         upper limit
    0.172
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    Tio 2.5 vs Olo 5 Day 85
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.064
         upper limit
    0.166
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    Tio 5 vs Tio 2.5 Day 85
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8241
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.006
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.045
         upper limit
    0.057
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    T+O 5/5 vs Olo 5 Day 170
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1000
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.158
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.108
         upper limit
    0.208
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 5/5 vs Tio 5 Day 170
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    995
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0048
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.072
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.022
         upper limit
    0.122
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 Day 170
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1003
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.101
         upper limit
    0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 Day 170
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    999
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.053
         upper limit
    0.152
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 Day 170
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    998
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0116
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.064
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.014
         upper limit
    0.113
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 Day 170
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7577
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.008
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.042
         upper limit
    0.058
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 Day 170
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    996
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.061
         upper limit
    0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    Tio 5 vs Olo 5 Day 170
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1001
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.086
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.037
         upper limit
    0.136
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    Tio 2.5 vs Olo 5 Day 170
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0621
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.048
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.002
         upper limit
    0.097
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    Tio 5 vs Tio 2.5 Day 170
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1266
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.039
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.011
         upper limit
    0.089
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 5/5 vs Olo 5 Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1000
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.156
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.104
         upper limit
    0.209
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027
    Statistical analysis title
    T+O 5/5 vs Tio 5 Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    995
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0013
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.087
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.034
         upper limit
    0.139
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 Day 365
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1003
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.118
         upper limit
    0.223
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 Day 365
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    999
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    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
    0.049
         upper limit
    0.154
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 Day 365
    Statistical analysis description
    Tio + Olo (T+O) 2.5/5 μg minus Tiotropium (Tio) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 2.5/5 µg v Tiotropium (Tio) 5 µg
    Number of subjects included in analysis
    998
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.048
         upper limit
    0.153
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tio + Olo (T+O) 2.5/5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tio + Olo (T+O) 2.5/5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6093
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.014
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.066
         upper limit
    0.039
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 Day 365
    Statistical analysis description
    Tio + Olo (T+O) 5/5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tio + Olo (T+O) 5/5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    996
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0011
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.088
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.035
         upper limit
    0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027
    Statistical analysis title
    Tio 5 vs Olo 5 Day 365
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1001
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0095
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.017
         upper limit
    0.123
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027
    Statistical analysis title
    Tio 2.5 vs Olo 5 Day 365
    Statistical analysis description
    Tiotropium (Tio) 2.5 μg minus Olodaterol (Olo) 5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 2.5 µg v Olodaterol (Olo) 5 µg
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0108
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.069
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.016
         upper limit
    0.121
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027
    Statistical analysis title
    Tio 5 vs Tio 2.5 Day 365
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Tiotropium (Tio) 2.5 μg. The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day,treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within−patient errors and Kenward-Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium (Tio) 5 µg v Tiotropium (Tio) 2.5 µg
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9627
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.001
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.051
         upper limit
    0.054
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days).
    Adverse event reporting additional description
    AE additional description
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Olodaterol (5 μg)
    Reporting group description
    Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

    Reporting group title
    Tiotropium (2.5 μg)
    Reporting group description
    Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

    Reporting group title
    Tiotropium (5 μg)
    Reporting group description
    Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

    Reporting group title
    Tio+Olo FDC (2.5/5 μg)
    Reporting group description
    Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

    Reporting group title
    Tio+Olo FDC (5/5 μg)
    Reporting group description
    Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.

    Serious adverse events
    Olodaterol (5 μg) Tiotropium (2.5 μg) Tiotropium (5 μg) Tio+Olo FDC (2.5/5 μg) Tio+Olo FDC (5/5 μg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    106 / 510 (20.78%)
    90 / 507 (17.75%)
    93 / 506 (18.38%)
    87 / 508 (17.13%)
    82 / 507 (16.17%)
         number of deaths (all causes)
    13
    5
    11
    8
    11
         number of deaths resulting from adverse events
    0
    0
    0
    0
    1
    Vascular disorders
    Aneurysm
         subjects affected / exposed
    0 / 510 (0.00%)
    0 / 507 (0.00%)
    0 / 506 (0.00%)
    1 / 508 (0.20%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    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
    Aortic aneurysm
         subjects affected / exposed
    1 / 510 (0.20%)
    0 / 507 (0.00%)
    0 / 506 (0.00%)
    0 / 508 (0.00%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm rupture
         subjects affected / exposed
    0 / 510 (0.00%)
    0 / 507 (0.00%)
    0 / 506 (0.00%)
    0 / 508 (0.00%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Arteritis
         subjects affected / exposed
    0 / 510 (0.00%)
    1 / 507 (0.20%)
    0 / 506 (0.00%)
    0 / 508 (0.00%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    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
    Deep vein thrombosis
         subjects affected / exposed
    0 / 510 (0.00%)
    0 / 507 (0.00%)
    1 / 506 (0.20%)
    0 / 508 (0.00%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    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
    Haemorrhage
         subjects affected / exposed
    0 / 510 (0.00%)
    0 / 507 (0.00%)
    0 / 506 (0.00%)
    1 / 508 (0.20%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypertension
         subjects affected / exposed
    0 / 510 (0.00%)
    0 / 507 (0.00%)
    1 / 506 (0.20%)
    0 / 508 (0.00%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypertensive crisis
         subjects affected / exposed
    0 / 510 (0.00%)
    0 / 507 (0.00%)
    1 / 506 (0.20%)
    0 / 508 (0.00%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypotension
         subjects affected / exposed
    1 / 510 (0.20%)
    1 / 507 (0.20%)
    0 / 506 (0.00%)
    0 / 508 (0.00%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    1 / 510 (0.20%)
    0 / 507 (0.00%)
    1 / 506 (0.20%)
    0 / 508 (0.00%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    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
    Leriche syndrome
         subjects affected / exposed
    1 / 510 (0.20%)
    0 / 507 (0.00%)
    0 / 506 (0.00%)
    0 / 508 (0.00%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    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
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 510 (0.00%)
    0 / 507 (0.00%)
    0 / 506 (0.00%)
    1 / 508 (0.20%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
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