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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 + 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
    2009-010668-40
    Trial protocol
    NL   FI   PT   SI   CZ   DE   HU   DK   EE   IT  
    Global end of trial date
    19 Sep 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
    1237.5
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01431274
    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, +1 800 2430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 2430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Nov 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Mar 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall 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
    Slovenia: 105
    Country: Number of subjects enrolled
    Denmark: 150
    Country: Number of subjects enrolled
    Finland: 81
    Country: Number of subjects enrolled
    Italy: 49
    Country: Number of subjects enrolled
    Netherlands: 119
    Country: Number of subjects enrolled
    Portugal: 74
    Country: Number of subjects enrolled
    Bulgaria: 94
    Country: Number of subjects enrolled
    Czech Republic: 59
    Country: Number of subjects enrolled
    Estonia: 49
    Country: Number of subjects enrolled
    France: 80
    Country: Number of subjects enrolled
    Germany: 301
    Country: Number of subjects enrolled
    Hungary: 89
    Country: Number of subjects enrolled
    United States: 553
    Country: Number of subjects enrolled
    Australia: 22
    Country: Number of subjects enrolled
    Canada: 131
    Country: Number of subjects enrolled
    Guatemala: 110
    Country: Number of subjects enrolled
    India: 99
    Country: Number of subjects enrolled
    Japan: 279
    Country: Number of subjects enrolled
    Mexico: 45
    Country: Number of subjects enrolled
    New Zealand: 30
    Country: Number of subjects enrolled
    China: 316
    Country: Number of subjects enrolled
    Argentina: 206
    Country: Number of subjects enrolled
    Russian Federation: 56
    Country: Number of subjects enrolled
    Korea, Republic of: 175
    Country: Number of subjects enrolled
    Turkey: 97
    Worldwide total number of subjects
    3369
    EEA total number of subjects
    1250
    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)
    1703
    From 65 to 84 years
    1651
    85 years and over
    15

    Subject disposition

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    Recruitment
    Recruitment details
    A "Missing" category is unavailable for the age group breakdown of enrolled patients. Hence, 8 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 one specialist site which would then ensure that they (the subjects) met all 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 orally 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.
    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 orally 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
    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 orally inhalation

    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
    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 orally 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 orally 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
    528
    525
    527
    522
    522
    Completed
    431
    448
    455
    462
    466
    Not completed
    97
    77
    72
    60
    56
         Protocol deviation
    5
    8
    4
    4
    4
         Adverse event, serious fatal
    4
    6
    4
    7
    7
         Adverse event, non-fatal
    47
    31
    39
    23
    30
         Consent withdrawn by subject
    29
    20
    17
    20
    11
         Reason other than specified above
    6
    5
    7
    2
    4
         Lost to follow-up
    6
    7
    1
    4
    -
    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.

    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
    528 525 527 522 522 2624
    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)
    63.7 ± 8 64.2 ± 8.6 64.2 ± 8.5 64.1 ± 8 64.8 ± 8.2 -
    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
    142 133 144 133 138 690
        Male
    386 392 383 389 384 1934

    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.

    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
    525 [1]
    524 [2]
    526 [3]
    521 [4]
    522 [5]
    Units: litre(s)
        least squares mean (standard error)
    0.133 ± 0.008
    0.148 ± 0.008
    0.139 ± 0.008
    0.241 ± 0.008
    0.256 ± 0.008
    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
    1047
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.123
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1
         upper limit
    0.146
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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
    1048
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.117
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.094
         upper limit
    0.14
    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
    1046
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.109
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.086
         upper limit
    0.132
    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
    1045
    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
    0.07
         upper limit
    0.116
    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
    1047
    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
    0.08
         upper limit
    0.125
    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
    1043
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2169
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.014
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.008
         upper limit
    0.037
    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
    1046
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.108
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.085
         upper limit
    0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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
    1051
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5849
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.006
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.017
         upper limit
    0.029
    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
    1049
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1863
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.016
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.007
         upper limit
    0.039
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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
    1050
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4352
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.009
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.032
         upper limit
    0.014
    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 the number of patients used in the FAS analysis for different endpoint will vary.
    End point type
    Primary
    End point timeframe
    1 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
    519 [6]
    519 [7]
    520 [8]
    518 [9]
    521 [10]
    Units: litre(s)
        least squares mean (standard error)
    0.054 ± 0.009
    0.083 ± 0.008
    0.065 ± 0.008
    0.111 ± 0.008
    0.136 ± 0.008
    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 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
    1040
    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
    0.059
         upper limit
    0.106
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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
    1041
    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
    0.047
         upper limit
    0.094
    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
    1037
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.058
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.034
         upper limit
    0.081
    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
    1037
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0174
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.029
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.005
         upper limit
    0.052
    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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.046
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.023
         upper limit
    0.07
    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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0407
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.024
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.001
         upper limit
    0.048
    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
    1040
    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
    0.03
         upper limit
    0.077
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3326
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.012
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.012
         upper limit
    0.035
    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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0151
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.029
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.006
         upper limit
    0.053
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1421
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.018
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.041
         upper limit
    0.006
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012

    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 the 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 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
    525 [11]
    524 [12]
    526 [13]
    521 [14]
    522 [15]
    Units: litre(s)
    least squares mean (standard error)
        Day 1
    0.205 ± 0.009
    0.148 ± 0.009
    0.157 ± 0.009
    0.226 ± 0.009
    0.237 ± 0.009
        Day 85
    0.161 ± 0.009
    0.176 ± 0.009
    0.162 ± 0.009
    0.271 ± 0.009
    0.289 ± 0.009
        Day 365
    0.096 ± 0.009
    0.116 ± 0.009
    0.122 ± 0.009
    0.214 ± 0.009
    0.237 ± 0.009
    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 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
    1047
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0067
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.033
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.009
         upper limit
    0.056
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1048
    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
    0.057
         upper limit
    0.104
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1046
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0746
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.022
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.002
         upper limit
    0.045
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1045
    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
    0.054
         upper limit
    0.101
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1047
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.046
         upper limit
    0.093
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1043
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3549
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.011
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.013
         upper limit
    0.035
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1046
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.089
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.065
         upper limit
    0.113
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1051
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.048
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.072
         upper limit
    -0.025
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1049
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.056
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.08
         upper limit
    -0.033
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1050
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5018
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.008
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.016
         upper limit
    0.032
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1047
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.128
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.104
         upper limit
    0.152
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1048
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.126
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.102
         upper limit
    0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1046
    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
    0.087
         upper limit
    0.135
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1047
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.109
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.085
         upper limit
    0.133
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1045
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.096
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.072
         upper limit
    0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1043
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1569
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.017
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.007
         upper limit
    0.041
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1046
    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
    0.089
         upper limit
    0.137
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1051
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8834
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.002
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.022
         upper limit
    0.026
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1049
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2129
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.015
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.009
         upper limit
    0.039
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1050
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2702
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.013
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.037
         upper limit
    0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1047
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.141
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.117
         upper limit
    0.166
    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 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
    1048
    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
    0.09
         upper limit
    0.139
    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 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
    1046
    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
    0.143
    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 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
    1045
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.099
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.074
         upper limit
    0.123
    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 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
    1047
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.092
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.067
         upper limit
    0.117
    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 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
    1043
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0717
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.023
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.002
         upper limit
    0.047
    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 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
    1046
    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
    0.097
         upper limit
    0.146
    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 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
    1051
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0344
    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
    0.051
    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 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
    1049
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1126
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.005
         upper limit
    0.045
    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 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
    1050
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6009
    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
    0.031
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013

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

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    End point title
    Trough FEV1 response on Day 15, Day 43, Day 85, Day 169, and Day 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 the number of patients used in the FAS analysis for different endpoint 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
    519 [16]
    519 [17]
    520 [18]
    518 [19]
    521 [20]
    Units: litre(s)
    least squares mean (standard error)
        Day 15
    0.085 ± 0.009
    0.101 ± 0.009
    0.094 ± 0.009
    0.132 ± 0.009
    0.157 ± 0.009
        Day 43
    0.083 ± 0.009
    0.097 ± 0.009
    0.088 ± 0.009
    0.12 ± 0.009
    0.163 ± 0.009
        Day 85
    0.057 ± 0.009
    0.077 ± 0.009
    0.07 ± 0.009
    0.128 ± 0.009
    0.146 ± 0.009
        Day 169
    0.033 ± 0.009
    0.047 ± 0.009
    0.05 ± 0.009
    0.094 ± 0.009
    0.112 ± 0.009
        Day 365
    0 ± 0.009
    0.028 ± 0.009
    0.036 ± 0.009
    0.075 ± 0.009
    0.099 ± 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 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
    1040
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.072
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.049
         upper limit
    0.096
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1041
    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
    0.039
         upper limit
    0.087
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1037
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.023
         upper limit
    0.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1037
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0122
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.007
         upper limit
    0.054
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0021
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.037
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.014
         upper limit
    0.061
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0347
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.026
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.002
         upper limit
    0.049
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1040
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.056
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.032
         upper limit
    0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Statistical analysis title
    Tio 5 vs Olo 5 on Day 15
    Statistical analysis description
    Tiotropium (Tio) 5 μg minus Olodaterol (Olo) 5μg.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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4407
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.009
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.014
         upper limit
    0.033
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1777
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.016
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.007
         upper limit
    0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5641
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.007
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.031
         upper limit
    0.017
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1040
    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
    0.057
         upper limit
    0.104
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1041
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.075
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.051
         upper limit
    0.099
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1037
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0018
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.038
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.014
         upper limit
    0.062
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1037
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0517
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.024
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0.047
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0072
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.033
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.009
         upper limit
    0.056
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.042
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.019
         upper limit
    0.066
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1040
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.066
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.042
         upper limit
    0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6619
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.005
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.018
         upper limit
    0.029
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2401
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.014
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.038
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4601
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.009
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.033
         upper limit
    0.015
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1040
    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
    0.064
         upper limit
    0.112
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1041
    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
    0.052
         upper limit
    0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1037
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.046
         upper limit
    0.094
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1037
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.051
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.027
         upper limit
    0.075
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.058
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.034
         upper limit
    0.082
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1405
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.018
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.006
         upper limit
    0.042
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1040
    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
    0.045
         upper limit
    0.093
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3118
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.012
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.012
         upper limit
    0.036
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1171
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.019
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.005
         upper limit
    0.043
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5759
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.007
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.031
         upper limit
    0.017
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1040
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.079
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.055
         upper limit
    0.103
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1041
    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
    0.038
         upper limit
    0.086
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1037
    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
    0.037
         upper limit
    0.085
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1037
    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
    0.071
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.044
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.019
         upper limit
    0.068
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.136
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.018
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.006
         upper limit
    0.042
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1040
    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
    0.041
         upper limit
    0.089
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1617
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.017
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.007
         upper limit
    0.041
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2476
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.014
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.039
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8083
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.003
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.021
         upper limit
    0.027
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1040
    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
    0.075
         upper limit
    0.124
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1041
    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
    0.088
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1037
    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
    0.1
    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 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
    1037
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    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
    0.072
    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 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
    1038
    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
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0554
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.024
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.001
         upper limit
    0.048
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1040
    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
    0.047
         upper limit
    0.096
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0041
    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
    0.06
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0248
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.028
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.004
         upper limit
    0.053
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5338
    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
    0.032
    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 169, and Day 365

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    End point title
    Forced vital capacity (FVC) AUC (0-3h) response on Day 1, Day 85, Day 169, and Day 365
    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
    525 [21]
    524 [22]
    526 [23]
    521 [24]
    522 [25]
    Units: litre(s)
    least squares mean (standard error)
        Day 1
    0.35 ± 0.017
    0.277 ± 0.017
    0.289 ± 0.017
    0.4 ± 0.017
    0.427 ± 0.017
        Day 85
    0.247 ± 0.017
    0.318 ± 0.017
    0.275 ± 0.017
    0.432 ± 0.017
    0.469 ± 0.017
        Day 169
    0.212 ± 0.017
    0.279 ± 0.017
    0.254 ± 0.017
    0.386 ± 0.017
    0.407 ± 0.017
        Day 365
    0.172 ± 0.018
    0.241 ± 0.018
    0.221 ± 0.018
    0.364 ± 0.018
    0.377 ± 0.018
    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 on 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
    1047
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0017
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.077
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.029
         upper limit
    0.125
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1048
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.138
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.09
         upper limit
    0.186
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1046
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0426
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.002
         upper limit
    0.098
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1045
    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
    0.074
         upper limit
    0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1047
    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
    0.063
         upper limit
    0.159
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1043
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2661
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.027
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.021
         upper limit
    0.075
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1046
    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
    0.102
         upper limit
    0.198
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1051
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0119
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.061
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.109
         upper limit
    -0.014
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1049
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0029
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.073
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.121
         upper limit
    -0.025
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1050
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6408
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.011
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.036
         upper limit
    0.059
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1047
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.221
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.173
         upper limit
    0.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1048
    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
    0.145
         upper limit
    0.242
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1046
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.185
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.136
         upper limit
    0.233
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1045
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.114
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.065
         upper limit
    0.162
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1047
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.157
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.108
         upper limit
    0.205
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1043
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1355
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.037
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.012
         upper limit
    0.085
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1046
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.151
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.102
         upper limit
    0.199
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1051
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2562
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.028
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.02
         upper limit
    0.076
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1049
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0041
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.071
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.022
         upper limit
    0.119
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1050
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0815
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.043
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.091
         upper limit
    0.005
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1047
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.195
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.149
         upper limit
    0.242
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1048
    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
    0.107
         upper limit
    0.199
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1046
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.174
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.128
         upper limit
    0.221
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1045
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.107
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.061
         upper limit
    0.154
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1047
    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
    0.086
         upper limit
    0.178
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1043
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3727
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.021
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.025
         upper limit
    0.067
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1046
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.128
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.082
         upper limit
    0.175
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1051
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0744
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.042
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.004
         upper limit
    0.089
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1049
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0047
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.067
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.021
         upper limit
    0.114
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1050
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2945
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.025
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.071
         upper limit
    0.022
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1047
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.205
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.155
         upper limit
    0.255
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1048
    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
    0.107
         upper limit
    0.206
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1046
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.192
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.142
         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 2.5 on 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
    1045
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.124
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.074
         upper limit
    0.174
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1047
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.144
    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 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 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
    1043
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6103
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.013
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.037
         upper limit
    0.062
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1046
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.137
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.087
         upper limit
    0.186
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1051
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0559
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.049
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.001
         upper limit
    0.098
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1049
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0073
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.068
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.018
         upper limit
    0.118
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1050
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4368
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.07
         upper limit
    0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025

    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 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 and 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
    519 [26]
    519 [27]
    520 [28]
    518 [29]
    521 [30]
    Units: litre(s)
    least squares mean (standard error)
        Day 15
    0.149 ± 0.018
    0.222 ± 0.018
    0.22 ± 0.018
    0.27 ± 0.018
    0.296 ± 0.018
        Day 43
    0.15 ± 0.018
    0.206 ± 0.018
    0.213 ± 0.018
    0.254 ± 0.018
    0.318 ± 0.018
        Day 85
    0.077 ± 0.018
    0.168 ± 0.018
    0.144 ± 0.018
    0.23 ± 0.018
    0.265 ± 0.018
        Day 170
    0.093 ± 0.017
    0.184 ± 0.017
    0.169 ± 0.017
    0.225 ± 0.017
    0.246 ± 0.017
        Day 365
    0.014 ± 0.018
    0.114 ± 0.018
    0.108 ± 0.018
    0.155 ± 0.018
    0.191 ± 0.018
    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 on Day 15
    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
    1040
    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 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 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
    1041
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0023
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.076
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.027
         upper limit
    0.125
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1037
    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
    0.072
         upper limit
    0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1037
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0545
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.048
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.001
         upper limit
    0.097
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0456
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.001
         upper limit
    0.099
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2949
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.026
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.023
         upper limit
    0.075
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1040
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0029
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.074
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.025
         upper limit
    0.123
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0045
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.071
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.022
         upper limit
    0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0035
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.073
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.024
         upper limit
    0.122
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9369
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.002
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.051
         upper limit
    0.047
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1040
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.168
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.119
         upper limit
    0.217
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1041
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.105
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.056
         upper limit
    0.154
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1037
    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
    0.054
         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 2.5 on Day 43
    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
    1037
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0585
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.002
         upper limit
    0.096
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1042
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.041
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.008
         upper limit
    0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0097
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.065
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.016
         upper limit
    0.114
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1040
    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
    0.063
         upper limit
    0.161
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.012
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.063
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.014
         upper limit
    0.112
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.025
    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
    Tio 5 vs Tio 2.5 on Day 43
    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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7889
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.007
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.042
         upper limit
    0.056
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1040
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.187
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.138
         upper limit
    0.237
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1041
    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
    0.072
         upper limit
    0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 on Day85
    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
    1037
    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
    0.103
         upper limit
    0.202
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1037
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0134
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.062
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.013
         upper limit
    0.111
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006
    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
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.167
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.035
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.015
         upper limit
    0.084
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1040
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.097
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.048
         upper limit
    0.146
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0085
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.066
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.017
         upper limit
    0.115
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.041
         upper limit
    0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3332
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.024
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.074
         upper limit
    0.025
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 5/5 vs Olo 5 on Day 170
    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
    1040
    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
    0.105
         upper limit
    0.201
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    Statistical analysis title
    T+O 5/5 vs Tio 5 on Day 170
    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
    1041
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0016
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.077
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.029
         upper limit
    0.125
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    Statistical analysis title
    T+O 2.5/5 vs Olo 5 on Day 170
    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
    1037
    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
    0.084
         upper limit
    0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    T+O 2.5/5 vs Tio 2.5 on Day 170
    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
    1037
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0926
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.041
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.007
         upper limit
    0.089
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    Statistical analysis title
    T+O 2.5/5 vs Tio 5 on Day 170
    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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0231
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.055
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.008
         upper limit
    0.103
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    Statistical analysis title
    T+O 5/5 vs T+O 2.5/5 on Day 170
    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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3802
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.021
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.026
         upper limit
    0.069
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    Statistical analysis title
    T+O 5/5 vs Tio 2.5 on Day 170
    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
    1040
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0105
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.062
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.015
         upper limit
    0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    Statistical analysis title
    Tio 5 vs Olo 5 on Day 170
    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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0018
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.076
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.028
         upper limit
    0.125
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    Tio 2.5 vs Olo 5 on Day 170
    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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.091
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.043
         upper limit
    0.139
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.025
    Statistical analysis title
    Tio 5 vs Tio 2.5 on Day 170
    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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5554
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.014
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.062
         upper limit
    0.034
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    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 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
    1040
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.178
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.127
         upper limit
    0.228
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    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 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
    1041
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0011
    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 Olo 5 on 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
    1037
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.142
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.091
         upper limit
    0.192
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    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 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
    1037
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1112
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.041
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.009
         upper limit
    0.091
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0632
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.048
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.003
         upper limit
    0.098
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1615
    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 Tio 2.5 on 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
    1040
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0027
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.077
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.027
         upper limit
    0.127
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    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 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
    1039
    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
    0.044
         upper limit
    0.144
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    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 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
    1038
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    0.101
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.05
         upper limit
    0.151
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    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 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
    1039
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7925
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.007
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.057
         upper limit
    0.044
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026

    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 447 days)
    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
    75 / 528 (14.20%)
    66 / 525 (12.57%)
    79 / 527 (14.99%)
    81 / 522 (15.52%)
    87 / 522 (16.67%)
         number of deaths (all causes)
    5
    11
    12
    10
    10
         number of deaths resulting from adverse events
    0
    1
    0
    0
    0
    Vascular disorders
    Arterial occlusive disease
         subjects affected / exposed
    0 / 528 (0.00%)
    1 / 525 (0.19%)
    0 / 527 (0.00%)
    0 / 522 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    0 / 528 (0.00%)
    1 / 525 (0.19%)
    0 / 527 (0.00%)
    0 / 522 (0.00%)
    0 / 522 (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
    Circulatory collapse
         subjects affected / exposed
    0 / 528 (0.00%)
    0 / 525 (0.00%)
    1 / 527 (0.19%)
    0 / 522 (0.00%)
    0 / 522 (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
    Deep vein thrombosis
         subjects affected / exposed
    1 / 528 (0.19%)
    0 / 525 (0.00%)
    0 / 527 (0.00%)
    0 / 522 (0.00%)
    1 / 522 (0.19%)
         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
    Hypertension
         subjects affected / exposed
    2 / 528 (0.38%)
    0 / 525 (0.00%)
    1 / 527 (0.19%)
    1 / 522 (0.19%)
    0 / 522 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 528 (0.00%)
    0 / 525 (0.00%)
    1 / 527 (0.19%)
    0 / 522 (0.00%)
    0 / 522 (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 / 1
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 528 (0.00%)
    1 / 525 (0.19%)
    0 / 527 (0.00%)
    0 / 522 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 528 (0.19%)
    0 / 525 (0.00%)
    0 / 527 (0.00%)
    0 / 522 (0.00%)
    0 / 522 (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 vascular disorder
         subjects affected / exposed
    2 / 528 (0.38%)
    0 / 525 (0.00%)
    0 / 527 (0.00%)
    0 / 522 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    0 / 528 (0.00%)
    0 / 525 (0.00%)
    1 / 527 (0.19%)
    0 / 522 (0.00%)
    0 / 522 (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
    Nasal septal operation
         subjects affected / exposed
    0 / 528 (0.00%)
    0 / 525 (0.00%)
    0 / 527 (0.00%)
    0 / 522 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all