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    Clinical Trial Results:
    A randomised, double-blind, placebo- and active-controlled parallel group study to assess the efficacy of 12 weeks of once daily treatment of two doses of orally inhaled tiotropium + olodaterol fixed dose combination (delivered by the Respimat® inhaler) in patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD)

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2013-002264-24
    Trial protocol
    		 SE   AT   SK   GR  
    Global end of trial date
    24 Nov 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Apr 2016
    First version publication date
    06 Apr 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1237.26
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02006732
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim Pharma GmbH & Co. KG, QRPE Processes and Systems Coordination, Clinical Trial, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim Pharma GmbH & Co. KG, QRPE Processes and Systems Coordination, Clinical Trial, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This trial was 1 of 2 randomised, double-blind, placebo- and active-controlled parallel group Phase IIIb trials with identical protocols (replicate trials with BI trial numbers 1237.25 and 1237.26) The objective of this trial was to evaluate maximal treatment effect in forced expiratory volume in one second (FEV1) response and St. George’s Respiratory Questionnaire (SGRQ) total score and safety after 12 weeks of treatment with 2 different doses of tiotropium + olodaterol fixed dose combination solution (2.5/5μg and 5/5μg) delivered by the RESPIMAT® inhaler by comparison with placebo in patients with moderate to severe 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 for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Nov 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 65
    Country: Number of subjects enrolled
    Austria: 58
    Country: Number of subjects enrolled
    Canada: 65
    Country: Number of subjects enrolled
    Germany: 213
    Country: Number of subjects enrolled
    Greece: 39
    Country: Number of subjects enrolled
    New Zealand: 16
    Country: Number of subjects enrolled
    Norway: 49
    Country: Number of subjects enrolled
    Slovakia: 39
    Country: Number of subjects enrolled
    South Africa: 27
    Country: Number of subjects enrolled
    Sweden: 48
    Country: Number of subjects enrolled
    United States: 488
    Worldwide total number of subjects
    1107
    EEA total number of subjects
    446
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    541
    From 65 to 84 years
    557
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 809 patients were randomised and treated.

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

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Once daily 2 puffs solution of placebo for inhalation with Respimat
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 actuations once daily in the morning. Dose not applicable.

    Arm title
    		 Tiotropium 5 μg
    Arm description
    		 Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tiotropium Bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 actuations once daily in the morning, for a total dose of 5 μg.

    Arm title
    		 Tiotropium 2.5 μg+ Olodaterol 5 μg
    Arm description
    		 Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat as a fixed combination with a single inhaler.
    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
    2 actuations once daily in the morning for a total dose of 5 μg

    Investigational medicinal product name
    Tiotropium Bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 actuations once daily in the morning for a total dose of 2.5 μg

    Arm title
    		 Tiotropium 5 μg + Olodaterol 5 μg
    Arm description
    		 Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat as a fixed combination with a single inhaler.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium Bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 actuations once daily in the morning, for a total dose of 5 μg.

    Investigational medicinal product name
    Olodaterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 actuations once daily in the morning, for a total dose of 5 μg.

    Number of subjects in period 1 [1]
    		Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
    Started
    202
    203
    202
    202
    Completed
    182
    191
    193
    198
    Not completed
    20
    12
    9
    4
         Consent withdrawn by subject
    3
    -
    4
    1
         Adverse event, non-fatal
    10
    7
    4
    2
         Lost to follow-up
    -
    1
    -
    -
         Lack of efficacy
    6
    3
    1
    1
         Protocol deviation
    1
    1
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on the patients who were randomized after successfully completing the screening period and received at least one of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Once daily 2 puffs solution of placebo for inhalation with Respimat

    Reporting group title
    Tiotropium 5 μg
    Reporting group description
    		 Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat

    Reporting group title
    Tiotropium 2.5 μg+ Olodaterol 5 μg
    Reporting group description
    		 Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat as a fixed combination with a single inhaler.

    Reporting group title
    Tiotropium 5 μg + Olodaterol 5 μg
    Reporting group description
    		 Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat as a fixed combination with a single inhaler.

    Reporting group values
    		 Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg Total
    Number of subjects
    		 202 203 202 202 809
    Age categorical
    Units: Subjects
    Age Continuous |
    Treated set (TS) which included all randomised patients who received at least one dose of trial medication represents the baseline analysis population.
    Units: years
        arithmetic mean (standard deviation)
    		 64 ( 8.3 ) 64.7 ( 8.4 ) 64.4 ( 8.6 ) 65.2 ( 8.5 ) -
    Gender, Male/Female
    Treated set (TS) which included all randomised patients who received at least one dose of trial medication represents the baseline analysis population.
    Units: participants
        Female
    		 85 73 76 69 303
        Male
    		 117 130 126 133 506

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Once daily 2 puffs solution of placebo for inhalation with Respimat

    Reporting group title
    Tiotropium 5 μg
    Reporting group description
    		 Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat

    Reporting group title
    Tiotropium 2.5 μg+ Olodaterol 5 μg
    Reporting group description
    		 Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat as a fixed combination with a single inhaler.

    Reporting group title
    Tiotropium 5 μg + Olodaterol 5 μg
    Reporting group description
    		 Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat as a fixed combination with a single inhaler.

    Primary: FEV1 AUC0-3h response (change from baseline)

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    End point title
    		 FEV1 AUC0-3h response (change from baseline)
    End point description
    Forced expiratory volume in one second (FEV1) Area under the curve (AUC) 0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in litres. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and standard error (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. The Full Analysis set (FAS) included all patients in the TS who had a baseline and at least one postbaseline measurement for any of the primary efficacy endpoints.
    End point type
    Primary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects analysed
    199 [1]
    201 [2]
    200 [3]
    200 [4]
    Units: Liter
        arithmetic mean (standard error)
    -0.006 ( 0.014 )
    0.188 ( 0.013 )
    0.279 ( 0.014 )
    0.293 ( 0.013 )
    Notes
    [1] - FAS including patients with available endpoint data at week 12
    [2] - FAS including patients with available endpoint data at week 12
    [3] - FAS including patients with available endpoint data at week 12
    [4] - FAS including patients with available endpoint data at week 12
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Placebo vs. Tiotropium 5 μg + Olodaterol 5 μg. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and standard error (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Placebo v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.299
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.261
         upper limit
    		 0.336
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.019
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Tiotropium 5 μg vs. Tiotropium 5 μg + 5 μg Olodaterol. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and SE are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium 5 μg v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.105
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.069
         upper limit
    		 0.141
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.019
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Placebo vs. Tiotropium 2.5 μg + Olodaterol 5 μg. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and SE are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Placebo v Tiotropium 2.5 μg+ Olodaterol 5 μg
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.284
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.246
         upper limit
    		 0.323
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Tiotropium 5 μg vs. Tiotropium 2.5 μg + Olodaterol 5 μg. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and SE are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium 5 μg v Tiotropium 2.5 μg+ Olodaterol 5 μg
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.091
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.053
         upper limit
    		 0.128
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.019
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    Placebo vs. Tiotropium 5 μg. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and SE are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Placebo v Tiotropium 5 μg
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.194
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.156
         upper limit
    		 0.232
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.019
    Statistical analysis title
    		 Statistical analysis 6
    Statistical analysis description
    Tiotropium 2.5 μg + Olodaterol 5 μg vs. Tiotropium 5 μg + Olodaterol 5 μg. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and SE are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium 2.5 μg+ Olodaterol 5 μg v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4499
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.014
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.023
         upper limit
    		 0.051
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.019

    Primary: Trough FEV1 response (change from baseline)

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    End point title
    		 Trough FEV1 response (change from baseline)
    End point description
    Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FEV1 measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. 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. The Full Analysis set (FAS) included all patients in the TS who had a baseline and at least one postbaseline measurement for any of the primary efficacy endpoints.
    End point type
    Primary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects analysed
    193 [5]
    197 [6]
    200 [7]
    199 [8]
    Units: Liter
        arithmetic mean (standard error)
    -0.003 ( 0.014 )
    0.124 ( 0.013 )
    0.166 ( 0.013 )
    0.163 ( 0.013 )
    Notes
    [5] - FAS including patients with available endpoint data at week 12
    [6] - FAS including patients with available endpoint data at week 12
    [7] - FAS including patients with available endpoint data at week 12
    [8] - FAS including patients with available endpoint data at week 12
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Placebo vs. Tiotropium 5 μg + Olodaterol 5 μg. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Placebo v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    392
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.166
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.129
         upper limit
    		 0.203
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.019
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Tiotropium 5 μg vs. Tiotropium 5 μg + Olodaterol 5 μg. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium 5 μg v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0395
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.039
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.002
         upper limit
    		 0.076
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.019
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Placebo vs. Tiotropium 2.5 μg + Olodaterol 5 μg. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Placebo v Tiotropium 2.5 μg+ Olodaterol 5 μg
    Number of subjects included in analysis
    393
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.169
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.132
         upper limit
    		 0.207
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.019
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Tiotropium 5 μg vs. Tiotropium 2.5 μg + Olodaterol 5 μg. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium 5 μg v Tiotropium 2.5 μg+ Olodaterol 5 μg
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0269
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.042
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.005
         upper limit
    		 0.079
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.019
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    Placebo vs. Tiotropium 5 μg. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Placebo v Tiotropium 5 μg
    Number of subjects included in analysis
    390
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.127
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.165
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.019
    Statistical analysis title
    		 Statistical analysis 6
    Statistical analysis description
    Tiotropium 2.5 μg + Olodaterol 5 μg vs. Tiotropium 5 μg + Olodaterol 5 μg. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium 2.5 μg+ Olodaterol 5 μg v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8669
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.034
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.019

    Primary: St. George’s Respiratory Questionnaire (SGRQ) total score based on data from this individal study

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    End point title
    		 St. George’s Respiratory Questionnaire (SGRQ) total score based on data from this individal study
    End point description
    The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life). 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. An additional combined endpoint is defined and analysed for trial 1237.25 and 1237.26, however due to the platform limitations those could not be provided. Results can be found on CT.gov study number: NCT02006732.
    End point type
    Primary
    End point timeframe
    12 weeks treatment
    End point values
    		 Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects analysed
    184 [9]
    192 [10]
    195 [11]
    197 [12]
    Units: units on a scale
        arithmetic mean (standard error)
    42.575 ( 0.711 )
    39.729 ( 0.694 )
    38.909 ( 0.691 )
    38.011 ( 0.683 )
    Notes
    [9] - FAS including patients with available endpoint data at week 12
    [10] - FAS including patients with available endpoint data at week 12
    [11] - FAS including patients with available endpoint data at week 12
    [12] - FAS including patients with available endpoint data at week 12
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Placebo vs. Tiotropium 5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Placebo v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.564
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.499
         upper limit
    		 -2.629
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.986
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Tiotropium 5 μg vs. Tiotropium 5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium 5 μg v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.078
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.717
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.628
         upper limit
    		 0.193
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.974
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Placebo vs. Tiotropium 2.5 μg + Olodaterol 5 μg. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Placebo v Tiotropium 2.5 μg+ Olodaterol 5 μg
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.666
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.611
         upper limit
    		 -1.721
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.991
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Tiotropium 5 μg vs. Tiotropium 2.5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium 5 μg v Tiotropium 2.5 μg+ Olodaterol 5 μg
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4028
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.741
         upper limit
    		 1.102
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.974
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    Placebo vs. Tiotropium 5 μg. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Placebo v Tiotropium 5 μg
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0042
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.846
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.796
         upper limit
    		 -0.897
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.993
    Statistical analysis title
    		 Statistical analysis 6
    Statistical analysis description
    Tiotropium 2.5 μg+ Olodaterol 5 μg vs. Tiotropium 5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium 2.5 μg+ Olodaterol 5 μg v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    392
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3555
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.898
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.804
         upper limit
    		 1.008
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.971

    Secondary: Trough forced vital capacity (FVC) response (change from baseline)

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    End point title
    		 Trough forced vital capacity (FVC) response (change from baseline)
    End point description
    Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FVC measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FVC response was defined as trough FVC minus baseline FVC. 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.
    End point type
    Secondary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects analysed
    193 [13]
    197 [14]
    200 [15]
    199 [16]
    Units: Liter
        arithmetic mean (standard error)
    -0.021 ( 0.024 )
    0.17 ( 0.023 )
    0.284 ( 0.023 )
    0.231 ( 0.023 )
    Notes
    [13] - FAS including patients with available endpoint data at week 12
    [14] - FAS including patients with available endpoint data at week 12
    [15] - FAS including patients with available endpoint data at week 12
    [16] - FAS including patients with available endpoint data at week 12
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Placebo vs. Tiotropium 5 μg+ Olodaterol 5 μg. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Placebo v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    392
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.252
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.187
         upper limit
    		 0.317
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.033
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Tiotropium 5 μg vs. Tiotropium 5 μg+ Olodaterol 5 μg. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium 5 μg v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0614
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.061
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.003
         upper limit
    		 0.125
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.061
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Placebo vs. Tiotropium 2.5 μg+ Olodaterol 5 μg. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Placebo v Tiotropium 2.5 μg+ Olodaterol 5 μg
    Number of subjects included in analysis
    393
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.305
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.033
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Tiotropium 5 μg vs. Tiotropium 2.5 μg+ Olodaterol 5 μg. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium 5 μg v Tiotropium 2.5 μg+ Olodaterol 5 μg
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.114
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.049
         upper limit
    		 0.178
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.033
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    Placebo vs. Tiotropium 5 μg. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Placebo v Tiotropium 5 μg
    Number of subjects included in analysis
    390
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.191
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.126
         upper limit
    		 0.256
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.033
    Statistical analysis title
    		 Statistical analysis 6
    Statistical analysis description
    Tiotropium 2.5 μg+ Olodaterol 5 μg vs. Tiotropium 5 μg+ Olodaterol 5 μg. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are 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 a random effect; spatial power covariance structure for within−patient errors and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    Tiotropium 2.5 μg+ Olodaterol 5 μg v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1089
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.053
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.117
         upper limit
    		 0.012
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.033

    Secondary: TDI focal score based on data from this individual study

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    End point title
    		 TDI focal score based on data from this individual study
    End point description
    Mahler Transitional Dyspnoea Index (TDI) focal score was performed to measure the effect of the treatment on patients' dyspnoea.(Rating scale of 3 components - change in functional impairment, change in magnitude of tasks, change in magnitude of efforts. Worst score = -9, best score = +9). The adjusted mean (SE) are obtained from fitting an MMRM model 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. An additional combined endpoint is defined and analysed for trial 1237.25 and 1237.26, however due to the platform limitations those could not be provided. Results can be found on CT.gov study number: NCT02006732.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects analysed
    183 [17]
    192 [18]
    195 [19]
    197 [20]
    Units: Units on a scale
        arithmetic mean (standard error)
    0.337 ( 0.195 )
    0.95 ( 0.191 )
    1.599 ( 0.189 )
    1.531 ( 0.187 )
    Notes
    [17] - FAS including patients with available endpoint data at week 12
    [18] - FAS including patients with available endpoint data at week 12
    [19] - FAS including patients with available endpoint data at week 12
    [20] - FAS including patients with available endpoint data at week 12
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Placebo vs. Tiotropium 5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are obtained from fitting an MMRM model 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
    Placebo v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.195
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.665
         upper limit
    		 1.725
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Tiotropium 5 μg vs. Tiotropium 5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are obtained from fitting an MMRM model 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 5 μg v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0296
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.582
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.058
         upper limit
    		 1.106
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.267
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Placebo vs. Tiotropium 2.5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are obtained from fitting an MMRM model 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
    Placebo v Tiotropium 2.5 μg+ Olodaterol 5 μg
    Number of subjects included in analysis
    378
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.263
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.796
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.272
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Tiotropium 5 μg vs. Tiotropium 2.5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are obtained from fitting an MMRM model 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 5 μg v Tiotropium 2.5 μg+ Olodaterol 5 μg
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0159
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.122
         upper limit
    		 1.178
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.269
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    Placebo vs. Tiotropium 5 μg. The adjusted mean (SE) are obtained from fitting an MMRM model 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
    Placebo v Tiotropium 5 μg
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0248
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.613
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.078
         upper limit
    		 1.148
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.273
    Statistical analysis title
    		 Statistical analysis 6
    Statistical analysis description
    Tiotropium 2.5 μg+ Olodaterol 5 μg vs. Tiotropium 5 μg+ Olodaterol 5 μg. The adjusted mean (SE) are obtained from fitting an MMRM model 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 2.5 μg+ Olodaterol 5 μg v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    392
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7984
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.068
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 0.454
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.266

    Secondary: FVC AUC0-3h response (change from baseline)

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    End point title
    		 FVC AUC0-3h response (change from baseline)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Placebo Tiotropium 5 μg Tiotropium 2.5 μg+ Olodaterol 5 μg Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects analysed
    199 [21]
    201 [22]
    200 [23]
    200 [24]
    Units: Liter
        arithmetic mean (standard error)
    -0.018 ( 0.025 )
    0.266 ( 0.023 )
    0.436 ( 0.024 )
    0.414 ( 0.023 )
    Notes
    [21] - FAS including patients with available endpoint data at week 12
    [22] - FAS including patients with available endpoint data at week 12
    [23] - FAS including patients with available endpoint data at week 12
    [24] - FAS including patients with available endpoint data at week 12
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Placebo vs. Tiotropium 5 μg+ Olodaterol 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
    Placebo v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.432
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.366
         upper limit
    		 0.498
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.033
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Tiotropium 5 μg vs. Tiotropium 5 μg+ Olodaterol 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 5 μg v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.148
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.084
         upper limit
    		 0.212
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.033
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Placebo vs. Tiotropium 2.5 μg+ Olodaterol 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
    Placebo v Tiotropium 2.5 μg+ Olodaterol 5 μg
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.455
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.387
         upper limit
    		 0.522
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.034
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Tiotropium 5 μg vs. Tiotropium 2.5 μg+ Olodaterol 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 5 μg v Tiotropium 2.5 μg+ Olodaterol 5 μg
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.171
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.105
         upper limit
    		 0.236
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.034
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    Placebo vs. Tiotropium 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
    Placebo v Tiotropium 5 μg
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.284
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.217
         upper limit
    		 0.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.034
    Statistical analysis title
    		 Statistical analysis 6
    Statistical analysis description
    Tiotropium 2.5 μg+ Olodaterol 5 μg vs. Tiotropium 5 μg+ Olodaterol 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 2.5 μg+ Olodaterol 5 μg v Tiotropium 5 μg + Olodaterol 5 μg
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4974
    Method
    		 Mixed Effects Model for Repeated Measure
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.022
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.087
         upper limit
    		 0.042
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.033

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration to the last drug administration plus 21 days up to 112 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Treatment period Placebo
    Reporting group description
    		 Once daily 2 puffs solution of placebo for inhalation with Respimat

    Reporting group title
    Treatment period Tiotropium 5 μg
    Reporting group description
    		 Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat

    Reporting group title
    Treatment period Tiotropium 2.5 μg+ Olodaterol 5 μg
    Reporting group description
    		 Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.

    Reporting group title
    Treatment period Tiotropium 5 μg+ Olodaterol 5 μg
    Reporting group description
    		 Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat.

    Serious adverse events
    		 Treatment period Placebo Treatment period Tiotropium 5 μg Treatment period Tiotropium 2.5 μg+ Olodaterol 5 μg Treatment period Tiotropium 5 μg+ Olodaterol 5 μg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 202 (1.98%)
    12 / 203 (5.91%)
    4 / 202 (1.98%)
    6 / 202 (2.97%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 203 (0.00%)
    1 / 202 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 202 (0.00%)
    2 / 203 (0.99%)
    0 / 202 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Large intestine polyp
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 202 (0.50%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 203 (0.00%)
    1 / 202 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 203 (0.00%)
    1 / 202 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcoholism
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 202 (0.00%)
    2 / 203 (0.99%)
    1 / 202 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 203 (0.00%)
    1 / 202 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment period Placebo Treatment period Tiotropium 5 μg Treatment period Tiotropium 2.5 μg+ Olodaterol 5 μg Treatment period Tiotropium 5 μg+ Olodaterol 5 μg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 202 (16.83%)
    15 / 203 (7.39%)
    25 / 202 (12.38%)
    14 / 202 (6.93%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    14 / 202 (6.93%)
    7 / 203 (3.45%)
    17 / 202 (8.42%)
    9 / 202 (4.46%)
         occurrences all number
    14
    7
    17
    9
    Dyspnoea
         subjects affected / exposed
    14 / 202 (6.93%)
    4 / 203 (1.97%)
    4 / 202 (1.98%)
    2 / 202 (0.99%)
         occurrences all number
    14
    4
    4
    2
    Cough
         subjects affected / exposed
    12 / 202 (5.94%)
    5 / 203 (2.46%)
    5 / 202 (2.48%)
    3 / 202 (1.49%)
         occurrences all number
    12
    5
    5
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 May 2014
    In this administrative revision of the trial protocol, medication restrictions and washout periods for bronchodilator medications were updated to define washout periods for bronchodilator medications marketed after finalisation of original protocol. Web cast training was added for sites that did not participate in hands-on training of MasterScope equipment during the investigator meeting to ensure that at least one staff member at each site was fully trained in the use of the ERT equipment.
    28 Aug 2014
    In this administrative revision of the trial protocol, the hypothesis testing strategy, text describing the hypothesis testing strategy and corresponding figure were updated to maintain consistency within the project. It was made explicit that safety laboratory tests and ECGs were to be performed locally and not collected in the database, and hence would not be analysed. Further details were added to provide clear guidance on visit rescheduling for patients recovering from acute exacerbations of COPD.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Additional combined primary and secondary endpoints are defined and analysed for trial 1237.25 and 1237.26, however due to the platform limitations those could not be provided. Results can be found on CT.gov study number: NCT02006732.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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