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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
    2013-002243-29
    Trial protocol
    FI   GB   CZ   ES   DK   BE  
    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

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    Trial identification
    Sponsor protocol code
    1237.25
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01964352
    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
    29 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
    Belgium: 42
    Country: Number of subjects enrolled
    Canada: 58
    Country: Number of subjects enrolled
    Czech Republic: 45
    Country: Number of subjects enrolled
    Denmark: 58
    Country: Number of subjects enrolled
    Finland: 52
    Country: Number of subjects enrolled
    Germany: 159
    Country: Number of subjects enrolled
    South Africa: 64
    Country: Number of subjects enrolled
    Spain: 81
    Country: Number of subjects enrolled
    United Kingdom: 49
    Country: Number of subjects enrolled
    United States: 446
    Worldwide total number of subjects
    1054
    EEA total number of subjects
    486
    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)
    505
    From 65 to 84 years
    541
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    814 were entered and randomized. One patient randomized to Tiotropium 5 μg was not treated. One patient entered the study with 2 different patient numbers. This patient was counted twice in the randomized set but only once in the treated set. Thus a total of 812 unique patients were 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
    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 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
    204
    203
    202
    203
    Completed
    178
    192
    196
    195
    Not completed
    26
    11
    6
    8
         Protocol deviation
    2
    4
    -
    2
         Lack of efficacy
    6
    -
    -
    -
         Adverse event, serious fatal
    -
    2
    -
    -
         Adverse event, non-fatal
    13
    1
    4
    3
         Consent withdrawn by subject
    4
    2
    1
    -
         Other than stated above
    -
    2
    1
    2
         Lost to follow-up
    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
    204 203 202 203 812
    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)
    65.1 ± 8.3 64.9 ± 8.2 64.7 ± 8.2 64.7 ± 8.9 -
    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
    77 79 86 89 331
        Male
    127 124 116 114 481

    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
    204 [1]
    203 [2]
    202 [3]
    202 [4]
    Units: Liter
        arithmetic mean (standard error)
    -0.014 ± 0.014
    0.205 ± 0.013
    0.285 ± 0.013
    0.316 ± 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
    406
    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
    0.331
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.293
         upper limit
    0.369
    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
    405
    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
    0.111
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.075
         upper limit
    0.148
    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
    406
    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
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.262
         upper limit
    0.337
    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. 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
    405
    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
    0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.044
         upper limit
    0.116
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.018
    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
    407
    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
    0.219
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.181
         upper limit
    0.258
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02
    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
    404
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0872
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (net)
    Point estimate
    0.031
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.005
         upper limit
    0.067
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.018

    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.
    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
    198 [5]
    200 [6]
    201 [7]
    200 [8]
    Units: Liter
        arithmetic mean (standard error)
    0.001 ± 0.014
    0.135 ± 0.014
    0.151 ± 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
    398
    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
    0.162
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.0124
         upper limit
    0.2
    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
    400
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1381
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (net)
    Point estimate
    0.028
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.009
         upper limit
    0.066
    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
    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
    0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.113
         upper limit
    0.188
    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
    401
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3872
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (net)
    Point estimate
    0.017
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.021
         upper limit
    0.054
    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
    398
    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
    0.134
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.096
         upper limit
    0.172
    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
    401
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5333
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (net)
    Point estimate
    0.012
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.025
         upper limit
    0.049
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.019

    Primary: St. George’s Respiratory Questionnaire (SGRQ) total score

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    End point title
    St. George’s Respiratory Questionnaire (SGRQ) total score
    End point description
    This endpoint was evaluated based on the data from this individual trial. 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. 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.
    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
    186 [9]
    192 [10]
    199 [11]
    196 [12]
    Units: units on a scale
        arithmetic mean (standard error)
    42.038 ± 0.738
    39.637 ± 0.717
    37.916 ± 0.708
    37.144 ± 0.71
    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
    382
    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
    -4.894
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.904
         upper limit
    -2.884
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.024
    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
    388
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0136
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.493
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.473
         upper limit
    -0.513
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.009
    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
    385
    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
    -4.122
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.129
         upper limit
    -2.114
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.023
    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
    391
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.088
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.721
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.698
         upper limit
    0.256
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.008
    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
    378
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0198
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.401
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.419
         upper limit
    -0.382
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.029
    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
    395
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4415
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.772
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.741
         upper limit
    1.196
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.003

    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
    198 [13]
    200 [14]
    201 [15]
    200 [16]
    Units: Liter
        arithmetic mean (standard error)
    0.025 ± 0.023
    0.223 ± 0.023
    0.233 ± 0.022
    0.244 ± 0.022
    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
    398
    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
    0.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.157
         upper limit
    0.282
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.032
    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
    400
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5052
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (net)
    Point estimate
    0.021
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.041
         upper limit
    0.084
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.032
    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
    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
    0.208
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.146
         upper limit
    0.271
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.032
    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
    401
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7566
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (net)
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.052
         upper limit
    0.072
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.032
    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
    398
    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
    0.198
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.136
         upper limit
    0.261
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.032
    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
    401
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7199
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (net)
    Point estimate
    0.011
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.051
         upper limit
    0.073
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.032

    Secondary: TDI focal score

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    End point title
    TDI focal score
    End point description
    This endpoint was evaluated based on the data from this individual trial. 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. 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.
    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
    187 [17]
    193 [18]
    199 [19]
    196 [20]
    Units: Units on a scale
        arithmetic mean (standard error)
    -0.113 ± 0.196
    1.332 ± 0.192
    1.839 ± 0.189
    1.939 ± 0.19
    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
    383
    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
    2.052
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.516
         upper limit
    2.588
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.273
    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
    = 0.0246
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (final values)
    Point estimate
    0.607
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.078
         upper limit
    1.137
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27
    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
    386
    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
    1.952
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.417
         upper limit
    2.487
    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
    392
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0599
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (final values)
    Point estimate
    0.507
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.021
         upper limit
    1.035
    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
    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
    1.445
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.907
         upper limit
    1.983
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.274
    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
    395
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7081
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.425
         upper limit
    0.626
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.268

    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
    204 [21]
    203 [22]
    202 [23]
    202 [24]
    Units: Liter
        arithmetic mean (standard error)
    -0.011 ± 0.025
    0.286 ± 0.024
    0.387 ± 0.023
    0.446 ± 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 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
    406
    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
    0.457
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    0.524
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.034
    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
    405
    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
    0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.095
         upper limit
    0.225
    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 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
    406
    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
    0.398
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.331
         upper limit
    0.465
    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 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
    405
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0023
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (net)
    Point estimate
    0.101
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.036
         upper limit
    0.165
    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. 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
    407
    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
    0.297
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.229
         upper limit
    0.365
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.035
    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
    404
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0701
    Method
    Mixed Effects Model for Repeated Measure
    Parameter type
    Mean difference (net)
    Point estimate
    0.059
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.005
         upper limit
    0.123
    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 2.5 μg tiotropium 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
    11 / 204 (5.39%)
    6 / 203 (2.96%)
    4 / 202 (1.98%)
    10 / 203 (4.93%)
         number of deaths (all causes)
    0
    2
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    1 / 202 (0.50%)
    0 / 203 (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
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    1 / 202 (0.50%)
    0 / 203 (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
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 203 (0.49%)
         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
    Clavicle fracture
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    1 / 202 (0.50%)
    0 / 203 (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
    Road traffic accident
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 203 (0.49%)
         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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm of unknown primary site
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 203 (0.49%)
         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 / 1
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 204 (0.49%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    0 / 203 (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
    2 / 204 (0.98%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 204 (0.49%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    0 / 203 (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
    Cardiomyopathy
         subjects affected / exposed
    1 / 204 (0.49%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    0 / 203 (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
    Ischaemic cardiomyopathy
         subjects affected / exposed
    1 / 204 (0.49%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    0 / 203 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 204 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 204 (1.47%)
    1 / 203 (0.49%)
    1 / 202 (0.50%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 203 (0.49%)
         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
    Pulmonary hypertension
         subjects affected / exposed
    0 / 204 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
    0 / 203 (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 failure
         subjects affected / exposed
    1 / 204 (0.49%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    0 / 203 (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
    Cerebrovascular accident
         subjects affected / exposed
    0 / 204 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
    0 / 203 (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 / 1
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 203 (0.49%)
         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
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 204 (0.49%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    0 / 203 (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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 203 (0.49%)
         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
    Psychiatric disorders
    Acute stress disorder
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 203 (0.49%)
         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
    Bipolar disorder
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 203 (0.49%)
         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
    Depression
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 203 (0.49%)
         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
    Suicide attempt
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 203 (0.49%)
         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
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 203 (0.49%)
         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
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 204 (0.49%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    0 / 203 (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
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    2 / 204 (0.98%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    1 / 202 (0.50%)
    0 / 203 (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
    Erysipelas
         subjects affected / exposed
    0 / 204 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
    0 / 203 (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
    Gangrene
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    1 / 202 (0.50%)
    0 / 203 (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
    Gastrointestinal bacterial infection
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 203 (0.49%)
         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
    Localised infection
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    1 / 202 (0.50%)
    0 / 203 (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
    Pneumonia
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    1 / 203 (0.49%)
         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
    Pneumonia bacterial
         subjects affected / exposed
    0 / 204 (0.00%)
    1 / 203 (0.49%)
    0 / 202 (0.00%)
    0 / 203 (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
    Sinusitis
         subjects affected / exposed
    1 / 204 (0.49%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    0 / 203 (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
    Viral infection
         subjects affected / exposed
    1 / 204 (0.49%)
    0 / 203 (0.00%)
    0 / 202 (0.00%)
    0 / 203 (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
    32 / 204 (15.69%)
    25 / 203 (12.32%)
    25 / 202 (12.38%)
    16 / 203 (7.88%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    20 / 204 (9.80%)
    19 / 203 (9.36%)
    16 / 202 (7.92%)
    9 / 203 (4.43%)
         occurrences all number
    22
    21
    16
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 204 (5.88%)
    9 / 203 (4.43%)
    9 / 202 (4.46%)
    7 / 203 (3.45%)
         occurrences all number
    12
    9
    9
    7

    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.
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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