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    Clinical Trial Results:
    An exploratory, 12 week, randomised, partially double-blinded, placebo-controlled parallel group trial to explore the effects of once daily treatments of orally inhaled tiotropium + olodaterol fixed dose combination or tiotropium (both delivered by Respimat® inhaler), supervised exercise training and behavior modification on exercise capacity and physical activity in patients with Chronic Obstructive Pulmonary Disease (COPD).

    Summary
    EudraCT number
    2013-002671-18
    Trial protocol
    GB   DK   BE   PT   DE   AT   PL  
    Global end of trial date
    31 Oct 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Oct 2016
    First version publication date
    15 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1237.16
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02085161
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall objective of this trial was to explore the effects of bronchodilator monotherapy (tiotropium) plus behavioural modification, bronchodilator combination therapy (tiotropium + olodaterol fixed dose combination [FDC]) plus behavioural modification, and bronchodilator combination therapy (tiotropium + olodaterol FDC) plus exercise training plus behavioural modification on exercise capacity and physical activity in COPD patients.
    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. Patients in placebo arm have used their maintenance inhaled corticosteroids through the study, have been, as all patients in the trial, provided with a short acting bronchodilator for rescue use, had to be clinically stable 4 weeks prior to randomization, and were withdrawn from the trial in case of COPD exacerbation requiring extensive treatment and/or hospitalization.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Mar 2014
    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
    Austria: 21
    Country: Number of subjects enrolled
    Australia: 36
    Country: Number of subjects enrolled
    Belgium: 53
    Country: Number of subjects enrolled
    Canada: 57
    Country: Number of subjects enrolled
    Germany: 134
    Country: Number of subjects enrolled
    Denmark: 27
    Country: Number of subjects enrolled
    New Zealand: 14
    Country: Number of subjects enrolled
    Portugal: 12
    Country: Number of subjects enrolled
    Poland: 29
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    United States: 40
    Worldwide total number of subjects
    448
    EEA total number of subjects
    301
    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)
    182
    From 65 to 84 years
    266
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    An exploratory, randomised, partially double-blinded, placebo-controlled, parallel group trial to explore the effects of tiotropium + olodaterol fixed dose combination (FDC) or tiotropium, supervised exercise training and behaviour modification on exercise capacity and physical activity in patients with Chronic Obstructive Pulmonary Disease (COPD)

    Pre-assignment
    Screening details
    All subjects were screened for eligibility to participate in the trial. Subjects attended a specialist site which ensured that they met all strictly implemented inclusion/exclusion criteria. Subjects were not to be entered 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
    Blinding implementation details
    Patients in this partially double-blind trial remained blinded with regard to the randomised treatment assignments until after database lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo with behavioural modification (BM)
    Arm description
    Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks. In total 76 subjects were randomised for this arm but one subject was not treated and hence the number of subjects started is 75.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo matching tiotropium + olodaterol_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo matching tiotropium + olodaterol FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.

    Investigational medicinal product name
    Placebo matching tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo matching tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.

    Arm title
    Tiotropium (Tio) 5 micro-grams (μg) with BM
    Arm description
    Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.

    Arm title
    Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Arm description
    Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Tiotropium + olodaterol_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.

    Arm title
    Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Arm description
    Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Tiotropium + olodaterol_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks.

    Number of subjects in period 1 [1]
    Placebo with behavioural modification (BM) Tiotropium (Tio) 5 micro-grams (μg) with BM Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Started
    75
    76
    76
    76
    Completed
    64
    66
    71
    66
    Not completed
    11
    10
    5
    10
         Protocol deviation
    -
    1
    -
    1
         Other Reason
    1
    -
    1
    1
         Adverse event, serious fatal
    1
    -
    1
    -
         Adverse event, non-fatal
    7
    5
    3
    5
         Consent withdrawn by subject
    2
    4
    -
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo with behavioural modification (BM)
    Reporting group description
    Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks. In total 76 subjects were randomised for this arm but one subject was not treated and hence the number of subjects started is 75.

    Reporting group title
    Tiotropium (Tio) 5 micro-grams (μg) with BM
    Reporting group description
    Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.

    Reporting group title
    Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Reporting group description
    Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.

    Reporting group title
    Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Reporting group description
    Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks.

    Reporting group values
    Placebo with behavioural modification (BM) Tiotropium (Tio) 5 micro-grams (μg) with BM Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM Total
    Number of subjects
    75 76 76 76 303
    Age categorical
    Units: Subjects
    Age Continuous
    Treated set (TS): This patient set included all patients of the Randomised set (All patients who signed informed consent form and were also randomised, regardless whether the patient was treated with study medication or not) who were dispensed study medication and were documented to have taken any dose of study medication.
    Units: Years
        arithmetic mean (standard deviation)
    64.4 ± 6.6 65.1 ± 6.4 65 ± 6.9 64.7 ± 6.5 -
    Gender, Male/Female
    Treated set (TS): This patient set included all patients of the Randomised set (All patients who signed informed consent form and were also randomised, regardless whether the patient was treated with study medication or not) who were dispensed study medication and were documented to have taken any dose of study medication.
    Units: Participants
        Female
    23 21 28 31 103
        Male
    52 55 48 45 200

    End points

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    End points reporting groups
    Reporting group title
    Placebo with behavioural modification (BM)
    Reporting group description
    Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks. In total 76 subjects were randomised for this arm but one subject was not treated and hence the number of subjects started is 75.

    Reporting group title
    Tiotropium (Tio) 5 micro-grams (μg) with BM
    Reporting group description
    Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.

    Reporting group title
    Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Reporting group description
    Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.

    Reporting group title
    Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Reporting group description
    Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks.

    Primary: Endurance time during Endurance Shuttle Walk Test (ESWT) to symptom limitation after 8 weeks

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    End point title
    Endurance time during Endurance Shuttle Walk Test (ESWT) to symptom limitation after 8 weeks
    End point description
    Endurance time during ESWT to symptom limitation at walking speed corresponding to 85% of predicted maximum oxygen consumption (VO2 peak) after 8 weeks of pharmacological treatment and non-pharmacological intervention. The numerical value of endurance time in seconds was transformed in log10 scale to correct for skewness and then an analysis of covariance (ANCOVA) was fitted to the log10-transformed data and the least square means (LSMean) and standard error (SE) were obtained. To present the results in a way easier for interpretation, the least square mean from the ANCOVA fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate to obtain the geometric mean and the corresponding SE was transformed using delta method to get the corresponding SE of the geometric mean. Full analysis set (FAS): This patient set included all patients in the TS who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint
    End point type
    Primary
    End point timeframe
    Week 8
    End point values
    Placebo with behavioural modification (BM) Tiotropium (Tio) 5 micro-grams (μg) with BM Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects analysed
    65 [1]
    67 [2]
    72 [3]
    70 [4]
    Units: Second
        geometric mean (standard error)
    244.07 ± 17.666
    254.18 ± 18.099
    315.32 ± 21.671
    355.73 ± 24.787
    Notes
    [1] - FAS. Patients assigned after implementation of data handling rules that set measurements to missing.
    [2] - FAS. Patients assigned after implementation of data handling rules that set measurements to missing.
    [3] - FAS. Patients assigned after implementation of data handling rules that set measurements to missing.
    [4] - FAS. Patients assigned after implementation of data handling rules that set measurements to missing.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    This treatment comparison is the first one in the alpha-protected hierarchical testing chain. ANCOVA model with categorical effect of treatment and baseline as covariate. Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method. Ratio of means calculated as back transformation of difference on log 10 scale between Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM v Placebo with behavioural modification (BM)
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    ANCOVA
    Parameter type
    Treatment ratio
    Point estimate
    1.458
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.196
         upper limit
    1.777
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.147
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    This treatment comparison is the second one in the alpha-protected hierarchical testing chain. ANCOVA model with categorical effect of treatment and baseline as covariate. Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method. Ratio of means calculated as back transformation of difference on log 10 scale between Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0109
    Method
    ANCOVA
    Parameter type
    Treatment ratio
    Point estimate
    1.292
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.061
         upper limit
    1.573
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.129
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    This treatment comparison is the third one in the alpha-protected hierarchical testing chain. ANCOVA model with categorical effect of treatment and baseline as covariate. Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method. Ratio of means calculated as back transformation of difference on log 10 scale between Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium (Tio) 5 micro-grams (μg) with BM
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6895 [5]
    Method
    ANCOVA
    Parameter type
    Treatment ratio
    Point estimate
    1.041
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.853
         upper limit
    1.272
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.106
    Notes
    [5] - Since the p-value for this treatment comparison is >0.05, the hierarchical testing chain is broken and all of the following hypothesis tests in this hierarchical chain are considered as descriptive only.
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    ANCOVA model with categorical effect of treatment and baseline as covariate. Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method. Ratio of means calculated as back transformation of difference on log 10 scale between Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM.
    Comparison groups
    Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM v Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2188
    Method
    ANCOVA
    Parameter type
    Treatment ratio
    Point estimate
    1.128
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.931
         upper limit
    1.368
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    ANCOVA model with categorical effect of treatment and baseline as covariate. Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method. Ratio of means calculated as back transformation of difference on log 10 scale between Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM.
    Comparison groups
    Tiotropium (Tio) 5 micro-grams (μg) with BM v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0303
    Method
    ANCOVA
    Parameter type
    Treatment ratio
    Point estimate
    1.241
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.021
         upper limit
    1.507
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.123

    Secondary: Average daily walking time measured by the activity monitor in the week prior to Week 12

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    End point title
    Average daily walking time measured by the activity monitor in the week prior to Week 12
    End point description
    Average daily walking time measured by the activity monitor in the week prior to Week 12. Full analysis set (FAS): This patient set included all patients in the TS who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint. Patients were assigned to the FAS after implementation of any data handling rules that set measurements to missing. Patients with available data were included.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo with behavioural modification (BM) Tiotropium (Tio) 5 micro-grams (μg) with BM Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects analysed
    55 [6]
    57 [7]
    60 [8]
    57 [9]
    Units: Second
        least squares mean (standard error)
    4670.78 ± 211.798
    4145.85 ± 207.351
    4831.85 ± 202.261
    4338.8 ± 207.252
    Notes
    [6] - FAS
    [7] - FAS
    [8] - FAS
    [9] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    An ANCOVA model with categorical effects of treatment and baseline as covariate. The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2639
    Method
    ANCOVA
    Parameter type
    LSMean Difference
    Point estimate
    -331.975
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -916.015
         upper limit
    252.064
    Variability estimate
    Standard error of the mean
    Dispersion value
    296.375
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    An ANCOVA model with categorical effects of treatment and baseline as covariate. The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5837
    Method
    ANCOVA
    Parameter type
    LSMean Difference
    Point estimate
    161.072
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -417.314
         upper limit
    739.459
    Variability estimate
    Standard error of the mean
    Dispersion value
    293.506
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    An ANCOVA model with categorical effects of treatment and baseline as covariate. The LSMean Difference is calculated as Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium (Tio) 5 micro-grams (μg) with BM
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0783
    Method
    ANCOVA
    Parameter type
    LSMean Difference
    Point estimate
    -524.926
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1109.806
         upper limit
    59.954
    Variability estimate
    Standard error of the mean
    Dispersion value
    296.802
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    An ANCOVA model with categorical effects of treatment and baseline as covariate. The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM.
    Comparison groups
    Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM v Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.09
    Method
    ANCOVA
    Parameter type
    LSMean Difference
    Point estimate
    -493.048
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1063.67
         upper limit
    77.575
    Variability estimate
    Standard error of the mean
    Dispersion value
    289.566
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    An ANCOVA model with categorical effects of treatment and baseline as covariate. The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM.
    Comparison groups
    Tiotropium (Tio) 5 micro-grams (μg) with BM v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0186
    Method
    ANCOVA
    Parameter type
    LSMean Difference
    Point estimate
    685.998
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    115.635
         upper limit
    1256.362
    Variability estimate
    Standard error of the mean
    Dispersion value
    289.435

    Secondary: Average daily walking intensity measured by the activity monitor in the week prior to 12 weeks of treatment

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    End point title
    Average daily walking intensity measured by the activity monitor in the week prior to 12 weeks of treatment
    End point description
    Average daily walking intensity measured by the activity monitor in the week prior to 12 weeks of treatment. Full analysis set (FAS): This patient set included all patients in the TS who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint. Patients were assigned to the FAS after implementation of any data handling rules that set measurements to missing. Patients with available data were included.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo with behavioural modification (BM) Tiotropium (Tio) 5 micro-grams (μg) with BM Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects analysed
    54 [10]
    56 [11]
    58 [12]
    57 [13]
    Units: Gravitational acceleration (g)
        least squares mean (standard error)
    0.2 ± 0.003
    0.2 ± 0.003
    0.2 ± 0.003
    0.2 ± 0.003
    Notes
    [10] - FAS
    [11] - FAS
    [12] - FAS
    [13] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    An ANCOVA model with categorical effects of treatment and baseline as covariate. The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5186
    Method
    ANCOVA
    Parameter type
    LSMean Difference
    Point estimate
    -0.002
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.005
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.004
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    An ANCOVA model with categorical effects of treatment and baseline as covariate. The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6436
    Method
    ANCOVA
    Parameter type
    LSMean Difference
    Point estimate
    0.002
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.006
         upper limit
    0.009
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.004
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    An ANCOVA model with categorical effects of treatment and baseline as covariate. The LSMean Difference is calculated as Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium (Tio) 5 micro-grams (μg) with BM
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1081
    Method
    ANCOVA
    Parameter type
    LSMean Difference
    Point estimate
    -0.006
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.014
         upper limit
    0.001
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.004
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    An ANCOVA model with categorical effects of treatment and baseline as covariate. The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM.
    Comparison groups
    Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM v Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2612
    Method
    ANCOVA
    Parameter type
    LSMean Difference
    Point estimate
    -0.004
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.011
         upper limit
    0.003
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.004
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    An ANCOVA model with categorical effects of treatment and baseline as covariate. The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM.
    Comparison groups
    Tiotropium (Tio) 5 micro-grams (μg) with BM v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0361
    Method
    ANCOVA
    Parameter type
    LSMean Difference
    Point estimate
    0.008
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.001
         upper limit
    0.015
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.004

    Secondary: Perceived difficulties as evaluated with Functional Performance Inventory (FPI) - Short Form (SF) total score at Week 12

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    End point title
    Perceived difficulties as evaluated with Functional Performance Inventory (FPI) - Short Form (SF) total score at Week 12
    End point description
    Perceived difficulties as evaluated with Functional Performance Inventory (FPI) - Short Form (SF) total score at Week 12. The FPI-SF self-report questionnaire consists of 2 pages of questions relating to 6 dimensions: body care, household maintenance, physical exercise, recreation, spiritual activities, and social activities. Five answer options were possible: “Do with no difficulty, do with some difficulty, do with great difficulty, don’t do because of health reasons, and don’t do because choose not to”. Domain scores and total scores were calculated from the answers. Full analysis set (FAS): This patient set included all patients in the TS who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint. Patients were assigned to the FAS after implementation of any data handling rules that set measurements to missing. Patients with available data were included.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo with behavioural modification (BM) Tiotropium (Tio) 5 micro-grams (μg) with BM Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects analysed
    64 [14]
    65 [15]
    71 [16]
    67 [17]
    Units: Units on a scale
        least squares mean (standard error)
    2.191 ± 0.04
    2.207 ± 0.04
    2.335 ± 0.038
    2.268 ± 0.039
    Notes
    [14] - FAS
    [15] - FAS
    [16] - FAS
    [17] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    An ANCOVA model with categorical effects of treatment and baseline as covariate. The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1727
    Method
    ANCOVA
    Parameter type
    LSMean Difference
    Point estimate
    0.076
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.034
         upper limit
    0.187
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.056
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    An ANCOVA model with categorical effects of treatment and baseline as covariate. The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0097
    Method
    ANCOVA
    Parameter type
    LSMean Difference
    Point estimate
    0.143
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.035
         upper limit
    0.252
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.055
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    An ANCOVA model with categorical effects of treatment and baseline as covariate. The LSMean Difference is calculated as Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium (Tio) 5 micro-grams (μg) with BM
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7815
    Method
    ANCOVA
    Parameter type
    LSMean Difference
    Point estimate
    0.016
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.095
         upper limit
    0.126
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.056
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    An ANCOVA model with categorical effects of treatment and baseline as covariate. The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM.
    Comparison groups
    Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM v Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2183
    Method
    ANCOVA
    Parameter type
    LSMean Difference
    Point estimate
    -0.067
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.174
         upper limit
    0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.054
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    An ANCOVA model with categorical effects of treatment and baseline as covariate. The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM
    Comparison groups
    Tiotropium (Tio) 5 micro-grams (μg) with BM v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0203
    Method
    ANCOVA
    Parameter type
    LSMean Difference
    Point estimate
    0.128
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.02
         upper limit
    0.236
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.055

    Secondary: Endurance time during Endurance Shuttle Walk Test (ESWT) to symptom limitation after 12 weeks

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    End point title
    Endurance time during Endurance Shuttle Walk Test (ESWT) to symptom limitation after 12 weeks
    End point description
    Endurance time during ESWT to symptom limitation at walking speed corresponding to 85% of maximum oxygen consumption (VO2peak) after 12 weeks of pharmacological treatment and non-pharmacological intervention. The numerical value of endurance time in seconds was transformed in log10 scale to correct for skewness and then the ANCOVA was fitted to the log10-transformed data and the least square means and SE were obtained. To present the results in a way easier for interpretation, the least square mean from the ANCOVA fitted to the log10- transformed data were transformed back taking 10 to the power of the least square estimate to obtain the geometric mean and the corresponding SE was transformed using delta method to get the corresponding SE of the geometric mean. Full analysis set (FAS): This patient set included all patients in the TS who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint. Patients with available data were included.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo with behavioural modification (BM) Tiotropium (Tio) 5 micro-grams (μg) with BM Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects analysed
    62 [18]
    64 [19]
    71 [20]
    66 [21]
    Units: Second
        geometric mean (standard error)
    243.3 ± 18.68
    255.67 ± 19.292
    302.61 ± 21.691
    324.21 ± 24.095
    Notes
    [18] - FAS. Patients assigned after implementation of data handling rules that set measurements to missing.
    [19] - FAS. Patients assigned after implementation of data handling rules that set measurements to missing.
    [20] - FAS. Patients assigned after implementation of data handling rules that set measurements to missing.
    [21] - FAS. Patients assigned after implementation of data handling rules that set measurements to missing.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    ANCOVA model with categorical effect of treatment and baseline as covariate. Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method. Ratio of means calculated as back transformation of difference on log 10 scale between Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0077
    Method
    ANCOVA
    Parameter type
    Treatment ratio
    Point estimate
    1.333
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.08
         upper limit
    1.645
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.142
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    ANCOVA model with categorical effect of treatment and baseline as covariate. Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method. Ratio of means calculated as back transformation of difference on log 10 scale between Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.039
    Method
    ANCOVA
    Parameter type
    Treatment ratio
    Point estimate
    1.244
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.011
         upper limit
    1.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.131
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    ANCOVA model with categorical effect of treatment and baseline as covariate. Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method. Ratio of means calculated as back transformation of difference on log 10 scale between Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium (Tio) 5 micro-grams (μg) with BM
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6452
    Method
    ANCOVA
    Parameter type
    Treatment ratio
    Point estimate
    1.051
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    1.299
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.113
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    ANCOVA model with categorical effect of treatment and baseline as covariate. Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method. Ratio of means calculated as back transformation of difference on log 10 scale between Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM.
    Comparison groups
    Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM v Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5048
    Method
    ANCOVA
    Parameter type
    Treatment ratio
    Point estimate
    1.071
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.874
         upper limit
    1.313
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.111
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    ANCOVA model with categorical effect of treatment and baseline as covariate. Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method. Ratio of means calculated as back transformation of difference on log 10 scale between Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM.
    Comparison groups
    Tiotropium (Tio) 5 micro-grams (μg) with BM v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1066
    Method
    ANCOVA
    Parameter type
    Treatment ratio
    Point estimate
    1.184
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.964
         upper limit
    1.453
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.123

    Secondary: One hour, Post-dose Forced Expiratory Volume in One Second (FEV1) after 8 weeks of treatment

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    End point title
    One hour, Post-dose Forced Expiratory Volume in One Second (FEV1) after 8 weeks of treatment
    End point description
    One hour, Post-dose Forced Expiratory Volume in One Second (FEV1) after 8 weeks of treatment. Full analysis set (FAS): This patient set included all patients in the TS who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint. Patients were assigned to the FAS after implementation of any data handling rules that set measurements to missing. Patients with available data were included.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Placebo with behavioural modification (BM) Tiotropium (Tio) 5 micro-grams (μg) with BM Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects analysed
    65 [22]
    67 [23]
    72 [24]
    70 [25]
    Units: Liter
        least squares mean (standard error)
    1.375 ± 0.027
    1.55 ± 0.027
    1.731 ± 0.026
    1.705 ± 0.026
    Notes
    [22] - FAS
    [23] - FAS
    [24] - FAS
    [25] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed effect Model Repeat Measurement (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect. Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSMean Difference
    Point estimate
    0.329
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.255
         upper limit
    0.403
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.038
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    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. Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSMean Difference
    Point estimate
    0.356
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.282
         upper limit
    0.429
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.037
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    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. Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The LSMean Difference is calculated as Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium (Tio) 5 micro-grams (μg) with BM
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSMean Difference
    Point estimate
    0.174
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.099
         upper limit
    0.249
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.038
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    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. Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM.
    Comparison groups
    Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM v Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4677
    Method
    Mixed models analysis
    Parameter type
    LSMean Difference
    Point estimate
    -0.027
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.099
         upper limit
    0.045
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.037
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    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. Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM.
    Comparison groups
    Tiotropium (Tio) 5 micro-grams (μg) with BM v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSMean Difference
    Point estimate
    0.182
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.109
         upper limit
    0.255
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.037

    Secondary: One hour, Post-dose Forced Vital Capacity (FVC) after 8 weeks of treatment

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    End point title
    One hour, Post-dose Forced Vital Capacity (FVC) after 8 weeks of treatment
    End point description
    One hour, Post-dose Forced Vital Capacity (FVC) after 8 weeks of treatment. Full analysis set (FAS): This patient set included all patients in the TS who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint. Patients were assigned to the FAS after implementation of any data handling rules that set measurements to missing. Patients with available data were included.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Placebo with behavioural modification (BM) Tiotropium (Tio) 5 micro-grams (μg) with BM Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects analysed
    65 [26]
    67 [27]
    72 [28]
    70 [29]
    Units: Liter
        least squares mean (standard error)
    2.974 ± 0.047
    3.259 ± 0.046
    3.504 ± 0.044
    3.452 ± 0.045
    Notes
    [26] - FAS
    [27] - FAS
    [28] - FAS
    [29] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed effect Model Repeat Measurement (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect. Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSMean Difference
    Point estimate
    0.478
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.35
         upper limit
    0.606
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.065
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    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. Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSMean Difference
    Point estimate
    0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.403
         upper limit
    0.657
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.064
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    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. Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The LSMean Difference is calculated as Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium (Tio) 5 micro-grams (μg) with BM
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSMean Difference
    Point estimate
    0.286
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.157
         upper limit
    0.415
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.066
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    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. Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM.
    Comparison groups
    Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM v Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4107
    Method
    Mixed models analysis
    Parameter type
    LSMean Difference
    Point estimate
    -0.052
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.176
         upper limit
    0.072
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.063
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    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. Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM.
    Comparison groups
    Tiotropium (Tio) 5 micro-grams (μg) with BM v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Mixed models analysis
    Parameter type
    LSMean Difference
    Point estimate
    0.244
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.119
         upper limit
    0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.064

    Secondary: Resting inspiratory capacity (IC) measured at 1.5 hours post dose after 8 weeks of treatment

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    End point title
    Resting inspiratory capacity (IC) measured at 1.5 hours post dose after 8 weeks of treatment
    End point description
    Resting inspiratory capacity (IC) measured at 1.5 hours post dose after 8 weeks of treatment. Full analysis set (FAS): This patient set included all patients in the TS who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint. Patients were assigned to the FAS after implementation of any data handling rules that set measurements to missing. Patients with available data were included.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Placebo with behavioural modification (BM) Tiotropium (Tio) 5 micro-grams (μg) with BM Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects analysed
    64 [30]
    66 [31]
    72 [32]
    68 [33]
    Units: Liter
        least squares mean (standard error)
    2.452 ± 0.051
    2.627 ± 0.05
    2.755 ± 0.048
    2.771 ± 0.049
    Notes
    [30] - FAS
    [31] - FAS
    [32] - FAS
    [33] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed effect Model Repeat Measurement (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect. Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSMean Difference
    Point estimate
    0.318
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.179
         upper limit
    0.457
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.071
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    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. Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSMean Difference
    Point estimate
    0.302
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.165
         upper limit
    0.439
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    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. Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The LSMean Difference is calculated as Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM).
    Comparison groups
    Placebo with behavioural modification (BM) v Tiotropium (Tio) 5 micro-grams (μg) with BM
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0145
    Method
    Mixed models analysis
    Parameter type
    LSMean Difference
    Point estimate
    0.174
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.035
         upper limit
    0.314
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.071
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    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. Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM.
    Comparison groups
    Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM v Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.815
    Method
    Mixed models analysis
    Parameter type
    LSMean Difference
    Point estimate
    0.016
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.118
         upper limit
    0.151
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.068
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    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. Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom. The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM.
    Comparison groups
    Tiotropium (Tio) 5 micro-grams (μg) with BM v Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0642
    Method
    Mixed models analysis
    Parameter type
    LSMean Difference
    Point estimate
    0.128
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.008
         upper limit
    0.263
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.069

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period, up to 134 days.
    Adverse event reporting additional description
    All adverse events, serious and non-serious, occurring during the course of the clinical trial (i.e. from signing the informed consent onwards through the observational phase) were to be collected, documented and reported to the sponsor by the investigator on the appropriate electronic case report form / serious adverse event reporting forms.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo with behavioural modification (BM)
    Reporting group description
    Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.

    Reporting group title
    Tiotropium (Tio) 5 micro-grams (μg) with BM
    Reporting group description
    Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.

    Reporting group title
    Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
    Reporting group description
    Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.

    Reporting group title
    Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM
    Reporting group description
    Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks.

    Reporting group title
    Total
    Reporting group description
    Total

    Serious adverse events
    Placebo with behavioural modification (BM) Tiotropium (Tio) 5 micro-grams (μg) with BM Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 75 (5.33%)
    11 / 76 (14.47%)
    3 / 76 (3.95%)
    8 / 76 (10.53%)
    26 / 303 (8.58%)
         number of deaths (all causes)
    1
    1
    0
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Rib fracture
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant genitourinary tract neoplasm
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma unspecified histology indolent stage IV
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic neoplasm
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer metastatic
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    2 / 303 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 75 (1.33%)
    2 / 76 (2.63%)
    1 / 76 (1.32%)
    1 / 76 (1.32%)
    5 / 303 (1.65%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 1
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    2 / 303 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hilum mass
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Compartment syndrome
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo with behavioural modification (BM) Tiotropium (Tio) 5 micro-grams (μg) with BM Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 75 (29.33%)
    19 / 76 (25.00%)
    16 / 76 (21.05%)
    19 / 76 (25.00%)
    76 / 303 (25.08%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    16 / 75 (21.33%)
    10 / 76 (13.16%)
    12 / 76 (15.79%)
    13 / 76 (17.11%)
    51 / 303 (16.83%)
         occurrences all number
    18
    13
    14
    15
    60
    Dyspnoea
         subjects affected / exposed
    2 / 75 (2.67%)
    6 / 76 (7.89%)
    2 / 76 (2.63%)
    2 / 76 (2.63%)
    12 / 303 (3.96%)
         occurrences all number
    2
    6
    2
    2
    12
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 75 (5.33%)
    1 / 76 (1.32%)
    2 / 76 (2.63%)
    1 / 76 (1.32%)
    8 / 303 (2.64%)
         occurrences all number
    4
    1
    2
    1
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 75 (10.67%)
    9 / 76 (11.84%)
    4 / 76 (5.26%)
    10 / 76 (13.16%)
    31 / 303 (10.23%)
         occurrences all number
    9
    11
    5
    11
    36

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Apr 2014
    This amendment includes the following; Waist circumference was removed from the measurements of moderating variables. Tiotropium was entered as a comparator product. SpO2 was entered under criteria for safety with exercise testing. Medical history was removed from the flowchart and in the main flowchart, timing of the trial follow-up visit was clarified. Medication washout check was entered also under Visit 2 for the washout of ipratropium in the main flowchart. Pedometer use was entered and MBS-S use corrected for the 6MWT. In the behavioural modification flowchart, visit windows were specified and names of questionnaires were corrected. Exercise capacity and physical activity were to be assessed after the end of supervised exercise training in the Tio+Olo 5/5 μg FDC + BM + ET arm. Patients were not to inhale trial medication on the morning of Visits 5 to 8. In safety laboratory urine examination added. Patient treatment preference assessment was added to the individual BM pre-session. Details on bronchodilator therapy required for treatment of GOLD Stage II and III patients were deleted. Intensity of breathing and leg discomfort recording during 6MWT was additionally specified, and timing of 6MWT after the ESWT on Visits 5 and 8 and IC measurement post dose on Visits 3, 5 and 8 was re-specified. Timing of baseline LF and exercise tests specified at Visit 3. Modified Borg Scale use during 6MWT has been clarified. Minor corrections and further clarifications were introduced.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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