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    Clinical Trial Results:
    A Phase III, randomised, double-blind, placebo-controlled, parallel group study to determine the effect of 12 weeks treatment of orally inhaled tiotropium + olodaterol fixed dose combination (2.5/5 µg, 5/5 µg) delivered by the Respimat® Inhaler, on exercise endurance time during constant work rate cycle ergometry in patients with Chronic Obstructive Pulmonary Disease (COPD) (TorractoTM)

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2011-004253-11
    Trial protocol
    		 FI   DE   HU   ES   IE   IT   GB  
    Global end of trial date
    26 Sep 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    1237.15
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01525615
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173 , Ingelheim am Rhein , Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 243 0127 , clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 243 0127 , 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
    06 Nov 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination (2.5/5 µg; 5/5 µg) with placebo on exercise tolerance after 12 weeks of treatment in patients with COPD. Exercise tolerance will be assessed by measurement of symptom-limited endurance time during constant work rate cycle ergometry at 75% Wcap (Maximal Work Capacity).
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were 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. Rescue medication was allowed for all patients as required. An individual patient could be withdrawn from the clinical trial prior to completion if any of the following criteria apply: 1. The patient was no longer able to participate for medical reasons (e.g. pregnancy, surgery, adverse events, or other diseases). 2. Administrative reasons (protocol violations, persistent non-compliance). 3. Decision by Boehringer Ingelheim to discontinue a specific patient (e.g. in case of SAEs)
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Mar 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 50
    Country: Number of subjects enrolled
    United Kingdom: 73
    Country: Number of subjects enrolled
    Finland: 24
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Germany: 76
    Country: Number of subjects enrolled
    Hungary: 76
    Country: Number of subjects enrolled
    Italy: 43
    Country: Number of subjects enrolled
    Argentina: 31
    Country: Number of subjects enrolled
    Canada: 56
    Country: Number of subjects enrolled
    United States: 93
    Worldwide total number of subjects
    544
    EEA total number of subjects
    364
    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)
    313
    From 65 to 84 years
    231
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    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 randomised to trial treatment if any one of the specific entry criteria were violated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Once daily 2 puffs, solution for inhalation Respimat placebo to tiotropium+olodaterol during the 12-week treatment period: comparator
    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
    Matching placebo During the 12-week treatment period, patients were to inhale 2 actuations from the RESPIMAT Inhaler, once a day, in the morning.

    Arm title
    		 Tio+Olo 2.5 / 5.0 μg
    Arm description
    		 Oral inhalation of fixed dose combination (FDC) of Tiotropium (Tio) 2.5 μg and Olodaterol (Olo) 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period.
    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
    2.5 μg tiotropium / 5 μg olodaterol (1.25 μg + 2.5 μg per actuation, respectively) During the 12-week treatment period, patients were to inhale 2 actuations from the RESPIMAT Inhaler, once a day, in the morning.

    Arm title
    		 Tio+Olo 5.0 / 5.0 μg
    Arm description
    		 Oral inhalation of FDC of Tiotropium (Tio) 5 μg and Olodaterol (Olo) 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period.
    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
    5 μg tiotropium / 5 μg olodaterol (2.5 μg each per actuation) During the 12-week treatment period, patients were to inhale 2 actuations from the RESPIMAT Inhaler, once a day, in the morning.

    Number of subjects in period 1 [1]
    		Placebo Tio+Olo 2.5 / 5.0 μg Tio+Olo 5.0 / 5.0 μg
    Started
    132
    133
    139
    Completed
    118
    126
    133
    Not completed
    14
    7
    6
         Adverse event, serious fatal
    -
    2
    -
         Consent withdrawn by subject
    1
    -
    -
         Adverse event, non-fatal
    11
    5
    5
         Not defined above
    1
    -
    1
         Lost to follow-up
    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 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
    Reporting group description
    		 Once daily 2 puffs, solution for inhalation Respimat placebo to tiotropium+olodaterol during the 12-week treatment period: comparator

    Reporting group title
    Tio+Olo 2.5 / 5.0 μg
    Reporting group description
    		 Oral inhalation of fixed dose combination (FDC) of Tiotropium (Tio) 2.5 μg and Olodaterol (Olo) 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period.

    Reporting group title
    Tio+Olo 5.0 / 5.0 μg
    Reporting group description
    		 Oral inhalation of FDC of Tiotropium (Tio) 5 μg and Olodaterol (Olo) 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period.

    Reporting group values
    		 Placebo Tio+Olo 2.5 / 5.0 μg Tio+Olo 5.0 / 5.0 μg Total
    Number of subjects
    		 132 133 139 404
    Age Categorical
    Units: participants
    Age Continuous |
    Treated set (TS): This analysis set includes all randomised patients who were dispensed study medication and were documented to have taken any dose of study medication.
    Units: years
        arithmetic mean (standard deviation)
    		 60.8 ( 7.6 ) 61.9 ( 7.3 ) 63.1 ( 7.5 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 45 46 44 135
        Male
    		 87 87 95 269

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Once daily 2 puffs, solution for inhalation Respimat placebo to tiotropium+olodaterol during the 12-week treatment period: comparator

    Reporting group title
    Tio+Olo 2.5 / 5.0 μg
    Reporting group description
    		 Oral inhalation of fixed dose combination (FDC) of Tiotropium (Tio) 2.5 μg and Olodaterol (Olo) 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period.

    Reporting group title
    Tio+Olo 5.0 / 5.0 μg
    Reporting group description
    		 Oral inhalation of FDC of Tiotropium (Tio) 5 μg and Olodaterol (Olo) 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period.

    Primary: Adjusted mean endurance time (sec) during constant work rate cycle ergometry (CWRCE) after 12 weeks

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    End point title
    		 Adjusted mean endurance time (sec) during constant work rate cycle ergometry (CWRCE) after 12 weeks
    End point description
    Primary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 12 weeks of treatment.The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean. Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Tio+Olo 2.5 / 5.0 μg Tio+Olo 5.0 / 5.0 μg
    Number of subjects analysed
    121 [1]
    129 [2]
    135 [3]
    Units: seconds
        least squares mean (standard error)
    463.63 ( 18.813 )
    503.64 ( 19.642 )
    527.51 ( 20.154 )
    Notes
    [1] - Full analysis set (FAS)
    [2] - FAS
    [3] - FAS
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Placebo
    Statistical analysis description
    Treatment ratio between Tio+Olo 5.0/5.0 and placebo. This treatment comparison is the first one in the alpha-protected hierarchical testing chain. Tio+Olo 5.0/5.0 is numerator and placebo is denominator.
    Comparison groups
    Placebo v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.0209 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    1.138
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 1.269
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.063
    Notes
    [4] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method.
    [5] - Mixed effects Model Repeated Measures (MMRM) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time), log10 (baseline endurance time) by test day interaction, and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 2.5 / 5.0 µg versus Placebo
    Statistical analysis description
    Treatment ratio between Tio+Olo 2.5/5.0 and placebo. This treatment comparison is the second one in the alpha-protected hierarchical testing chain. 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. Tio+Olo 2.5/5.0 is numerator and placebo is denominator.
    Comparison groups
    Placebo v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    250
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.1419 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    1.086
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.973
         upper limit
    		 1.213
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.061
    Notes
    [6] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method.
    [7] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg
    Statistical analysis description
    Treatment ratio between Tio+Olo 5.0/5.0 and Tio+Olo 2.5/5.0. This treatment comparison is not included in the alpha-protected hierarchical testing chain. Tio+Olo 5.0/5.0 is numerator and Tio+Olo 2.5/5.0 is denominator.
    Comparison groups
    Tio+Olo 2.5 / 5.0 μg v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.397 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    1.047
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.941
         upper limit
    		 1.166
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.057
    Notes
    [8] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method.
    [9] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction and patient as a random effect.

    Secondary: Adjusted mean endurance time (sec) during endurance shuttle walk test (ESWT) after 12 weeks

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    End point title
    		 Adjusted mean endurance time (sec) during endurance shuttle walk test (ESWT) after 12 weeks
    End point description
    Key secondary endpoint was endurance time during endurance shuttle walk test to symptom limitation at 85% of predicted maximum oxygen consumption (VO2) peak after 12 weeks of treatment.The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale & then MMRM model was fitted to the log10-transformed data &the least square means &SEs were obtained.To present the results in a way easier for interpretation, least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean & the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean. Endurance shuttle walk test (ESWT) substudy set: It includes all patients in the TS who had given informed consent for participating in the ESWT substudy &had a baseline and at least one postbaseline measurement during ESWT before or at Week 12.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Tio+Olo 2.5 / 5.0 μg Tio+Olo 5.0 / 5.0 μg
    Number of subjects analysed
    50 [10]
    56 [11]
    59 [12]
    Units: seconds
        least squares mean (standard error)
    311.41 ( 22.519 )
    377.2 ( 25.942 )
    376.39 ( 25.033 )
    Notes
    [10] - ESWT substudy set
    [11] - ESWT substudy set
    [12] - ESWT substudy set
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Placebo
    Statistical analysis description
    Treatment ratio between Tio+Olo 5.0/5.0 and placebo. Since the hierarchical testing chain has been broken, even though this treatment comparison is included as the 3rd one in the alpha-protected hierarchical testing chain, this hypothesis test is descriptive only. Tio+Olo 5.0/5.0 is the numerator and placebo is the denominator.
    Comparison groups
    Placebo v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.0552 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    1.209
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.996
         upper limit
    		 1.467
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.119
    Notes
    [13] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method.
    [14] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 2.5 / 5.0 µg versus Placebo
    Statistical analysis description
    Treatment ratio between Tio+Olo 2.5/5.0 and placebo. Tio+Olo 2.5/5.0 is the numerator and placebo is the denominator. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.0562 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    1.211
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.995
         upper limit
    		 1.475
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.121
    Notes
    [15] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method.
    [16] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg
    Statistical analysis description
    Treatment ratio between Tio+Olo 5.0/5.0 and Tio+Olo 2.5/5.0. This treatment comparison is not included in the alpha-protected hierarchical testing chain. The hypothesis test is descriptive only. Tio+Olo 5.0/5.0 is the numerator and Tio+Olo 2.5/5.0 is the denominator.
    Comparison groups
    Tio+Olo 2.5 / 5.0 μg v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.9822 [18]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    0.998
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.826
         upper limit
    		 1.205
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.095
    Notes
    [17] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method.
    [18] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction andpatient as a random effect.

    Secondary: Adjusted mean inspiratory capacity (L) at pre-exercise after 12 weeks

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    End point title
    		 Adjusted mean inspiratory capacity (L) at pre-exercise after 12 weeks
    End point description
    Secondary endpoint was inspiratory capacity (IC) before constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap) after 12 weeks of treatment. Full analysis set (FAS): This patient set included all patients in the TS who had a baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Tio+Olo 2.5 / 5.0 μg Tio+Olo 5.0 / 5.0 μg
    Number of subjects analysed
    119 [19]
    128 [20]
    133 [21]
    Units: liters
        least squares mean (standard error)
    2.39 ( 0.038 )
    2.597 ( 0.036 )
    2.624 ( 0.035 )
    Notes
    [19] - FAS
    [20] - FAS
    [21] - FAS
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [22]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0.234
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.133
         upper limit
    		 0.336
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.052
    Notes
    [22] - MMRM for inspiratory capacity with fixed effects of treatment, test day, treatment by test day interaction, baseline inspiratory capacity, baseline inspiratory capacity by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 2.5 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [23]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0.207
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.105
         upper limit
    		 0.309
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.052
    Notes
    [23] - MMRM for inspiratory capacity with fixed effects of treatment, test day, treatment by test day interaction, baseline inspiratory capacity, baseline inspiratory capacity by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0. The hypothesis test is descriptive only.
    Comparison groups
    Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5892 [24]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0.027
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.072
         upper limit
    		 0.126
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Notes
    [24] - MMRM for inspiratory capacity with fixed effects of treatment, test day, treatment by test day interaction, baseline inspiratory capacity, baseline inspiratory capacity by test day interaction and patient as a random effect.

    Secondary: Adjusted mean endurance time (sec) during constant work rate cycle ergometry (CWRCE) on Day 1

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    End point title
    		 Adjusted mean endurance time (sec) during constant work rate cycle ergometry (CWRCE) on Day 1
    End point description
    Secondary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity on Day 1. Analysis of covariance model on log10 transformed data. Adjusted means are back transformed to report in original units as geometric mean. Standard errors (SEs) are calculated using the delta method. The V4 set included all patients in the TS who had evaluable measurements of endurance time at Baseline (Visit 3) and at Visit 4 (Day 1) during CWRCE. Patients were assigned to the Visit 4 set after implementation of data handling rules that set measurements to missing.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Placebo Tio+Olo 2.5 / 5.0 μg Tio+Olo 5.0 / 5.0 μg
    Number of subjects analysed
    77 [25]
    77 [26]
    80 [27]
    Units: seconds
        least squares mean (standard error)
    478.59 ( 17.861 )
    527.69 ( 19.67 )
    538.76 ( 19.715 )
    Notes
    [25] - Visit 4 (V4) set
    [26] - V4 set
    [27] - V4 set
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Placebo
    Statistical analysis description
    Treatment ratio between Tio+Olo 5.0/5.0 and placebo. Tio+Olo 5.0/5.0 is numerator and placebo is denominator. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0245 [28]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment ratio
    Point estimate
    1.126
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.015
         upper limit
    		 1.248
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.059
    Notes
    [28] - ANCOVA model for log10 (endurance time [s]) with categorical effects of treatment and (log10-transformed) baseline as continuous covariate.
    Statistical analysis title
    		 Tio+Olo 2.5 / 5.0 µg versus Placebo
    Statistical analysis description
    Treatment ratio between Tio+Olo 2.5/5.0 and placebo. Tio+Olo 2.5/5.0 is numerator and placebo is denominator. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0655 [29]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment ratio
    Point estimate
    1.103
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.994
         upper limit
    		 1.223
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.058
    Notes
    [29] - ANCOVA model for log10 (endurance time [s]) with categorical effects of treatment and (log10-transformed) baseline as continuous covariate.
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg
    Statistical analysis description
    Treatment ratio between Tio+Olo 5.0/5.0 and Tio+Olo 2.5/5.0. Tio+Olo 5.0/5.0 is numerator and Tio+Olo 2.5/5.0 is denominator. The hypothesis test is descriptive only.
    Comparison groups
    Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6912 [30]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment ratio
    Point estimate
    1.021
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.921
         upper limit
    		 1.132
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.053
    Notes
    [30] - ANCOVA model for log10 (endurance time [s]) with categorical effects of treatment and (log10-transformed) baseline as continuous covariate.

    Secondary: Adjusted mean endurance time (sec) during constant work rate cycle ergometry (CWRCE) after 6 weeks treatment

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    End point title
    		 Adjusted mean endurance time (sec) during constant work rate cycle ergometry (CWRCE) after 6 weeks treatment
    End point description
    Secondary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment. The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean. Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Placebo Tio+Olo 2.5 / 5.0 μg Tio+Olo 5.0 / 5.0 μg
    Number of subjects analysed
    121 [31]
    129 [32]
    135 [33]
    Units: seconds
        least squares mean (standard error)
    427.74 ( 17.093 )
    522.26 ( 20.232 )
    525.62 ( 19.99 )
    Notes
    [31] - FAS
    [32] - FAS
    [33] - FAS
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Placebo
    Statistical analysis description
    Treatment ratio between Tio+Olo 5.0/5.0 and placebo. Hypothesis test is descriptive. Tio+Olo 5.0/5.0 is numerator and placebo is denominator.
    Comparison groups
    Placebo v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 = 0.0002 [35]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    1.229
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.103
         upper limit
    		 1.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.068
    Notes
    [34] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method.
    [35] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 2.5 / 5.0 µg versus Placebo
    Statistical analysis description
    Treatment ratio between Tio+Olo 2.5/5.0 and placebo. Hypothesis test is descriptive. Tio+Olo 2.5/5.0 is numerator and placebo is denominator.
    Comparison groups
    Placebo v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    250
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [36]
    P-value
    		 = 0.0004 [37]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    1.221
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.095
         upper limit
    		 1.362
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.068
    Notes
    [36] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method.
    [37] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg
    Statistical analysis description
    Treatment ratio between Tio+Olo 5.0/5.0 and Tio+Olo 2.5/5.0. Hypothesis test is descriptive. Tio+Olo 5.0/5.0 is numerator and Tio+Olo 2.5/5.0 is denominator.
    Comparison groups
    Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [38]
    P-value
    		 = 0.9062 [39]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    1.006
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.905
         upper limit
    		 1.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.055
    Notes
    [38] - Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was calculated using the delta method.
    [39] - MMRM for log10 (endurance time [s]) with fixed effects of treatment, test day, treatment by test day interaction, log10 (baseline endurance time [s]), log10 (baseline endurance time [s]) by test day interaction and patient as a random effect.

    Secondary: Adjusted mean inspiratory capacity (L) at pre-exercise on Day 1

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    End point title
    		 Adjusted mean inspiratory capacity (L) at pre-exercise on Day 1
    End point description
    Secondary endpoint was pre-exercise inspiratory capacity (IC) on Day 1. The V4 set included all patients in the TS who had evaluable measurements of endurance time at Baseline (Visit 3) and at Visit 4 (Day 1) during CWRCE. Patients were assigned to the Visit 4 set after implementation of data handling rules that set measurements to missing.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Placebo Tio+Olo 2.5 / 5.0 μg Tio+Olo 5.0 / 5.0 μg
    Number of subjects analysed
    75 [40]
    77 [41]
    76 [42]
    Units: liters
        least squares mean (standard error)
    2.44 ( 0.041 )
    2.642 ( 0.041 )
    2.605 ( 0.041 )
    Notes
    [40] - V4 set
    [41] - V4 set
    [42] - V4 set
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0049 [43]
    Method
    		 ANCOVA
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0.165
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.051
         upper limit
    		 0.279
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.058
    Notes
    [43] - ANCOVA model for inspiratory capacity (liters) with categorical effect of treatment and baseline as continuous covariate.
    Statistical analysis title
    		 Tio+Olo 2.5 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Tio+Olo 2.5 / 5.0 μg v Placebo
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006 [44]
    Method
    		 ANCOVA
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0.202
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.088
         upper limit
    		 0.316
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.058
    Notes
    [44] - ANCOVA model for inspiratory capacity (liters) with categorical effect of treatment and baseline as continuous covariate.
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0. The hypothesis test is descriptive only.
    Comparison groups
    Tio+Olo 2.5 / 5.0 μg v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5162 [45]
    Method
    		 ANCOVA
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    -0.037
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.151
         upper limit
    		 0.076
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.058
    Notes
    [45] - ANCOVA model for inspiratory capacity (liters) with categorical effect of treatment and baseline as continuous covariate.

    Secondary: Adjusted mean inspiratory capacity (L) at pre-exercise after 6 weeks

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    End point title
    		 Adjusted mean inspiratory capacity (L) at pre-exercise after 6 weeks
    End point description
    Secondary endpoint was pre-exercise inspiratory capacity (IC) after 6 weeks of treatment. Full analysis set (FAS): This patient set included all patients in the TS who had a baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Placebo Tio+Olo 2.5 / 5.0 μg Tio+Olo 5.0 / 5.0 μg
    Number of subjects analysed
    119 [46]
    128 [47]
    133 [48]
    Units: liters
        least squares mean (standard error)
    2.402 ( 0.037 )
    2.589 ( 0.036 )
    2.627 ( 0.035 )
    Notes
    [46] - FAS
    [47] - FAS
    [48] - FAS
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [49]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0.225
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.124
         upper limit
    		 0.326
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.051
    Notes
    [49] - MMRM for inspiratory capacity with fixed effects of treatment, test day, treatment by test day interaction, baseline inspiratory capacity, baseline inspiratory capacity by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 2.5 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003 [50]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0.187
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.086
         upper limit
    		 0.288
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.052
    Notes
    [50] - MMRM for inspiratory capacity with fixed effects of treatment, test day, treatment by test day interaction, baseline inspiratory capacity, baseline inspiratory capacity by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0. The hypothesis test is descriptive only.
    Comparison groups
    Tio+Olo 2.5 / 5.0 μg v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4541 [51]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0.038
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.061
         upper limit
    		 0.137
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Notes
    [51] - MMRM for inspiratory capacity with fixed effects of treatment, test day, treatment by test day interaction, baseline inspiratory capacity, baseline inspiratory capacity by test day interaction and patient as a random effect.

    Secondary: Adjusted mean slope of the intensity of breathing discomfort on Day 1

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    End point title
    		 Adjusted mean slope of the intensity of breathing discomfort on Day 1
    End point description
    Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 1 day of treatment. The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates slowing down in decline in breathing, i.e., favorable results. The V4 set included all patients in the TS who had evaluable measurements of endurance time at Baseline (Visit 3) and at Visit 4 (Day 1) during CWRCE. Patients were assigned to the Visit 4 set after implementation of data handling rules that set measurements to missing.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Placebo Tio+Olo 2.5 / 5.0 μg Tio+Olo 5.0 / 5.0 μg
    Number of subjects analysed
    76 [52]
    77 [53]
    80 [54]
    Units: units / seconds
        least squares mean (standard error)
    0.014 ( 0.001 )
    0.012 ( 0.001 )
    0.012 ( 0.001 )
    Notes
    [52] - V4 set
    [53] - V4 set
    [54] - V4 set
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0468 [55]
    Method
    		 ANCOVA
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    -0.002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.004
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.001
    Notes
    [55] - ANCOVA model for mean slope of the intensity of breathing discomfort with categorical effect of treatment and baseline as continuous covariate.
    Statistical analysis title
    		 Tio+Olo 2.5 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.018 [56]
    Method
    		 ANCOVA
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    -0.002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.005
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.001
    Notes
    [56] - ANCOVA model for mean slope of the intensity of breathing discomfort with categorical effect of treatment and baseline as continuous covariate.
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0. The hypothesis test is descriptive only.
    Comparison groups
    Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6856 [57]
    Method
    		 ANCOVA
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.002
         upper limit
    		 0.002
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.001
    Notes
    [57] - ANCOVA model for mean slope of the intensity of breathing discomfort with categorical effect of treatment and baseline as continuous covariate.

    Secondary: Adjusted mean slope of the intensity of breathing discomfort after week 6

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    End point title
    		 Adjusted mean slope of the intensity of breathing discomfort after week 6
    End point description
    Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment. The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates favorable results. Full analysis set (FAS): This patient set included all patients in the TS who had a baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Placebo Tio+Olo 2.5 / 5.0 μg Tio+Olo 5.0 / 5.0 μg
    Number of subjects analysed
    120 [58]
    129 [59]
    135 [60]
    Units: units / seconds
        least squares mean (standard error)
    0.016 ( 0.001 )
    0.013 ( 0.001 )
    0.013 ( 0.001 )
    Notes
    [58] - FAS
    [59] - FAS
    [60] - FAS
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0081 [61]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    -0.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.005
         upper limit
    		 -0.001
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.001
    Notes
    [61] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 2.5 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0099 [62]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    -0.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.005
         upper limit
    		 -0.001
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.001
    Notes
    [62] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0. The hypothesis test is descriptive only.
    Comparison groups
    Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9626 [63]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.002
         upper limit
    		 0.002
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.001
    Notes
    [63] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect.

    Secondary: Adjusted mean slope of the intensity of breathing discomfort after week 12

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    End point title
    		 Adjusted mean slope of the intensity of breathing discomfort after week 12
    End point description
    Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 12 weeks of treatment. The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates favorable results. Full analysis set (FAS): This patient set included all patients in the TS who had a baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Tio+Olo 2.5 / 5.0 μg Tio+Olo 5.0 / 5.0 μg
    Number of subjects analysed
    120 [64]
    129 [65]
    135 [66]
    Units: units / seconds
        least squares mean (standard error)
    0.015 ( 0.001 )
    0.013 ( 0.001 )
    0.013 ( 0.001 )
    Notes
    [64] - FAS
    [65] - FAS
    [66] - FAS
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0598 [67]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    -0.002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.004
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.001
    Notes
    [67] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 2.5 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0218 [68]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    -0.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.005
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.001
    Notes
    [68] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0. The hypothesis test is descriptive only.
    Comparison groups
    Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6549 [69]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.002
         upper limit
    		 0.003
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.001
    Notes
    [69] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect.

    Secondary: Adjusted mean 1-hour post-dose Forced Expiratory Volume in one second (FEV1) (L) on Day 1

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    End point title
    		 Adjusted mean 1-hour post-dose Forced Expiratory Volume in one second (FEV1) (L) on Day 1
    End point description
    Secondary endpoint was adjusted mean 1-hour post-dose Forced Expiratory Volume in one second (FEV1) observed on Day 1. Full analysis set (FAS): This patient set included all patients in the TS who had a baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Placebo Tio+Olo 2.5 / 5.0 μg Tio+Olo 5.0 / 5.0 μg
    Number of subjects analysed
    121 [70]
    129 [71]
    135 [72]
    Units: liters
        least squares mean (standard error)
    1.509 ( 0.02 )
    1.693 ( 0.019 )
    1.679 ( 0.019 )
    Notes
    [70] - FAS
    [71] - FAS
    [72] - FAS
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [73]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.116
         upper limit
    		 0.224
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [73] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 2.5 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    250
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [74]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0.184
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.129
         upper limit
    		 0.239
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [74] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0. The hypothesis test is descriptive only.
    Comparison groups
    Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6105 [75]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    -0.014
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.067
         upper limit
    		 0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027
    Notes
    [75] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect.

    Secondary: Adjusted mean 1-hour post-dose Forced Expiratory Volume in one second (FEV1) (L) after 6 weeks

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    End point title
    		 Adjusted mean 1-hour post-dose Forced Expiratory Volume in one second (FEV1) (L) after 6 weeks
    End point description
    Secondary endpoint was adjusted mean 1-hour post-dose Forced Expiratory Volume in one second (FEV1) observed after 6 weeks of treatment. Full analysis set (FAS): This patient set included all patients in the TS who had a baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Placebo Tio+Olo 2.5 / 5.0 μg Tio+Olo 5.0 / 5.0 μg
    Number of subjects analysed
    121 [76]
    129 [77]
    135 [78]
    Units: liters
        least squares mean (standard error)
    1.517 ( 0.02 )
    1.79 ( 0.019 )
    1.763 ( 0.019 )
    Notes
    [76] - FAS
    [77] - FAS
    [78] - FAS
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [79]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0.246
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.192
         upper limit
    		 0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [79] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 2.5 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 2.5 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    250
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [80]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0.273
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.218
         upper limit
    		 0.328
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [80] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0. The hypothesis test is descriptive only.
    Comparison groups
    Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3236 [81]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    -0.027
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.027
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027
    Notes
    [81] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect.

    Secondary: Adjusted mean 1-hour post-dose Forced Expiratory Volume in one second (FEV1) (L) after 12 weeks

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    End point title
    		 Adjusted mean 1-hour post-dose Forced Expiratory Volume in one second (FEV1) (L) after 12 weeks
    End point description
    Secondary endpoint was adjusted mean 1-hour post-dose Forced Expiratory Volume in one second (FEV1) observed after 12 weeks of treatment. Full analysis set (FAS): This patient set included all patients in the TS who had a baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Tio+Olo 2.5 / 5.0 μg Tio+Olo 5.0 / 5.0 μg
    Number of subjects analysed
    121 [82]
    129 [83]
    135 [84]
    Units: liters
        least squares mean (standard error)
    1.527 ( 0.02 )
    1.784 ( 0.019 )
    1.778 ( 0.019 )
    Notes
    [82] - FAS
    [83] - FAS
    [84] - FAS
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 5.0 / 5.0 μg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [85]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0.251
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.196
         upper limit
    		 0.305
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [85] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 2.5 / 5.0 µg versus Placebo
    Statistical analysis description
    Difference calculated as Tio+Olo 2.5/ 5.0 minus Placebo. The hypothesis test is descriptive only.
    Comparison groups
    Placebo v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    250
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [86]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    0.257
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.202
         upper limit
    		 0.312
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.028
    Notes
    [86] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect.
    Statistical analysis title
    		 Tio+Olo 5.0 / 5.0 µg versus Tio+Olo 2.5 / 5.0 µg
    Statistical analysis description
    Difference calculated as Tio+Olo 5.0 / 5.0 minus Tio+Olo 2.5 / 5.0. The hypothesis test is descriptive only.
    Comparison groups
    Tio+Olo 5.0 / 5.0 μg v Tio+Olo 2.5 / 5.0 μg
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8156 [87]
    Method
    		 Mixed models analysis
    Parameter type
    		 LSMean Difference-Final Values
    Point estimate
    -0.006
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.047
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027
    Notes
    [87] - MMRM with fixed effects of treatment, test day, treatment by test day interaction, baseline, baseline by test day interaction and patient as a random effect.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    142 days
    Adverse event reporting additional description
    All adverse events, occurring during the course of the clinical trial (i.e. from signing the informed consent onwards throughout the 12 week treatment period and the 21-day follow up period) were to be collected, documented, and reported to the sponsor 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
    16.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Once daily 2 puffs, solution for inhalation Respimat placebo to tiotropium+olodaterol during the 12-week treatment period: comparator

    Reporting group title
    Tio+Olo 5.0 / 5.0 µg
    Reporting group description
    		 Oral inhalation of FDC of Tiotropium (Tio) 5 μg and Olodaterol (Olo) 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period.

    Reporting group title
    Tio+Olo 2.5 / 5.0 µg
    Reporting group description
    		 Oral inhalation of fixed dose combination (FDC) of Tiotropium (Tio) 2.5 μg and Olodaterol (Olo) 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning during the 12-week treatment period.

    Serious adverse events
    		 Placebo Tio+Olo 5.0 / 5.0 µg Tio+Olo 2.5 / 5.0 µg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 132 (3.79%)
    4 / 139 (2.88%)
    9 / 133 (6.77%)
         number of deaths (all causes)
    0
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 139 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 139 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Malignant neoplasm of unknown primary site
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 139 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to adrenals
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 139 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 139 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 139 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 139 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 139 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraneoplastic syndrome
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 139 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Toxicity to various agents
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 139 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 139 (0.72%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 139 (0.72%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 139 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 139 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 139 (0.72%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 139 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 139 (0.72%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 139 (0.72%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 132 (1.52%)
    0 / 139 (0.00%)
    5 / 133 (3.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 139 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 139 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 139 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 139 (0.72%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Tio+Olo 5.0 / 5.0 µg Tio+Olo 2.5 / 5.0 µg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 132 (18.94%)
    16 / 139 (11.51%)
    25 / 133 (18.80%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 132 (6.06%)
    2 / 139 (1.44%)
    9 / 133 (6.77%)
         occurrences all number
    8
    2
    9
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    15 / 132 (11.36%)
    10 / 139 (7.19%)
    10 / 133 (7.52%)
         occurrences all number
    16
    10
    11
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 132 (4.55%)
    4 / 139 (2.88%)
    9 / 133 (6.77%)
         occurrences all number
    6
    4
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Mar 2012
    Additional guidance was provided for premature withdrawal, if the patient forgot to take study medication within the specified time window, regarding concomitant medications, and regarding the rescheduling of visits. As a recommendation of local authorities to restrict the trial population to Gold Stage II and III, the inclusion criteria were restricted to patients with a post-bronchodilator 30% ≤FEV1 <80% of predicted normal. A clarification was added that patients had to remain clinically stable for 3 weeks prior to the randomisation visit. For safety reasons, patients with chronic respiratory failure were excluded from the trial. Individual withdrawal criteria were defined. In alignment with the statistical section the list of ‘other endpoints’ was changed to refer to ‘secondary endpoints’. A specification that SAEs needed to be reported until 21 days after the last administration of study medication was added and a list of ‘always serious‘ AEs was included to comply with a new BI internal procedure. For consistency with the recovery phase after cycle ergometry, the IC-maneuver was included in the recovery phase after shuttle walking at sites using the Oxycon Mobile. The procedure of measuring IC was clarified. Administrative changes, minor corrections and further clarifications were introduced.
    22 Oct 2012
    The procedure for clinical evaluation of drug-induced liver injury was specified to implement a new BI guideline to comply with the FDA guidance for industry ‘Drug-Induced Liver Injury: Premarketing Clinical Evaluation’. As part of the reporting procedure of drug-induced liver injury, protocol-specific significant events were introduced. The period during which a pregnancy test after end of treatment was to be performed was specified. It was specified that mortality adjudication and SAE adjudication was to be performed separately and that vital signs were to be taken prior to each PFT. Clarifications regarding the use of PDE4-inhibitors and on medication restrictions prior to exercise testing were added. The definition of moderate COPD exacerbations was corrected. A clarification was added that more detailed information on exercise testing, equipment and calibration requirements was available in a Manual of Procedures. Administrative changes, minor corrections and further clarifications were introduced.
    25 Jun 2013
    The description and categorisation of secondary and other endpoints was changed for the following reasons: Since this was a parallel-group trial, isotime was based on only one treatment. This change resulted in treatment comparisons at isotime to be based on different time points. Therefore, endpoints defined at isotime were regarded as less precise and important for treatment comparisons than planned in the original protocol and were relegated to other endpoints. In addition, slope of the intensity of breathing discomfort was used as a measure of the improvement of breathing discomfort during exercise and was added as one of the secondary efficacy endpoints. To be consistent with other exercise trials in the 1237.P1 project, the list of secondary efficacy endpoints was shortened.

    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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