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    Clinical Trial Results:
    A randomised, placebo-controlled, double-blind, single dose, cross-over study to evaluate the efficacy and safety of orally inhaled tiotropium + olodaterol as both a fixed dose combination and a free combination (both delivered by the Respimat® inhaler) in patients with Chronic Obstructive Pulmonary Disease (COPD)

    Summary
    EudraCT number
    		 2013-002652-32
    Trial protocol
    		 DE  
    Global end of trial date
    06 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2016
    First version publication date
    26 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1237.7
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02030535
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 2430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 2430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the efficacy and safety of orally inhaled tiotropium and olodaterol as both a fixed dose combination and a free combination with respect to lung function and Electrocardiogram (ECG) parameters
    Protection of trial subjects
    Only stable COPD patients that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct.
    Background therapy
    		 -
    Evidence for comparator
    		 Tiotropium inhalation solution, Olodaterol inhalation solution and Placebo inhalation solution
    Actual start date of recruitment
    09 Jan 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
    Germany: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    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)
    27
    From 65 to 84 years
    33
    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 one specialist site which would then ensure that they (the subjects) met all inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

    Period 1
    Period 1 title
    Overall trial
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Arm title
    		 Overall Study
    Arm description
    		 Total number of patients randomised and treated in the study. (This is a cross-over trial consisting of a minimum two-week screening period. After screening, eligible patients were randomly assigned to one of 12 treatment sequences. Each patient received all three treatments as single doses on the three test days. Between test days with single dose administration there are 3-week washout periods.)
    Arm type
    		 Overall trial by periods

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations ante meridiem (a.m.) dosing.

    Investigational medicinal product name
    Tiotropium +Olodaterol FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations a.m. dosing via RESPIMAT® inhaler

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations a.m. dosing via RESPIMAT® inhaler

    Investigational medicinal product name
    Olodaterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations a.m. dosing via RESPIMAT® inhaler

    Number of subjects in period 1
    		Overall Study
    Started
    53
    Treatment Period 1 (1 Day)
    53
    Washout Period 1 (21 Days)
    53
    Treatment Period 2 (1 Day)
    52
    Washout Period 2 (21 Days)
    52
    Treatment Period 3 (1 Day)
    52
    Completed
    52
    Not completed
    1
         Adverse event, non-fatal
    1
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo
    Arm description
    		 Single test dose of oral inhalation of Placebo via RESPIMAT® inhaler. 2 inhalations ante meridiem (a.m.) dosing.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations (a.m.) dosing.

    Arm title
    		 Tio+Olo 5/5μg FDC
    Arm description
    		 Single test dose of oral inhalation of Tio+Olo FDC (fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium +Olodaterol FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations a.m. dosing via RESPIMAT® inhaler

    Arm title
    		 Tiotropium 5μg + Olodaterol 5μg FC
    Arm description
    		 Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination); Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations a.m. dosing via RESPIMAT® inhaler

    Investigational medicinal product name
    Olodaterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations a.m. dosing via RESPIMAT® inhaler

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 evaluates the overall trial by periods, while period 2 reflects the treatment arms, hence period 2 was selected as baseline.
    Number of subjects in period 2
    		Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Started
    53
    52
    52
    Completed
    52
    52
    52
    Not completed
    1
    0
    0
         Adverse event, non-fatal
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Treatment period
    Reporting group description
    		 -

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects 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 of the study medication.
    Reporting group values
    		 Treatment period Total
    Number of subjects
    		 53 53
    Age categorical
    Units: Subjects
    Age Continuous
    Treated set (TS): This patient set included all randomised patients who were administered study medication.
    Units: years
        arithmetic mean (standard deviation)
    		 64.4 ± 6.8 -
    Gender, Male/Female
    Treated set (TS): This patient set included all randomised patients who were administered study medication.
    Units: participants
        Female
    		 22 22
        Male
    		 31 31

    End points

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    End points reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 Total number of patients randomised and treated in the study. (This is a cross-over trial consisting of a minimum two-week screening period. After screening, eligible patients were randomly assigned to one of 12 treatment sequences. Each patient received all three treatments as single doses on the three test days. Between test days with single dose administration there are 3-week washout periods.)
    Reporting group title
    Placebo
    Reporting group description
    		 Single test dose of oral inhalation of Placebo via RESPIMAT® inhaler. 2 inhalations ante meridiem (a.m.) dosing.

    Reporting group title
    Tio+Olo 5/5μg FDC
    Reporting group description
    		 Single test dose of oral inhalation of Tio+Olo FDC (fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler

    Reporting group title
    Tiotropium 5μg + Olodaterol 5μg FC
    Reporting group description
    		 Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination); Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler.

    Primary: Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3hours) Response after single-dose administration

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    End point title
    		 Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3hours) Response after single-dose administration
    End point description
    The response was defined as the change from patient baseline. Patient baseline was the average of the mean pre-dose values (period baseline) on each test day (Visit 2 (Day 1), Visit 3 (Day 3 (±7days)), and Visit 4 (Day 43±7days)). For patients who did not complete all periods, patient baseline was the average of the available period baselines. The means presented are the adjusted means. Full Analysis Set (FAS): This patient set included all patients in the TS who had at least 1 visit (Visit 2 (Day1), Visit 3 (Day6), or Visit 4(Day43)) with both the period baseline value plus any evaluable post-dose spirometry measurement from the same visit.
    End point type
    Primary
    End point timeframe
    1 hour (h) and 10 min pre-dose and at 15 min, 30 min, 1 h, 2 h and 3 h post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    53 [1]
    52 [2]
    52 [3]
    Units: Litres
        arithmetic mean (standard error)
    0.014 ± 0.016
    0.233 ± 0.016
    0.266 ± 0.016
    Notes
    [1] - FAS
    [2] - FAS
    [3] - FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; patient baseline and period baseline as covariates; patient as a random effect. Tio+Olo 5/5μg minus Placebo.
    Comparison groups
    Placebo v Tio+Olo 5/5μg FDC
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.0001 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.219
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.187
         upper limit
    		 0.252
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.016
    Notes
    [4] - The actual number of subjects analyzed is 53. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (105) does not reflect the actual number.
    [5] - Kenward−Roger approximation of denominator degrees of freedom. Compound symmetry covariance structure for within−patient variation
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; patient baseline and period baseline as covariates; patient as a random effect. Tiotropium 5μg + Olodaterol 5μg minus Placebo.
    Comparison groups
    Placebo v Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.0001 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.252
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 0.284
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.016
    Notes
    [6] - The actual number of subjects analyzed is 53. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (105) does not reflect the actual number.
    [7] - Kenward−Roger approximation of denominator degrees of freedom. Compound symmetry covariance structure for within−patient variation
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Descriptive comparison. This analysis was not pre-specified in the Clinical trial protocol, but specified in the trial statistical analysis plan.
    Comparison groups
    Tio+Olo 5/5μg FDC v Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    Method
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.033
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.065
         upper limit
    		 -0.001
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.016
    Notes
    [8] - The actual number of subjects analyzed is 53. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (104) does not reflect the actual number.

    Secondary: Mean Heart Rate Corrected QT Interval (Using Fredericia Adjustment) (QTcF) interval change from patient baseline over all post-dose time points

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    End point title
    		 Mean Heart Rate Corrected QT Interval (Using Fredericia Adjustment) (QTcF) interval change from patient baseline over all post-dose time points
    End point description
    Mean QTcF interval change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [9]
    52 [10]
    52 [11]
    Units: ms
        arithmetic mean (standard deviation)
    1.3 ± 7.1
    2.2 ± 6.9
    1.9 ± 6.9
    Notes
    [9] - Treated set (observed cases)
    [10] - Treated set (observed cases)
    [11] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: Peak QTcF interval change from patient baseline over all post-dose time points

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    End point title
    		 Peak QTcF interval change from patient baseline over all post-dose time points
    End point description
    Peak QTcF interval change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [12]
    52 [13]
    52 [14]
    Units: ms
        arithmetic mean (standard deviation)
    5.2 ± 8.3
    5.7 ± 7.6
    5.7 ± 7.3
    Notes
    [12] - Treated set (observed cases)
    [13] - Treated set (observed cases)
    [14] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: Mean heart rate change from patient baseline over all post-dose time points

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    End point title
    		 Mean heart rate change from patient baseline over all post-dose time points
    End point description
    Mean heart rate change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [15]
    52 [16]
    52 [17]
    Units: bpm
        arithmetic mean (standard deviation)
    -3 ± 5.2
    -2.5 ± 5.5
    -3.6 ± 4.3
    Notes
    [15] - Treated set (observed cases)
    [16] - Treated set (observed cases)
    [17] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: Peak heart rate change from patient baseline over all post-dose time points

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    End point title
    		 Peak heart rate change from patient baseline over all post-dose time points
    End point description
    Peak heart rate change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [18]
    52 [19]
    52 [20]
    Units: bpm
        arithmetic mean (standard deviation)
    -0.7 ± 5.5
    -0.3 ± 5.7
    -1.2 ± 4.4
    Notes
    [18] - Treated set (observed cases)
    [19] - Treated set (observed cases)
    [20] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: Mean RR (Time Interval of ECG) change from patient baseline over all post-dose time points

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    End point title
    		 Mean RR (Time Interval of ECG) change from patient baseline over all post-dose time points
    End point description
    Mean RR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [21]
    52 [22]
    52 [23]
    Units: ms
        arithmetic mean (standard deviation)
    40.4 ± 57.7
    29.3 ± 57.1
    39.5 ± 51.5
    Notes
    [21] - Treated set (observed cases)
    [22] - Treated set (observed cases)
    [23] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: Peak RR change from patient baseline over all post-dose time points

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    End point title
    		 Peak RR change from patient baseline over all post-dose time points
    End point description
    Peak RR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [24]
    52 [25]
    52 [26]
    Units: ms
        arithmetic mean (standard deviation)
    68.8 ± 64.3
    55.5 ± 59.5
    68 ± 52.7
    Notes
    [24] - Treated set (observed cases)
    [25] - Treated set (observed cases)
    [26] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: RR Change From Patient Baseline at Individual Post-dose Time Points

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    End point title
    		 RR Change From Patient Baseline at Individual Post-dose Time Points
    End point description
    RR Change From Patient Baseline at Individual Post-dose Time Points
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [27]
    52 [28]
    52 [29]
    Units: ms
    arithmetic mean (standard deviation)
        5 min
    29.9 ± 62.5
    29.7 ± 58.5
    31.9 ± 55.5
        10 min
    38.8 ± 68.9
    28.1 ± 57.4
    33.5 ± 56.1
        25 min
    40.4 ± 59.4
    33 ± 65.7
    50 ± 59.9
        50 min
    52.3 ± 62.7
    25.2 ± 64.9
    44 ± 57
    Notes
    [27] - Treated set (observed cases)
    [28] - Treated set (observed cases)
    [29] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: Mean QT (Time Interval of ECG) change from patient baseline over all post-dose time points

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    End point title
    		 Mean QT (Time Interval of ECG) change from patient baseline over all post-dose time points
    End point description
    Mean QT change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [30]
    52 [31]
    52 [32]
    Units: ms
        arithmetic mean (standard deviation)
    7.2 ± 10.7
    6.5 ± 11.1
    7.9 ± 9.9
    Notes
    [30] - Treated set (observed cases)
    [31] - Treated set (observed cases)
    [32] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: Peak QT (Time Interval of ECG) change from patient baseline over all post-dose time points

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    End point title
    		 Peak QT (Time Interval of ECG) change from patient baseline over all post-dose time points
    End point description
    Peak QT change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [33]
    52 [34]
    52 [35]
    Units: ms
        arithmetic mean (standard deviation)
    12.4 ± 11.5
    11.5 ± 11.1
    13.4 ± 10.6
    Notes
    [33] - Treated set (observed cases)
    [34] - Treated set (observed cases)
    [35] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: QT(c) Change From Patient Baseline at Individual Post-dose Time Points

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    End point title
    		 QT(c) Change From Patient Baseline at Individual Post-dose Time Points
    End point description
    QT(c) Change From Patient Baseline at Individual Post-dose Time Points
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [36]
    52 [37]
    52 [38]
    Units: ms
    arithmetic mean (standard deviation)
        5 min
    4.3 ± 10.7
    5.5 ± 11.2
    4.9 ± 10.4
        10 min
    7.1 ± 12.6
    6.3 ± 11.8
    7.9 ± 11.3
        25 min
    7.9 ± 11.4
    7.4 ± 12
    9.6 ± 11.1
        50 min
    9.4 ± 12.1
    6.7 ± 12.6
    9.4 ± 10.9
    Notes
    [36] - Treated set (observed cases)
    [37] - Treated set (observed cases)
    [38] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: Mean Heart Rate Corrected QT Interval (Using Bazett Adjustment) (QTcB) change from patient baseline over all post-dose time points

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    End point title
    		 Mean Heart Rate Corrected QT Interval (Using Bazett Adjustment) (QTcB) change from patient baseline over all post-dose time points
    End point description
    Mean QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment))change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [39]
    52 [40]
    52 [41]
    Units: ms
        arithmetic mean (standard deviation)
    -1.9 ± 9
    -0.2 ± 8.6
    -1.4 ± 8.1
    Notes
    [39] - Treated set (observed cases)
    [40] - Treated set (observed cases)
    [41] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: Peak QTcB change from patient baseline over all post-dose time points

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    End point title
    		 Peak QTcB change from patient baseline over all post-dose time points
    End point description
    Peak QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment))change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [42]
    52 [43]
    52 [44]
    Units: ms
        arithmetic mean (standard deviation)
    3 ± 10.7
    4.2 ± 9.7
    3.5 ± 8.5
    Notes
    [42] - Treated set (observed cases)
    [43] - Treated set (observed cases)
    [44] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: Mean PR (Time Interval of ECG) change from patient baseline over all post-dose time points

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    End point title
    		 Mean PR (Time Interval of ECG) change from patient baseline over all post-dose time points
    End point description
    Mean PR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [45]
    52 [46]
    52 [47]
    Units: ms
        arithmetic mean (standard deviation)
    0.6 ± 4.9
    1.6 ± 6.3
    1.4 ± 6.4
    Notes
    [45] - Treated set (observed cases)
    [46] - Treated set (observed cases)
    [47] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: Peak PR (Time Interval of ECG) change from patient baseline over all post-dose time points

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    End point title
    		 Peak PR (Time Interval of ECG) change from patient baseline over all post-dose time points
    End point description
    Peak PR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [48]
    52 [49]
    52 [50]
    Units: ms
        arithmetic mean (standard deviation)
    3.9 ± 4.8
    4.6 ± 5.9
    4.7 ± 7.2
    Notes
    [48] - Treated set (observed cases)
    [49] - Treated set (observed cases)
    [50] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: PR Change From Patient Baseline at Individual Post-dose Time Points

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    End point title
    		 PR Change From Patient Baseline at Individual Post-dose Time Points
    End point description
    PR Change From Patient Baseline at Individual Post-dose Time Points
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [51]
    52 [52]
    52 [53]
    Units: ms
    arithmetic mean (standard deviation)
        5 min
    0.1 ± 5.9
    1.2 ± 7.3
    -0.2 ± 6.6
        10 min
    0.1 ± 6
    2.5 ± 8.4
    1.4 ± 7.1
        25 min
    0.1 ± 6.5
    0.8 ± 6.3
    1.9 ± 7.8
        50 min
    2.2 ± 5.4
    1.9 ± 5.4
    2.7 ± 7.7
    Notes
    [51] - Treated set (observed cases)
    [52] - Treated set (observed cases)
    [53] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: Mean QRS (Time Interval of ECG) change from patient baseline over all post-dose time points

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    End point title
    		 Mean QRS (Time Interval of ECG) change from patient baseline over all post-dose time points
    End point description
    Mean QRS change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [54]
    52 [55]
    52 [56]
    Units: ms
        arithmetic mean (standard deviation)
    -0.3 ± 1.3
    0.1 ± 1.5
    0.1 ± 1.3
    Notes
    [54] - Treated set (observed cases)
    [55] - Treated set (observed cases)
    [56] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: Peak QRS (Time Interval of ECG) change from patient baseline over all post-dose time points

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    End point title
    		 Peak QRS (Time Interval of ECG) change from patient baseline over all post-dose time points
    End point description
    Peak QRS change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [57]
    52 [58]
    52 [59]
    Units: ms
        arithmetic mean (standard deviation)
    0.6 ± 1.5
    0.9 ± 1.5
    1 ± 1.3
    Notes
    [57] - Treated set (observed cases)
    [58] - Treated set (observed cases)
    [59] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: QRS at individual post-dose time pointsQRS change from patient baseline at individual post-dose time points

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    End point title
    		 QRS at individual post-dose time pointsQRS change from patient baseline at individual post-dose time points
    End point description
    QRS change from patient baseline at individual post-dose time points
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [60]
    52 [61]
    52 [62]
    Units: ms
    arithmetic mean (standard deviation)
        5 min
    -0.3 ± 1.5
    -0.2 ± 1.8
    0 ± 1.6
        10 min
    -0.3 ± 1.6
    0.1 ± 1.6
    0.1 ± 1.6
        25 min
    -0.3 ± 1.4
    0.1 ± 1.6
    0 ± 1.4
        50 min
    -0.4 ± 1.7
    0.2 ± 1.7
    0.2 ± 1.6
    Notes
    [60] - Treated set (observed cases)
    [61] - Treated set (observed cases)
    [62] - Treated set (observed cases)
    No statistical analyses for this end point

    Secondary: Heart Rate Change From Patient Baseline at Individual Postdose Time Points

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    End point title
    		 Heart Rate Change From Patient Baseline at Individual Postdose Time Points
    End point description
    Heart rate change from patient baseline at individual postdose time points
    End point type
    Secondary
    End point timeframe
    40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
    End point values
    		 Placebo Tio+Olo 5/5μg FDC Tiotropium 5μg + Olodaterol 5μg FC
    Number of subjects analysed
    52 [63]
    52 [64]
    52 [65]
    Units: bpm
    arithmetic mean (standard deviation)
        5 min
    -2.3 ± 5.2
    -2.5 ± 5.5
    -2.9 ± 4.6
        10 min
    -2.7 ± 5.9
    -2.4 ± 5.5
    -3.1 ± 4.6
        25 min
    -3.1 ± 5.5
    -2.6 ± 6
    -4.5 ± 5
        50 min
    -4.1 ± 5.6
    -2.4 ± 6
    -3.9 ± 4.7
    Notes
    [63] - Treated set (observed cases)
    [64] - Treated set (observed cases)
    [65] - Treated set (observed cases)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) occurring up to the minimum of 21 days after drug stop date or the start of the next treatment period were considered on treatment; Up to 64 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.

    Reporting group title
    Tiotropium 5μg + Olodaterol 5μg FC
    Reporting group description
    		 Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler

    Reporting group title
    Tio+Olo 5/5μg FDC
    Reporting group description
    		 Single test dose of oral inhalation of Tio+Olo FDC (fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation via RESPIMAT® inhaler. 2 inhalations a.m. dosing.

    Serious adverse events
    		 Placebo Tiotropium 5μg + Olodaterol 5μg FC Tio+Olo 5/5μg FDC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 52 (3.85%)
    0 / 52 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Prinzmetal angina
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (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
    Reproductive system and breast disorders
    Cystocele
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (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 Tiotropium 5μg + Olodaterol 5μg FC Tio+Olo 5/5μg FDC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 52 (3.85%)
    1 / 52 (1.92%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 52 (3.85%)
    1 / 52 (1.92%)
         occurrences all number
    3
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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