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To Evaluate the Effect of Inhaled Medication Together With Exercise and Activity Training on Exercise Capacity and Daily Activities in Patients With Chronic Lung Disease With Obstruction of Airways

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ClinicalTrials.gov Identifier: NCT02085161
Recruitment Status : Completed
First Posted : March 12, 2014
Results First Posted : January 6, 2017
Last Update Posted : January 6, 2017
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Single;   Primary Purpose: Treatment
Condition Pulmonary Disease, Chronic Obstructive
Interventions Drug: placebo to tiotropium + olodaterol
Drug: tiotropium+olodaterol
Drug: tiotropium +olodaterol
Drug: tiotropium
Enrollment 304
Recruitment Details  
Pre-assignment Details An exploratory, randomised, partially double-blinded, placebo-controlled, parallel group trial to explore the effects of tiotropium + olodaterol fixed dose combination (FDC) or tiotropium, supervised exercise training and behaviour modification on exercise capacity and physical activity in patients with Chronic Obstructive Pulmonary Disease (COPD)
Arm/Group Title Placebo With Behavioural Modification (BM) Tiotropium (Tio) 5 Micro-grams (μg) With BM Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Hide Arm/Group Description Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks. Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks. Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks. Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks.
Period Title: Overall Study
Started 76 76 76 76
Completed 64 66 71 66
Not Completed 12 10 5 10
Reason Not Completed
Not Treated             1             0             0             0
Adverse Event             8             5             4             5
Protocol Violation             0             1             0             1
Withdrawal by Subject             2             4             0             3
Other Reason             1             0             1             1
Arm/Group Title Placebo With Behavioural Modification (BM) Tiotropium (Tio) 5 Micro-grams (μg) With BM Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM Total
Hide Arm/Group Description Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks. Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks. Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks. Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks. Total of all reporting groups
Overall Number of Baseline Participants 75 76 76 76 303
Hide Baseline Analysis Population Description
Treated set (TS): This patient set included all patients of the Randomised set (All patients who signed informed consent form and were also randomised, regardless whether the patient was treated with study medication or not.) who were dispensed study medication and were documented to have taken any dose of study medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 75 participants 76 participants 76 participants 76 participants 303 participants
64.4  (6.6) 65.1  (6.4) 65.0  (6.9) 64.7  (6.5) 64.8  (6.6)
Gender  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 75 participants 76 participants 76 participants 76 participants 303 participants
Female
23
  30.7%
21
  27.6%
28
  36.8%
31
  40.8%
103
  34.0%
Male
52
  69.3%
55
  72.4%
48
  63.2%
45
  59.2%
200
  66.0%
1.Primary Outcome
Title Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 8 Weeks
Hide Description Endurance time during ESWT to symptom limitation at walking speed corresponding to 85% of predicted maximum oxygen consumption (VO2 peak) after 8 weeks of pharmacological treatment and non-pharmacological intervention. The numerical value of endurance time in seconds was transformed in log10 scale to correct for skewness and then an analysis of covariance (ANCOVA) was fitted to the log10-transformed data and the least square means (LSMean) and standard error (SE) were obtained. To present the results in a way easier for interpretation, the least square mean from the ANCOVA fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate to obtain the geometric mean and the corresponding SE was transformed using delta method to get the corresponding SE of the geometric mean.
Time Frame Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS): This patient set included all patients in the Treated set (TS) who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint. Patients were assigned to the FAS after implementation of any data handling rules that set measurements to missing. Patients with available data were included.
Arm/Group Title Placebo With Behavioural Modification (BM) Tiotropium (Tio) 5 Micro-grams (μg) With BM Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Hide Arm/Group Description:
Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks.
Overall Number of Participants Analyzed 65 67 72 70
Geometric Mean (Standard Error)
Unit of Measure: Second
244.07  (17.666) 254.18  (18.099) 315.32  (21.671) 355.73  (24.787)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments This treatment comparison is the first one in the alpha-protected hierarchical testing chain.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments ANCOVA model with categorical effect of treatment and baseline as covariate.
Method ANCOVA
Comments Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method.
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 1.458
Confidence Interval (2-Sided) 95%
1.196 to 1.777
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.147
Estimation Comments Ratio of means calculated as back transformation of difference on log 10 scale between Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments This treatment comparison is the second one in the alpha-protected hierarchical testing chain.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0109
Comments ANCOVA model with categorical effect of treatment and baseline as covariate.
Method ANCOVA
Comments Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method.
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 1.292
Confidence Interval (2-Sided) 95%
1.061 to 1.573
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.129
Estimation Comments Ratio of means calculated as back transformation of difference on log 10 scale between Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM).
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium (Tio) 5 Micro-grams (μg) With BM
Comments This treatment comparison is the third 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6895
Comments ANCOVA model with categorical effect of treatment and baseline as covariate.
Method ANCOVA
Comments Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method.
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 1.041
Confidence Interval (2-Sided) 95%
0.853 to 1.272
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.106
Estimation Comments Ratio of means calculated as back transformation of difference on log 10 scale between Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM).
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM, Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2188
Comments ANCOVA model with categorical effect of treatment and baseline as covariate.
Method ANCOVA
Comments Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method.
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 1.128
Confidence Interval (2-Sided) 95%
0.931 to 1.368
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.110
Estimation Comments Ratio of means calculated as back transformation of difference on log 10 scale between Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM.
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (Tio) 5 Micro-grams (μg) With BM, Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0303
Comments ANCOVA model with categorical effect of treatment and baseline as covariate.
Method ANCOVA
Comments Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method.
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 1.241
Confidence Interval (2-Sided) 95%
1.021 to 1.507
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.123
Estimation Comments Ratio of means calculated as back transformation of difference on log 10 scale between Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM.
2.Secondary Outcome
Title Average Daily Walking Time Measured by the Activity Monitor in the Week Prior to Week 12
Hide Description Average daily walking time measured by the activity monitor in the week prior to Week 12.
Time Frame Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS): This patient set included all patients in the TS who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint. Patients were assigned to the FAS after implementation of any data handling rules that set measurements to missing. Patients with available data were included.
Arm/Group Title Placebo With Behavioural Modification (BM) Tiotropium (Tio) 5 Micro-grams (μg) With BM Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Hide Arm/Group Description:
Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks.
Overall Number of Participants Analyzed 55 57 60 57
Least Squares Mean (Standard Error)
Unit of Measure: Second
4670.78  (211.798) 4145.85  (207.351) 4831.85  (202.261) 4338.80  (207.252)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2639
Comments An ANCOVA model with categorical effects of treatment and baseline as covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value -331.975
Confidence Interval (2-Sided) 95%
-916.015 to 252.064
Parameter Dispersion
Type: Standard Error of the mean
Value: 296.375
Estimation Comments The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5837
Comments An ANCOVA model with categorical effects of treatment and baseline as covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 161.072
Confidence Interval (2-Sided) 95%
-417.314 to 739.459
Parameter Dispersion
Type: Standard Error of the mean
Value: 293.506
Estimation Comments The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium (Tio) 5 Micro-grams (μg) With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0783
Comments An ANCOVA model with categorical effects of treatment and baseline as covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value -524.926
Confidence Interval (2-Sided) 95%
-1109.806 to 59.954
Parameter Dispersion
Type: Standard Error of the mean
Value: 296.802
Estimation Comments The LSMean Difference is calculated as Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM, Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0900
Comments An ANCOVA model with categorical effects of treatment and baseline as covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value -493.048
Confidence Interval (2-Sided) 95%
-1063.670 to 77.575
Parameter Dispersion
Type: Standard Error of the mean
Value: 289.566
Estimation Comments The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (Tio) 5 Micro-grams (μg) With BM, Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0186
Comments An ANCOVA model with categorical effects of treatment and baseline as covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 685.998
Confidence Interval (2-Sided) 95%
115.635 to 1256.362
Parameter Dispersion
Type: Standard Error of the mean
Value: 289.435
Estimation Comments The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM
3.Secondary Outcome
Title Average Daily Walking Intensity Measured by the Activity Monitor in the Week Prior to 12 Weeks of Treatment
Hide Description Average daily walking intensity measured by the activity monitor in the week prior to 12 weeks of treatment. The Movement Intensity (MI) is derived from the acceleration signals. Since seismic sensors measure gravitational acceleration (g) in static situations, the acceleration signal is expressed relative to g (1g = 9.81m/s2). To calculate movement intensity (MI) the gravitational acceleration in static situations was removed and the rotation vector of the three accelerometer signals was calculated. The MI gives an indication of the power of movements.
Time Frame Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS): This patient set included all patients in the TS who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint. Patients were assigned to the FAS after implementation of any data handling rules that set measurements to missing. Patients with available data were included.
Arm/Group Title Placebo With Behavioural Modification (BM) Tiotropium (Tio) 5 Micro-grams (μg) With BM Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Hide Arm/Group Description:
Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks.
Overall Number of Participants Analyzed 54 56 58 57
Least Squares Mean (Standard Error)
Unit of Measure: Multiple of 9.8*(meters / (second^2))
0.20  (0.003) 0.20  (0.003) 0.20  (0.003) 0.20  (0.003)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5186
Comments An ANCOVA model with categorical effects of treatment and baseline as covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value -0.002
Confidence Interval (2-Sided) 95%
-0.010 to 0.005
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.004
Estimation Comments The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6436
Comments An ANCOVA model with categorical effects of treatment and baseline as covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.002
Confidence Interval (2-Sided) 95%
-0.006 to 0.009
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.004
Estimation Comments The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium (Tio) 5 Micro-grams (μg) With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1081
Comments An ANCOVA model with categorical effects of treatment and baseline as covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value -0.006
Confidence Interval (2-Sided) 95%
-0.014 to 0.001
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.004
Estimation Comments The LSMean Difference is calculated as Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM, Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2612
Comments An ANCOVA model with categorical effects of treatment and baseline as covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value -0.004
Confidence Interval (2-Sided) 95%
-0.011 to 0.003
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.004
Estimation Comments The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (Tio) 5 Micro-grams (μg) With BM, Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0361
Comments An ANCOVA model with categorical effects of treatment and baseline as covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.008
Confidence Interval (2-Sided) 95%
0.001 to 0.015
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.004
Estimation Comments The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM
4.Secondary Outcome
Title Perceived Difficulties as Evaluated With Functional Performance Inventory-Short Form (FPI-SF) Total Score at Week 12
Hide Description Perceived difficulties as evaluated with FPI-SF. FPI-SF self-report questionnaire has 6 domains: Body care(5 items), Household maintenance(8 items), Physical exercise(5 items), Recreation(5 items), Spiritual activities(4 items) and Social interaction(5 items) with five possible answers on each item: Do with no difficulty - 3, Do with some difficulty - 2, Do with great difficulty - 1, don’t do because of health reasons - 0, and don’t do because choose not to - 0. Domain scores are expressed as mean values, with at least 6 non-missing items required for the household maintenance domain and at least 3 non-missing items for the other domains. Total score is the mean across the six domains. So total and domain scores range from 0 to 3, with higher scores indicating higher levels of functional activity within and across domains. Respondents engaged in many activities with no difficulty will score high on the FPI, while those who perform few activities with much difficulty will score low.
Time Frame Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS): This patient set included all patients in the TS who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint. Patients were assigned to the FAS after implementation of any data handling rules that set measurements to missing. Patients with available data were included.
Arm/Group Title Placebo With Behavioural Modification (BM) Tiotropium (Tio) 5 Micro-grams (μg) With BM Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Hide Arm/Group Description:
Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks.
Overall Number of Participants Analyzed 64 65 71 67
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
2.191  (0.040) 2.207  (0.040) 2.335  (0.038) 2.268  (0.039)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1727
Comments An ANCOVA model with categorical effects of treatment and baseline as covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.076
Confidence Interval (2-Sided) 95%
-0.034 to 0.187
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.056
Estimation Comments The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0097
Comments An ANCOVA model with categorical effects of treatment and baseline as covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.143
Confidence Interval (2-Sided) 95%
0.035 to 0.252
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.055
Estimation Comments The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium (Tio) 5 Micro-grams (μg) With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7815
Comments An ANCOVA model with categorical effects of treatment and baseline as covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.016
Confidence Interval (2-Sided) 95%
-0.095 to 0.126
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.056
Estimation Comments The LSMean Difference is calculated as Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM, Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2183
Comments An ANCOVA model with categorical effects of treatment and baseline as covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value -0.067
Confidence Interval (2-Sided) 95%
-0.174 to 0.040
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.054
Estimation Comments The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (Tio) 5 Micro-grams (μg) With BM, Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0203
Comments An ANCOVA model with categorical effects of treatment and baseline as covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.128
Confidence Interval (2-Sided) 95%
0.020 to 0.236
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.055
Estimation Comments The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM
5.Secondary Outcome
Title Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 12 Weeks
Hide Description Endurance time during ESWT to symptom limitation at walking speed corresponding to 85% of maximum oxygen consumption (VO2 peak) after 12 weeks of pharmacological treatment and non-pharmacological intervention. The numerical value of endurance time in seconds was transformed in log10 scale to correct for skewness and then the ANCOVA was fitted to the log10-transformed data and the least square means and SE were obtained. To present the results in a way easier for interpretation, the least square mean from the ANCOVA fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate to obtain the geometric mean and the corresponding SE was transformed using delta method to get the corresponding SE of the geometric mean.
Time Frame Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS): This patient set included all patients in the TS who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint. Patients were assigned to the FAS after implementation of any data handling rules that set measurements to missing. Patients with available data were included.
Arm/Group Title Placebo With Behavioural Modification (BM) Tiotropium (Tio) 5 Micro-grams (μg) With BM Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Hide Arm/Group Description:
Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks.
Overall Number of Participants Analyzed 62 64 71 66
Geometric Mean (Standard Error)
Unit of Measure: Second
243.30  (18.680) 255.67  (19.292) 302.61  (21.691) 324.21  (24.095)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0077
Comments ANCOVA model with categorical effect of treatment and baseline as covariate.
Method ANCOVA
Comments Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method.
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 1.333
Confidence Interval (2-Sided) 95%
1.080 to 1.645
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.142
Estimation Comments Ratio of means calculated as back transformation of difference on log 10 scale between Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0390
Comments ANCOVA model with categorical effect of treatment and baseline as covariate.
Method ANCOVA
Comments Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method.
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 1.244
Confidence Interval (2-Sided) 95%
1.011 to 1.530
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.131
Estimation Comments Ratio of means calculated as back transformation of difference on log 10 scale between Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM).
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium (Tio) 5 Micro-grams (μg) With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6452
Comments ANCOVA model with categorical effect of treatment and baseline as covariate.
Method ANCOVA
Comments Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method.
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 1.051
Confidence Interval (2-Sided) 95%
0.850 to 1.299
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.113
Estimation Comments Ratio of means calculated as back transformation of difference on log 10 scale between Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM).
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM, Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5048
Comments ANCOVA model with categorical effect of treatment and baseline as covariate.
Method ANCOVA
Comments Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method.
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 1.071
Confidence Interval (2-Sided) 95%
0.874 to 1.313
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.111
Estimation Comments Ratio of means calculated as back transformation of difference on log 10 scale between Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM.
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (Tio) 5 Micro-grams (μg) With BM, Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1066
Comments ANCOVA model with categorical effect of treatment and baseline as covariate.
Method ANCOVA
Comments Mean and 95% confidence limits were transformed from log10 back to the original scale. SE was back transformed using the delta method.
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 1.184
Confidence Interval (2-Sided) 95%
0.964 to 1.453
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.123
Estimation Comments Ratio of means calculated as back transformation of difference on log 10 scale between Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM.
6.Secondary Outcome
Title One Hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 8 Weeks of Treatment
Hide Description One hour, Post-dose Forced Expiratory Volume in One Second (FEV1) after 8 weeks of treatment.
Time Frame Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS): This patient set included all patients in the TS who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint. Patients were assigned to the FAS after implementation of any data handling rules that set measurements to missing. Patients with available data were included.
Arm/Group Title Placebo With Behavioural Modification (BM) Tiotropium (Tio) 5 Micro-grams (μg) With BM Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Hide Arm/Group Description:
Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks.
Overall Number of Participants Analyzed 65 67 72 70
Least Squares Mean (Standard Error)
Unit of Measure: Liter
1.375  (0.027) 1.550  (0.027) 1.731  (0.026) 1.705  (0.026)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Mixed effect Model Repeat Measurement (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect
Method Mixed Models Analysis
Comments Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.329
Confidence Interval (2-Sided) 95%
0.255 to 0.403
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.038
Estimation Comments The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect
Method Mixed Models Analysis
Comments Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.356
Confidence Interval (2-Sided) 95%
0.282 to 0.429
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.037
Estimation Comments The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium (Tio) 5 Micro-grams (μg) With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect
Method Mixed Models Analysis
Comments Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.174
Confidence Interval (2-Sided) 95%
0.099 to 0.249
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.038
Estimation Comments The LSMean Difference is calculated as Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM, Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4677
Comments MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect
Method Mixed Models Analysis
Comments Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value -0.027
Confidence Interval (2-Sided) 95%
-0.099 to 0.045
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.037
Estimation Comments The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (Tio) 5 Micro-grams (μg) With BM, Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect
Method Mixed Models Analysis
Comments Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.182
Confidence Interval (2-Sided) 95%
0.109 to 0.255
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.037
Estimation Comments The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM
7.Secondary Outcome
Title One Hour, Post-dose Forced Vital Capacity (FVC) After 8 Weeks of Treatment
Hide Description One hour, Post-dose Forced Vital Capacity (FVC) after 8 weeks of treatment.
Time Frame Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS): This patient set included all patients in the TS who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint. Patients were assigned to the FAS after implementation of any data handling rules that set measurements to missing. Patients with available data were included.
Arm/Group Title Placebo With Behavioural Modification (BM) Tiotropium (Tio) 5 Micro-grams (μg) With BM Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Hide Arm/Group Description:
Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks.
Overall Number of Participants Analyzed 65 67 72 70
Least Squares Mean (Standard Error)
Unit of Measure: Liter
2.974  (0.047) 3.259  (0.046) 3.504  (0.044) 3.452  (0.045)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Mixed effect Model Repeat Measurement (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect
Method Mixed Models Analysis
Comments Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.478
Confidence Interval (2-Sided) 95%
0.350 to 0.606
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.065
Estimation Comments The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect
Method Mixed Models Analysis
Comments Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.530
Confidence Interval (2-Sided) 95%
0.403 to 0.657
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.064
Estimation Comments The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium (Tio) 5 Micro-grams (μg) With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect
Method Mixed Models Analysis
Comments Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.286
Confidence Interval (2-Sided) 95%
0.157 to 0.415
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.066
Estimation Comments The LSMean Difference is calculated as Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM, Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4107
Comments MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect
Method Mixed Models Analysis
Comments Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value -0.052
Confidence Interval (2-Sided) 95%
-0.176 to 0.072
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.063
Estimation Comments The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (Tio) 5 Micro-grams (μg) With BM, Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect
Method Mixed Models Analysis
Comments Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.244
Confidence Interval (2-Sided) 95%
0.119 to 0.370
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.064
Estimation Comments The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM
8.Secondary Outcome
Title Resting Inspiratory Capacity (IC) Measured at 1.5 Hours Post Dose After 8 Weeks of Treatment
Hide Description Resting inspiratory capacity (IC) measured at 1.5 hours post dose after 8 weeks of treatment.
Time Frame Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS): This patient set included all patients in the TS who had baseline measurement and at least 1 post-baseline measurement for the primary endpoint. Patients were assigned to the FAS after implementation of any data handling rules that set measurements to missing. Patients with available data were included.
Arm/Group Title Placebo With Behavioural Modification (BM) Tiotropium (Tio) 5 Micro-grams (μg) With BM Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Hide Arm/Group Description:
Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks.
Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks.
Overall Number of Participants Analyzed 64 66 72 68
Least Squares Mean (Standard Error)
Unit of Measure: Liter
2.452  (0.051) 2.627  (0.050) 2.755  (0.048) 2.771  (0.049)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Mixed effect Model Repeat Measurement (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect
Method Mixed Models Analysis
Comments Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.318
Confidence Interval (2-Sided) 95%
0.179 to 0.457
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.071
Estimation Comments The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect
Method Mixed Models Analysis
Comments Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.302
Confidence Interval (2-Sided) 95%
0.165 to 0.439
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.070
Estimation Comments The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo With Behavioural Modification (BM), Tiotropium (Tio) 5 Micro-grams (μg) With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0145
Comments MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect
Method Mixed Models Analysis
Comments Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.174
Confidence Interval (2-Sided) 95%
0.035 to 0.314
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.071
Estimation Comments The LSMean Difference is calculated as Tiotropium (Tio) 5 micro-grams (μg) with BM minus Placebo with behavioural modification (BM)
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM, Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8150
Comments MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect
Method Mixed Models Analysis
Comments Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.016
Confidence Interval (2-Sided) 95%
-0.118 to 0.151
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.068
Estimation Comments The LSMean Difference is calculated as Tio+Olo (5/5 μg) FDC with exercise training (ET) and BM minus Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tiotropium (Tio) 5 Micro-grams (μg) With BM, Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0642
Comments MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect
Method Mixed Models Analysis
Comments Compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom
Method of Estimation Estimation Parameter LSMean Difference
Estimated Value 0.128
Confidence Interval (2-Sided) 95%
-0.008 to 0.263
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.069
Estimation Comments The LSMean Difference is calculated as Tiotropium + olodaterol (Olo) (5/5 μg) FDC with BM minus Tiotropium (Tio) 5 micro-grams (μg) with BM
Time Frame From first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period, up to 134 days.
Adverse Event Reporting Description All adverse events, serious and non-serious, occurring during the course of the clinical trial (i.e. from signing the informed consent onwards through the observational phase) were to be collected, documented and reported to the sponsor by the investigator on the appropriate electronic case report form / serious adverse event reporting forms.
 
Arm/Group Title Placebo With Behavioural Modification (BM) Tiotropium (Tio) 5 Micro-grams (μg) With BM Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM Total
Hide Arm/Group Description Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks. Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks. Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks. Tiotropium 5 μg plus olodaterol 5 μg FDC solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks; ET was conducted for 8 weeks. Total
All-Cause Mortality
Placebo With Behavioural Modification (BM) Tiotropium (Tio) 5 Micro-grams (μg) With BM Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM Total
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo With Behavioural Modification (BM) Tiotropium (Tio) 5 Micro-grams (μg) With BM Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM Total
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   4/75 (5.33%)   11/76 (14.47%)   3/76 (3.95%)   8/76 (10.53%)   26/303 (8.58%) 
Cardiac disorders           
Acute myocardial infarction  1  0/75 (0.00%)  0/76 (0.00%)  0/76 (0.00%)  1/76 (1.32%)  1/303 (0.33%) 
Angina pectoris  1  0/75 (0.00%)  0/76 (0.00%)  0/76 (0.00%)  1/76 (1.32%)  1/303 (0.33%) 
Atrial fibrillation  1  0/75 (0.00%)  0/76 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  1/303 (0.33%) 
Coronary artery disease  1  1/75 (1.33%)  0/76 (0.00%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Hepatobiliary disorders           
Cholelithiasis  1  0/75 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Hepatotoxicity  1  1/75 (1.33%)  0/76 (0.00%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Infections and infestations           
Abdominal abscess  1  0/75 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Infective exacerbation of chronic obstructive airways disease  1  0/75 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Pneumonia  1  0/75 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Urinary tract infection  1  0/75 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Injury, poisoning and procedural complications           
Alcohol poisoning  1  1/75 (1.33%)  0/76 (0.00%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Rib fracture  1  0/75 (0.00%)  0/76 (0.00%)  0/76 (0.00%)  1/76 (1.32%)  1/303 (0.33%) 
Road traffic accident  1  0/75 (0.00%)  0/76 (0.00%)  0/76 (0.00%)  1/76 (1.32%)  1/303 (0.33%) 
Metabolism and nutrition disorders           
Hypokalaemia  1  0/75 (0.00%)  0/76 (0.00%)  0/76 (0.00%)  1/76 (1.32%)  1/303 (0.33%) 
Musculoskeletal and connective tissue disorders           
Compartment syndrome  1  0/75 (0.00%)  0/76 (0.00%)  0/76 (0.00%)  1/76 (1.32%)  1/303 (0.33%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)           
Basal cell carcinoma  1  0/75 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Lung adenocarcinoma  1  0/75 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Malignant genitourinary tract neoplasm  1  0/75 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Non-Hodgkin's lymphoma unspecified histology indolent stage IV  1  1/75 (1.33%)  0/76 (0.00%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Non-small cell lung cancer  1  0/75 (0.00%)  0/76 (0.00%)  0/76 (0.00%)  1/76 (1.32%)  1/303 (0.33%) 
Pancreatic neoplasm  1  0/75 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Small cell lung cancer  1  0/75 (0.00%)  0/76 (0.00%)  0/76 (0.00%)  1/76 (1.32%)  1/303 (0.33%) 
Small cell lung cancer metastatic  1  0/75 (0.00%)  1/76 (1.32%)  1/76 (1.32%)  0/76 (0.00%)  2/303 (0.66%) 
Nervous system disorders           
Carotid artery stenosis  1  0/75 (0.00%)  0/76 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  1/303 (0.33%) 
Syncope  1  0/75 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Reproductive system and breast disorders           
Benign prostatic hyperplasia  1  0/75 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Prostatitis  1  0/75 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Respiratory, thoracic and mediastinal disorders           
Chronic obstructive pulmonary disease  1  1/75 (1.33%)  2/76 (2.63%)  1/76 (1.32%)  1/76 (1.32%)  5/303 (1.65%) 
Pneumothorax  1  0/75 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  1/76 (1.32%)  2/303 (0.66%) 
Pulmonary embolism  1  0/75 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Pulmonary hilum mass  1  1/75 (1.33%)  0/76 (0.00%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Vascular disorders           
Aortic aneurysm  1  0/75 (0.00%)  0/76 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  1/303 (0.33%) 
Aortic stenosis  1  0/75 (0.00%)  1/76 (1.32%)  0/76 (0.00%)  0/76 (0.00%)  1/303 (0.33%) 
Peripheral arterial occlusive disease  1  0/75 (0.00%)  0/76 (0.00%)  0/76 (0.00%)  1/76 (1.32%)  1/303 (0.33%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo With Behavioural Modification (BM) Tiotropium (Tio) 5 Micro-grams (μg) With BM Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM Total
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   22/75 (29.33%)   19/76 (25.00%)   16/76 (21.05%)   19/76 (25.00%)   76/303 (25.08%) 
Infections and infestations           
Nasopharyngitis  1  8/75 (10.67%)  9/76 (11.84%)  4/76 (5.26%)  10/76 (13.16%)  31/303 (10.23%) 
Musculoskeletal and connective tissue disorders           
Back pain  1  4/75 (5.33%)  1/76 (1.32%)  2/76 (2.63%)  1/76 (1.32%)  8/303 (2.64%) 
Respiratory, thoracic and mediastinal disorders           
Chronic obstructive pulmonary disease  1  16/75 (21.33%)  10/76 (13.16%)  12/76 (15.79%)  13/76 (17.11%)  51/303 (16.83%) 
Dyspnoea  1  2/75 (2.67%)  6/76 (7.89%)  2/76 (2.63%)  2/76 (2.63%)  12/303 (3.96%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI’s intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim, Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02085161     History of Changes
Other Study ID Numbers: 1237.16
2013-002671-18 ( EudraCT Number: EudraCT )
First Submitted: March 7, 2014
First Posted: March 12, 2014
Results First Submitted: August 30, 2016
Results First Posted: January 6, 2017
Last Update Posted: January 6, 2017