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Effect on Exercise Endurance and Lung Hyperinflation of Tiotropium + Olodaterol in COPD Patients.

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ClinicalTrials.gov Identifier: NCT01533935
Recruitment Status : Completed
First Posted : February 16, 2012
Results First Posted : September 15, 2015
Last Update Posted : September 15, 2015
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double;   Primary Purpose: Treatment
Condition Pulmonary Disease, Chronic Obstructive
Interventions Drug: Placebo
Drug: Tiotropium + Olodaterol
Drug: tiotropium + Olodaterol
Drug: Tiotropium
Drug: Olodaterol
Device: Respimat
Enrollment 291

Recruitment Details  
Pre-assignment Details This was a randomised, 4-period incomplete block cross-over trial. 291 patients were randomized to one of five treatments sequences and treated. It was a double-blind trial in which each treatment period lasted 6 weeks with a washout period of 21 days between each.
Arm/Group Title Tio+Olo 2.5/5 / Tio+Olo 5/5 / Tio / Olo Tio+Olo 5/5 / Tio / Olo / Placebo Tio / Olo / Placebo / Tio+Olo 2.5/5 Olo / Placebo / Tio+Olo 2.5/5 / Tio+Olo 5/5 Placebo / Tio+Olo 2.5/5 / Tio+Olo 5/5 / Tio
Hide Arm/Group Description

Patients received a total of four treatments, and each treatment period is separated by a washout period of 21 days. The treatments administered, by oral inhalation delivered once daily in the morning, via the respimat inhaler, were

  • Fixed dose combination (FDC) of Tiotropium 2.5 µg and Olodaterol 5 µg.
  • Fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 5 µg
  • Tiotropium fixed dose 5 µg
  • Olodaterol fixed dose 5 µg

Patients received a total of four treatments, and each treatment period is separated by a washout period of 21 days. The treatments administered, by oral inhalation delivered once daily in the morning, via the respimat inhaler, were

  • Fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 5 µg
  • Tiotropium fixed dose 5 µg
  • Olodaterol fixed dose 5 µg
  • Oral inhalation of placebo

Patients received a total of four treatments, and each treatment period is separated by a washout period of 21 days. The treatments administered, by oral inhalation delivered once daily in the morning, via the respimat inhaler, were

  • Tiotropium fixed dose 5 µg
  • Olodaterol fixed dose 5 µg
  • Oral inhalation of placebo
  • Fixed dose combination (FDC) of Tiotropium 2.5 µg and Olodaterol 5 µg

Patients received a total of four treatments, and each treatment period is separated by a washout period of 21 days. The treatments administered, by oral inhalation delivered once daily in the morning, via the respimat inhaler, were

  • Olodaterol fixed dose 5 µg
  • Oral inhalation of placebo
  • Fixed dose combination (FDC) of Tiotropium 2.5 µg and Olodaterol 5 µg
  • Fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 5 µg

Patients received a total of four treatments, and each treatment period is separated by a washout period of 21 days. The treatments administered, by oral inhalation delivered once daily in the morning, via the respimat inhaler, were

  • Oral inhalation of placebo
  • Fixed dose combination (FDC) of Tiotropium 2.5 µg and Olodaterol 5 µg
  • Fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 5 µg
  • Tiotropium fixed dose 5 µg
Period Title: Overall Study
Started 58 58 58 59 58
Received Placebo 0 47 52 57 58
Received Olo 5 52 52 55 59 0
Received Tio 5 54 54 58 0 52
Received Tio+Olo 2.5/5 58 0 49 56 56
Received Tio+Olo 5/5 56 58 1 [1] 54 55
Completed 52 [2] 45 [2] 50 [2] 52 [2] 50 [2]
Not Completed 6 13 8 7 8
Reason Not Completed
Adverse Event             5             7             1             5             3
Protocol Violation             0             2             0             0             0
Lost to Follow-up             0             0             1             0             0
Withdrawal by Subject             0             4             5             2             4
Other reason not defined above             1             0             1             0             1
[1]
One patient received Tio+Olo 5/5 instead of Tio+Olo 2.5/5 by mistake.
[2]
All treatment periods
Arm/Group Title Overall Study
Hide Arm/Group Description

A randomised, double-blind, placebo controlled, 5 treatment, 4-period, incomplete, crossover study. Each treatment period was separated by a washout period of 21 days. The treatments administered, by oral inhalation delivered once daily in the morning, via the respimat inhaler, were:

  • Oral inhalation of placebo
  • Tiotropium fixed dose 5 µg
  • Olodaterol fixed dose 5 µg
  • Fixed dose combination (FDC) of Tiotropium 2.5 µg and Olodaterol 5 µg
  • Fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 5 µg

Treatment sequence is not considered as a factor which may affect the treatment effect due to sufficient washout period added between treatment cycles. As a result, we only display baseline characteristics as a whole population, but not by treatment sequence

Overall Number of Baseline Participants 291
Hide Baseline Analysis Population Description
Treated Set (TS) : This patient set included all patients of the Randomised Set (RS : patients who signed the informed consent form and were also randomised, regardless of whether the patient was treated with study medication or not) who were dispensed study medication and were documented to have taken at least 1 dose of study medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 291 participants
61.2  (7.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 291 participants
Female
87
  29.9%
Male
204
  70.1%
1.Primary Outcome
Title Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity
Hide Description

Inspiratory capacity (IC) at rest before constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap).

Wcap was defined as the maximum work rate achieved for at least 30 seconds during the incremental cycle ergometry performed at Visit 1.

The presented means are adjusted means from the MMRM (Mixed Effects Model Repeated Measures) model.

Time Frame 6 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) : This patient set included all patients in the TS who had the study baseline and at least 1 evaluable post-dose measurement for 1 of the primary endpoints. Assignment to the FAS was done after implementation of any data handling rules,which set measurements to missing.
Arm/Group Title Placebo Olodaterol 5 µg Tiotropium 5 µg Tiotropium + Olodaterol 2.5/5 Tiotropium + Olodaterol 5/5
Hide Arm/Group Description:
Oral inhalation of placebo, 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of Olodaterol fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 µg and Olodaterol 5 µg (Tiotropium: 1.25 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Overall Number of Participants Analyzed 202 208 208 212 218
Mean (Standard Error)
Unit of Measure: Litres
2.502  (0.026) 2.687  (0.025) 2.679  (0.025) 2.776  (0.025) 2.767  (0.025)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium + Olodaterol 5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.265
Confidence Interval (2-Sided) 95%
0.215 to 0.315
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.025
Estimation Comments Difference calculated as Tiotropium + olodaterol 5/5 QD minus Placebo QD
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Olodaterol 5 µg, Tiotropium + Olodaterol 5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0015
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.080
Confidence Interval (2-Sided) 95%
0.031 to 0.129
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.025
Estimation Comments Difference calculated as Tiotropium + olodaterol 5/5 QD minus Olodaterol 5 mcg QD
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 µg, Tiotropium + Olodaterol 5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.088
Confidence Interval (2-Sided) 95%
0.039 to 0.137
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.025
Estimation Comments Difference calculated as Tiotropium + olodaterol 5/5 QD minus Tiotropium 5 mcg QD
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium + Olodaterol 2.5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.274
Confidence Interval (2-Sided) 95%
0.224 to 0.324
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.025
Estimation Comments Difference calculated as Tiotropium + olodaterol 2.5/5 QD minus Placebo QD
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Olodaterol 5 µg, Tiotropium + Olodaterol 2.5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.089
Confidence Interval (2-Sided) 95%
0.039 to 0.138
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.025
Estimation Comments Difference calculated as Tiotropium + olodaterol 2.5/5 QD minus Olodaterol 5 mcg QD
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 µg, Tiotropium + Olodaterol 2.5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.097
Confidence Interval (2-Sided) 95%
0.047 to 0.147
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.025
Estimation Comments Difference calculated as Tiotropium + olodaterol 2.5/5 QD minus Tiotropium 5 mcg QD
2.Primary Outcome
Title Endurance Time During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap
Hide Description

Endurance time during constant work rate cycle ergometry (CWRCE) to symptom limitation at 75% Wcap

Wcap was defined as the maximum work rate achieved for at least 30 seconds during the incremental cycle ergometry performed at Visit 1.

The presented means are adjusted mean from the MMRM model.

Time Frame 6 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Olodaterol 5 µg Tiotropium 5 µg Tiotropium + Olodaterol 2.5/5 Tiotropium + Olodaterol 5/5
Hide Arm/Group Description:
Oral inhalation of placebo, 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of Olodaterol fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 µg and Olodaterol 5 µg (Tiotropium: 1.25 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Overall Number of Participants Analyzed 205 207 209 212 216
Geometric Mean (Standard Error)
Unit of Measure: seconds
410.77  (12.009) 419.06  (12.207) 446.50  (12.958) 460.66  (13.310) 465.68  (13.359)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium + Olodaterol 5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio
Estimated Value 1.134
Confidence Interval (2-Sided) 95%
1.065 to 1.206
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.036
Estimation Comments Ratio calculated as Tiotropium + olodaterol 5/5 QD divided by Placebo QD
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Olodaterol 5 µg, Tiotropium + Olodaterol 5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0009
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio
Estimated Value 1.111
Confidence Interval (2-Sided) 95%
1.045 to 1.182
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.035
Estimation Comments Ratio calculated Tiotropium + olodaterol 5/5 QD as divided by Olodaterol 5 mcg QD
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 µg, Tiotropium + Olodaterol 5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1807
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio
Estimated Value 1.043
Confidence Interval (2-Sided) 95%
0.981 to 1.109
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments Ratio calculated as Tiotropium + olodaterol 5/5 QD divided by Tiotropium 5 mcg QD
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium + Olodaterol 2.5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio
Estimated Value 1.121
Confidence Interval (2-Sided) 95%
1.054 to 1.193
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.036
Estimation Comments Ratio calculated as Tiotropium + olodaterol 2.5/5 QD divided by Placebo QD
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Olodaterol 5 µg, Tiotropium + Olodaterol 2.5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0029
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio
Estimated Value 1.099
Confidence Interval (2-Sided) 95%
1.033 to 1.170
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.035
Estimation Comments Ratio calculated as Tiotropium + olodaterol 2.5/5 QD divided by Olodaterol 5 mcg QD
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 µg, Tiotropium + Olodaterol 2.5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3240
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio
Estimated Value 1.032
Confidence Interval (2-Sided) 95%
0.970 to 1.098
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.033
Estimation Comments Ratio calculated as Tiotropium + olodaterol 2.5/5 QD divided by Tiotropium 5 mcg QD
3.Secondary Outcome
Title Slope of the Intensity of Breathing Discomfort (Borg Scale) During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap
Hide Description

Slope of the intensity of breathing discomfort (Borg Scale) during CWRCE to symptom limitation at 75% Wcap. The intensity of breathing discomfort was rated using the modified Borg scale with ratings from 0 (nothing at all) to 10 (maximal).

Slope is defined as : (intensity of breathing discomfort at the end of exercise minus intensity of breathing discomfort at rest) / endurance time.

A decrease in slope indicates improvement.

The presented means are adjusted means from MMRM model.

Time Frame 6 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Olodaterol 5 µg Tiotropium 5 µg Tiotropium + Olodaterol 2.5/5 Tiotropium + Olodaterol 5/5
Hide Arm/Group Description:
Oral inhalation of placebo, 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of Olodaterol fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 µg and Olodaterol 5 µg (Tiotropium: 1.25 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Overall Number of Participants Analyzed 205 207 208 212 216
Mean (Standard Error)
Unit of Measure: units on a scale / s
0.018  (0.001) 0.017  (0.001) 0.015  (0.001) 0.014  (0.001) 0.015  (0.001)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium + Olodaterol 5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.003
Confidence Interval (2-Sided) 95%
-0.004 to -0.002
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.001
Estimation Comments Difference calculated as Tiotropium + olodaterol 5/5 QD minus Placebo QD
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Olodaterol 5 µg, Tiotropium + Olodaterol 5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0033
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.002
Confidence Interval (2-Sided) 95%
-0.003 to -0.001
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.001
Estimation Comments Difference calculated as Tiotropium + olodaterol 5/5 QD minus Olodaterol 5 mcg QD
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 µg, Tiotropium + Olodaterol 5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2306
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.001
Confidence Interval (2-Sided) 95%
-0.002 to 0.001
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.001
Estimation Comments Difference calculated as Tiotropium + olodaterol 5/5 QD minus Tiotropium 5 mcg QD
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium + Olodaterol 2.5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.003
Confidence Interval (2-Sided) 95%
-0.005 to -0.002
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.001
Estimation Comments Difference calculated as Tiotropium + olodaterol 2.5/5 QD minus Placebo QD
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Olodaterol 5 µg, Tiotropium + Olodaterol 2.5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0010
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.002
Confidence Interval (2-Sided) 95%
-0.004 to -0.001
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.001
Estimation Comments Difference calculated as Tiotropium + olodaterol 2.5/5 QD minus Olodaterol 5 mcg QD
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 µg, Tiotropium + Olodaterol 2.5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1206
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.001
Confidence Interval (2-Sided) 95%
-0.002 to 0.000
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.001
Estimation Comments Difference calculated as Tiotropium + olodaterol 2.5/5 QD minus Tiotropium 5 mcg QD
4.Secondary Outcome
Title FEV1 (1 Hour Post-dose)
Hide Description

Forced Expiratory Volume in 1 Second (FEV1) (one hour post-dose).

The presented means are adjusted means from MMRM model.

Time Frame 6 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients in FAS with available FEV1 data at baseline and week 6 are included in the analysis.
Arm/Group Title Placebo Olodaterol 5 µg Tiotropium 5 µg Tiotropium + Olodaterol 2.5/5 Tiotropium + Olodaterol 5/5
Hide Arm/Group Description:
Oral inhalation of placebo, 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of Olodaterol fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 µg and Olodaterol 5 µg (Tiotropium: 1.25 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Oral inhalation of fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
Overall Number of Participants Analyzed 210 215 211 215 219
Mean (Standard Error)
Unit of Measure: Litres
1.548  (0.016) 1.742  (0.016) 1.741  (0.016) 1.852  (0.016) 1.876  (0.016)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium + Olodaterol 5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.329
Confidence Interval (2-Sided) 95%
0.294 to 0.364
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Difference calculated as Tiotropium + olodaterol 5/5 QD minus Placebo QD
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Olodaterol 5 µg, Tiotropium + Olodaterol 5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.134
Confidence Interval (2-Sided) 95%
0.099 to 0.169
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Difference calculated as Tiotropium + olodaterol 5/5 QD minus Olodaterol 5 mcg QD
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 µg, Tiotropium + Olodaterol 5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.135
Confidence Interval (2-Sided) 95%
0.100 to 0.170
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Difference calculated as Tiotropium + olodaterol 5/5 QD minus Tiotropium 5 mcg QD
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Tiotropium + Olodaterol 2.5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.305
Confidence Interval (2-Sided) 95%
0.269 to 0.340
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Difference calculated as Tiotropium + olodaterol 2.5/5 QD minus Placebo QD
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Olodaterol 5 µg, Tiotropium + Olodaterol 2.5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.110
Confidence Interval (2-Sided) 95%
0.075 to 0.145
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Difference calculated as Tiotropium + olodaterol 2.5/5 QD minus Olodaterol 5 mcg QD
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 µg, Tiotropium + Olodaterol 2.5/5
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.111
Confidence Interval (2-Sided) 95%
0.076 to 0.146
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Difference calculated as Tiotropium + olodaterol 2.5/5 QD minus Tiotropium 5 mcg QD
Time Frame From drug administration until 21 days after the last administration, up to 139 days
Adverse Event Reporting Description One patient received treatment for 118 days, rather than 6 weeks, due to non-compliance with study visit requirements.
 
Arm/Group Title Placebo Olodaterol 5 µg Tiotropium 5 µg Tiotropium + Olodaterol 2.5/5 Tiotropium + Olodaterol 5/5
Hide Arm/Group Description Oral inhalation of placebo, 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of Olodaterol fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of Tiotropium fixed dose 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 µg and Olodaterol 5 µg (Tiotropium: 1.25 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning. Oral inhalation of fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 5 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning.
All-Cause Mortality
Placebo Olodaterol 5 µg Tiotropium 5 µg Tiotropium + Olodaterol 2.5/5 Tiotropium + Olodaterol 5/5
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 Olodaterol 5 µg Tiotropium 5 µg Tiotropium + Olodaterol 2.5/5 Tiotropium + Olodaterol 5/5
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/214 (1.40%)   3/218 (1.38%)   8/218 (3.67%)   3/219 (1.37%)   4/224 (1.79%) 
Cardiac disorders           
Atrial fibrillation  1  0/214 (0.00%)  0/218 (0.00%)  1/218 (0.46%)  0/219 (0.00%)  0/224 (0.00%) 
Sick sinus syndrome  1  0/214 (0.00%)  0/218 (0.00%)  1/218 (0.46%)  0/219 (0.00%)  0/224 (0.00%) 
Supraventricular tachycardia  1  0/214 (0.00%)  0/218 (0.00%)  1/218 (0.46%)  0/219 (0.00%)  0/224 (0.00%) 
Gastrointestinal disorders           
Abdominal discomfort  1  0/214 (0.00%)  0/218 (0.00%)  0/218 (0.00%)  1/219 (0.46%)  0/224 (0.00%) 
Diarrhoea  1  0/214 (0.00%)  0/218 (0.00%)  0/218 (0.00%)  0/219 (0.00%)  1/224 (0.45%) 
Nausea  1  0/214 (0.00%)  0/218 (0.00%)  0/218 (0.00%)  0/219 (0.00%)  1/224 (0.45%) 
Vomiting  1  0/214 (0.00%)  0/218 (0.00%)  0/218 (0.00%)  0/219 (0.00%)  1/224 (0.45%) 
General disorders           
Death  1  0/214 (0.00%)  0/218 (0.00%)  1/218 (0.46%)  0/219 (0.00%)  0/224 (0.00%) 
Pain  1  0/214 (0.00%)  1/218 (0.46%)  0/218 (0.00%)  0/219 (0.00%)  0/224 (0.00%) 
Infections and infestations           
Acute tonsillitis  1  1/214 (0.47%)  0/218 (0.00%)  0/218 (0.00%)  0/219 (0.00%)  0/224 (0.00%) 
Cellulitis gangrenous  1  0/214 (0.00%)  0/218 (0.00%)  1/218 (0.46%)  0/219 (0.00%)  0/224 (0.00%) 
Infective exacerbation of chronic obstructive airways disease  1  0/214 (0.00%)  0/218 (0.00%)  0/218 (0.00%)  1/219 (0.46%)  0/224 (0.00%) 
Parainfluenzae virus infection  1  0/214 (0.00%)  0/218 (0.00%)  1/218 (0.46%)  0/219 (0.00%)  0/224 (0.00%) 
Pneumonia  1  0/214 (0.00%)  1/218 (0.46%)  0/218 (0.00%)  0/219 (0.00%)  0/224 (0.00%) 
Injury, poisoning and procedural complications           
Concussion  1  0/214 (0.00%)  0/218 (0.00%)  0/218 (0.00%)  0/219 (0.00%)  1/224 (0.45%) 
Contusion  1  0/214 (0.00%)  0/218 (0.00%)  0/218 (0.00%)  0/219 (0.00%)  1/224 (0.45%) 
Overdose  1  0/214 (0.00%)  0/218 (0.00%)  0/218 (0.00%)  0/219 (0.00%)  1/224 (0.45%) 
Road traffic accident  1  0/214 (0.00%)  0/218 (0.00%)  0/218 (0.00%)  0/219 (0.00%)  1/224 (0.45%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)           
Gastric neoplasm  1  0/214 (0.00%)  0/218 (0.00%)  0/218 (0.00%)  1/219 (0.46%)  0/224 (0.00%) 
Prostate cancer  1  0/214 (0.00%)  0/218 (0.00%)  1/218 (0.46%)  0/219 (0.00%)  0/224 (0.00%) 
Rectal cancer  1  0/214 (0.00%)  1/218 (0.46%)  0/218 (0.00%)  0/219 (0.00%)  0/224 (0.00%) 
Nervous system disorders           
Convulsion  1  0/214 (0.00%)  0/218 (0.00%)  0/218 (0.00%)  0/219 (0.00%)  1/224 (0.45%) 
Psychiatric disorders           
Suicide attempt  1  0/214 (0.00%)  0/218 (0.00%)  1/218 (0.46%)  0/219 (0.00%)  1/224 (0.45%) 
Respiratory, thoracic and mediastinal disorders           
Acute respiratory failure  1  0/214 (0.00%)  0/218 (0.00%)  0/218 (0.00%)  0/219 (0.00%)  1/224 (0.45%) 
Chronic obstructive pulmonary disease  1  2/214 (0.93%)  0/218 (0.00%)  2/218 (0.92%)  0/219 (0.00%)  1/224 (0.45%) 
Dyspnoea  1  0/214 (0.00%)  0/218 (0.00%)  1/218 (0.46%)  0/219 (0.00%)  0/224 (0.00%) 
Skin and subcutaneous tissue disorders           
Rash  1  0/214 (0.00%)  0/218 (0.00%)  0/218 (0.00%)  0/219 (0.00%)  1/224 (0.45%) 
Vascular disorders           
Peripheral arterial occlusive disease  1  0/214 (0.00%)  0/218 (0.00%)  1/218 (0.46%)  0/219 (0.00%)  0/224 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 16.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Olodaterol 5 µg Tiotropium 5 µg Tiotropium + Olodaterol 2.5/5 Tiotropium + Olodaterol 5/5
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   41/214 (19.16%)   42/218 (19.27%)   48/218 (22.02%)   36/219 (16.44%)   40/224 (17.86%) 
Infections and infestations           
Nasopharyngitis  1  10/214 (4.67%)  14/218 (6.42%)  13/218 (5.96%)  18/219 (8.22%)  16/224 (7.14%) 
Respiratory, thoracic and mediastinal disorders           
Chronic obstructive pulmonary disease  1  16/214 (7.48%)  24/218 (11.01%)  19/218 (8.72%)  15/219 (6.85%)  20/224 (8.93%) 
Cough  1  11/214 (5.14%)  5/218 (2.29%)  8/218 (3.67%)  4/219 (1.83%)  3/224 (1.34%) 
Dyspnoea  1  12/214 (5.61%)  6/218 (2.75%)  13/218 (5.96%)  6/219 (2.74%)  6/224 (2.68%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 16.1
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
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01533935     History of Changes
Other Study ID Numbers: 1237.14
2011-004660-30 ( EudraCT Number: EudraCT )
First Submitted: February 13, 2012
First Posted: February 16, 2012
Results First Submitted: June 19, 2015
Results First Posted: September 15, 2015
Last Update Posted: September 15, 2015