Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The primary objective of the present study is to evaluate the effect of tiotropium + olodaterol fixed dose combination (FDC) compared to tiotropium monotherapy on the intensity of breathlessness during the 3min constant speed shuttle test (CSST). A secondary objective is to explore the relationship between reductions in breathlessness during the 3min CSST and reductions in breathlessness during activities of everyday living as measured by the dyspnea domain of the Chronic Respiratory Questionnaire (CRQ) following bronchodilator therapy.
Interventions
DRUGTiotropium
fixed dose combination once daily
DRUGOlodaterol
fixed dose combination once daily
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients must sign an informed consent consistent with International Conference on Harmonization Good Clinical Practice guidelines prior to participation in the trial, including medication washout and restrictions * Diagnosis of Chronic Obstructive Pulmonary Disease and relatively stable airway obstruction: post bronchodilator 30%\<= Forced Expiratory Volume in 1st second (FEV1)\<80% of predicted normal (European Coal and Steel Community) and a post bronchodilator FEV1/Forced Vital Capacity\<0.70 at visit 1 * Male or female patients \>=40 and =\<75 years of age on day of signing consent. * Current or ex-smokers with a smoking history \> 10 pack-years. Patients who have never smoked cigarettes must be excluded. * Baseline Dyspnea Index score\< 8 at visit 0. * Hyperinflation at rest, defined as Functional Residual Capacity \> 120% predicted at visit 1. * Borg dyspnea score \>=4 at the end of 3min Constant Speed Shuttle Test at visit 2 * Perform technically acceptable pulmonary function tests (spirometry and body plethysmography) and complete multiple shuttle tests during the study period * Inhale medication in a competent manner from the Respimat® inhaler and from a metered dose inhaler
Exclusion criteria
* Significant disease other than Chronic Obstructive Pulmonary Disease (COPD); a significant disease which, in the investigator's opinion, may (i) put the patient at risk (ii) influence the study results or (iii) cause concern regarding the patient's ability to participate * Clinically relevant abnormal baseline haematology, blood chemistry, in the investigator's opinion, or creatinine \>x2 Upper Limit Normal will be excluded regardless of clinical condition * Current documented diagnosis of asthma * COPD exacerbation in the 6 weeks prior to screening * Diagnosis of thyrotoxicosis * History of myocardial infarction within 6 months of screening * Life-threatening cardiac arrhythmia (investigator judgment) * Known active tuberculosis * Any malignancy unless free of disease for at least 5 years (treated basal cell carcinoma or squamous cell skin cancers are allowed) * History of cystic fibrosis * Clinically relevant bronchiectasis (investigator judgment) * Severe emphysema requiring endobronchial interventions within 6 months prior to screening * History of significant alcohol or drug abuse (investigator judgment) * Any contraindications for exercise testing * Patients who have undergone thoracotomy with pulmonary resection * Treatment with any oral or patch ß-adrenergics * Treatment with oral corticosteroid medication at unstable doses or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day * Treatment with antibiotics for any reason within 4 weeks of screening * Patients being treated with Phosphodiesterase Type 4 (PDE4) inhibitors within 3 months of screening visit should not be enrolled and PDE4 inhibitors should not be withdrawn for the purpose of enrolling in this study * Regular use of daytime oxygen therapy for \>1 hour per day and in the investigator's opinion will be unable to abstain from use during clinic visits * Completion of a pulmonary rehabilitation program 6 weeks prior to screening or currently in a program * Limitation of exercise performance as a result of factors other than fatigue or exertional dyspnea, such as arthritis in the leg, angina pectoris, claudication, morbid obesity * Endurance time \>=12 minutes during the incremental shuttle walk test * Oxygen saturation \< 85% (on room air) at rest or during exercise. * Taken an investigational drug within 1 month or 6 half-lives or in case the investigational drug class is listed within the washout period specified prior to screening visit * Known hypersensitivity to ß-adrenergics and/or anticholinergic drugs, Benzalkonium Chloride, Ethylenediaminetetraacetic acid or any other component of the Respimat® inhalation solution * Women who are pregnant, nursing, or who plan to become pregnant while in the trial * Women of childbearing potential not using a highly effective method of birth control * Previously been randomized in this study or are currently participating in another study * Unable to comply with pulmonary medication restrictions prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Intensity of Breathlessness Measured Using the Modified Borg Scale at the End of the 3 Minute (Min) Constant Speed Shuttle Test After 6 Weeks of Treatment. | Baseline and week 6 | At 3 min or end of exercise (if 3 min not achieved), patients were asked to estimate the intensity of breathing discomfort that they were experiencing by matching their subjective estimate to descriptive phrases that best described the intensity of each sensation using the Modified Borg Scale (MBS-S). The modified Borg scale is 10-point subjective scoring system, in which a patient rates effort of exertion while performing a particular activity. The scale is 0 to 10, the higher the score, the greater the perceived difficulty. Measure type is actually Adjusted Mean Change from Baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline After 6 Weeks of Treatment for Inspiratory Capacity Measured at the End of Exercise | Baseline and week 6 | Inspiratory Capacity (IC) is a standard measurement for the assessment of lung function. IC measurements were performed at the end of the 3min Constant Speed Shuttle Test (CSST). Measure type is actually Adjusted Mean Change from Baseline. |
| Change From Baseline After 6 Weeks of Treatment for 1 Hour Post-dose Forced Expiratory Volume | Baseline and week 6 | Forced Expiratory Volume in 1st second (FEV1) is a standard measurement for the assessment of lung function. The best of 3 efforts was defined as the highest FEV1, each obtained on any of 3 manoeuvres meeting the American Thoracic Society (ATS) criteria (to a maximum of 5 attempts). Measure type is actually Adjusted Mean Change from Baseline. |
| Change From Baseline After 6 Weeks of Treatment for 1 Hour Post-dose Forced Vital Capacity | Baseline and week 6 | Forced Vital Capacity (FVC) is a standard measurement for the assessment of lung function. The best of 3 efforts was defined as the highest FVC, each obtained on any of 3 manoeuvres meeting the American Thoracic Society (ATS) criteria (to a maximum of 5 attempts). Measure type is actually Adjusted Mean Change from Baseline. |
| Change From Baseline After 6 Weeks of Treatment for Inspiratory Capacity Measured Prior to Exercise | Baseline and week 6 | Inspiratory Capacity (IC) is a standard measurement for the assessment of lung function. IC measurements were performed prior to the 3min Constant Speed Shuttle Test (CSST) (at rest). Measure type is actually Adjusted Mean Change from Baseline. |
| Change From Baseline After 6 Weeks of Treatment for Chronic Respiratory Questionnaire - Self Administered Individualized (CRQ-SAI) Dyspnoea Domain Score | Baseline and week 6 | CRQ-SAI refers to the CRQ-Self-administered individualized format as it contains a dyspnea domain that is individualized to each patient. This version was derived from the original CRQ tool & therefore, is scored on 7-point Likert-type scale (1: maximum impairment to 7: no impairment) for each 4 domains covering: dyspnea, fatigue, emotional function & mastery. Dyspnea items may be selected from list of 26 suggested items or written in by the patients. The patients are asked to select up to 5 activities associated with breathlessness that they perform frequently and are most important to them. The scores for each question of each domain were added together and divided by the number of questions answered in each domain. The higher scores indicate better health-related quality of life in the respective domain. Measure type is actually Adjusted Mean Change from Baseline. |
| Change From Baseline After 6 Weeks of Treatment for Chronic Respiratory Questionnaire - Self Administered Standardized (CRQ-SAS) Dyspnoea Domain Score | Baseline and week 6 | CRQ-SAS was questionnaire to assess patients' perception of COPD and measures the impact of COPD on their life. This version was derived from the original CRQ tool & therefore, is scored on 7-point Likert-type scale (1: maximum impairment to 7: no impairment) for each 4 domains covering: dyspnea, fatigue, emotional function & mastery. The CRQ-SAS refers to the CRQ-Self-administered standardized format & contains 20 questions. The first part of the questionnaire contains 5 standardized dyspnea questions and the patients must indicate how much shortness of breath they have experienced while performing each of these 5 activities. The scores for each question of each domain were added together and divided by the number of questions answered in each domain. The higher scores indicate better health-related quality of life in the respective domain. Measure type is actually Adjusted Mean Change from Baseline. |
| Change From Baseline After 6 Weeks of Treatment for Intensity of Breathlessness (MBS-S) at 1, 2 and 2.5 Minute (Min) During the 3 Min Constant Speed Shuttle Test | Baseline and week 6 | At 1, 2 and 2.5 min during exercise, patients were asked to estimate the intensity of breathing discomfort that they were experiencing by matching their subjective estimate to descriptive phrases that best described the intensity of each sensation using the Modified Borg Scale (MBS-S). At 3 min or end of exercise (if 3 min not achieved), patients were asked to estimate the intensity of breathing discomfort that they were experiencing by matching their subjective estimate to descriptive phrases that best described the intensity of each sensation using the Modified Borg Scale (MBS-S). The modified Borg scale is 10-point subjective scoring system, in which a patient rates effort of exertion while performing a particular activity. The scale is 0 to 10, the higher the score, the greater the perceived difficulty. Measure type is actually Adjusted Mean Change from Baseline. |
Countries
Belgium, Canada, Germany, Netherlands
Participant flow
Recruitment details
This was a randomised, double-blind, active-controlled, 2-period crossover, Phase IV study to evaluate the effects of once daily administration of orally inhaled tiotropium + olodaterol fixed dose combination compared with tiotropium on the intensity of breathlessness in patients with Chronic Obstructive Pulmonary Disease (COPD).
Pre-assignment details
All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which then ensured that all patients met all inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any specific entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Total Subjects This patient set was nested within the randomized set (RS) and included all patients who were dispensed study medication and were documented to have taken any dose of study medication. | 106 |
| Total | 106 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 1 | Adverse Event | 0 | 3 |
| Washout Period | Adverse Event | 1 | 0 |
| Washout Period | Worsening of COPD | 0 | 3 |
Baseline characteristics
| Characteristic | Total Subjects |
|---|---|
| Age, Continuous | 63.6 Years STANDARD_DEVIATION 7.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 105 Participants |
| Sex: Female, Male Female | 40 Participants |
| Sex: Female, Male Male | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 100 | 0 / 105 | 0 / 106 |
| other Total, other adverse events | 21 / 100 | 31 / 105 | 44 / 106 |
| serious Total, serious adverse events | 1 / 100 | 5 / 105 | 6 / 106 |
Outcome results
Primary
Change From Baseline in Intensity of Breathlessness Measured Using the Modified Borg Scale at the End of the 3 Minute (Min) Constant Speed Shuttle Test After 6 Weeks of Treatment.
At 3 min or end of exercise (if 3 min not achieved), patients were asked to estimate the intensity of breathing discomfort that they were experiencing by matching their subjective estimate to descriptive phrases that best described the intensity of each sensation using the Modified Borg Scale (MBS-S). The modified Borg scale is 10-point subjective scoring system, in which a patient rates effort of exertion while performing a particular activity. The scale is 0 to 10, the higher the score, the greater the perceived difficulty. Measure type is actually Adjusted Mean Change from Baseline.
Time frame: Baseline and week 6
Population: Full analysis set (FAS): This patient set was nested within the treated set (TS) and included patients who had baseline measurement and at least one post-baseline measurement for the primary endpoint. FAS including participants with available data for change from baseline in intensity of breathlessness after 6 weeks of treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tiotropium 5 Microgram (μg) | Change From Baseline in Intensity of Breathlessness Measured Using the Modified Borg Scale at the End of the 3 Minute (Min) Constant Speed Shuttle Test After 6 Weeks of Treatment. | -0.968 Unit on Scale | Standard Error 0.137 |
| Tiotropium + Olodaterol 5/5 μg | Change From Baseline in Intensity of Breathlessness Measured Using the Modified Borg Scale at the End of the 3 Minute (Min) Constant Speed Shuttle Test After 6 Weeks of Treatment. | -1.325 Unit on Scale | Standard Error 0.136 |
Comparison: The adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within-patient variation.p-value: 0.021795% CI: [-0.661, -0.053]Mixed Effect Model Repeated Measures
Secondary
Change From Baseline After 6 Weeks of Treatment for 1 Hour Post-dose Forced Expiratory Volume
Forced Expiratory Volume in 1st second (FEV1) is a standard measurement for the assessment of lung function. The best of 3 efforts was defined as the highest FEV1, each obtained on any of 3 manoeuvres meeting the American Thoracic Society (ATS) criteria (to a maximum of 5 attempts). Measure type is actually Adjusted Mean Change from Baseline.
Time frame: Baseline and week 6
Population: FAS including participants with available data for change from baseline for FEV1 after 6 weeks of treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tiotropium 5 Microgram (μg) | Change From Baseline After 6 Weeks of Treatment for 1 Hour Post-dose Forced Expiratory Volume | 0.163 Litre (L) | Standard Error 0.021 |
| Tiotropium + Olodaterol 5/5 μg | Change From Baseline After 6 Weeks of Treatment for 1 Hour Post-dose Forced Expiratory Volume | 0.318 Litre (L) | Standard Error 0.021 |
Comparison: The adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within-patient variation.p-value: <0.000195% CI: [0.117, 0.194]Mixed Effect Model Repeated Measures
Secondary
Change From Baseline After 6 Weeks of Treatment for 1 Hour Post-dose Forced Vital Capacity
Forced Vital Capacity (FVC) is a standard measurement for the assessment of lung function. The best of 3 efforts was defined as the highest FVC, each obtained on any of 3 manoeuvres meeting the American Thoracic Society (ATS) criteria (to a maximum of 5 attempts). Measure type is actually Adjusted Mean Change from Baseline.
Time frame: Baseline and week 6
Population: FAS including participants with available data for change from baseline for FVC after 6 weeks of treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tiotropium 5 Microgram (μg) | Change From Baseline After 6 Weeks of Treatment for 1 Hour Post-dose Forced Vital Capacity | 0.258 Litre (L) | Standard Error 0.04 |
| Tiotropium + Olodaterol 5/5 μg | Change From Baseline After 6 Weeks of Treatment for 1 Hour Post-dose Forced Vital Capacity | 0.459 Litre (L) | Standard Error 0.039 |
Comparison: The adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within-patient variation.p-value: <0.000195% CI: [0.134, 0.267]Mixed Effect Model Repeated Measures
Secondary
Change From Baseline After 6 Weeks of Treatment for Chronic Respiratory Questionnaire - Self Administered Individualized (CRQ-SAI) Dyspnoea Domain Score
CRQ-SAI refers to the CRQ-Self-administered individualized format as it contains a dyspnea domain that is individualized to each patient. This version was derived from the original CRQ tool & therefore, is scored on 7-point Likert-type scale (1: maximum impairment to 7: no impairment) for each 4 domains covering: dyspnea, fatigue, emotional function & mastery. Dyspnea items may be selected from list of 26 suggested items or written in by the patients. The patients are asked to select up to 5 activities associated with breathlessness that they perform frequently and are most important to them. The scores for each question of each domain were added together and divided by the number of questions answered in each domain. The higher scores indicate better health-related quality of life in the respective domain. Measure type is actually Adjusted Mean Change from Baseline.
Time frame: Baseline and week 6
Population: FAS including participants with available data for change from baseline for CRQ-SAI questionnaire after 6 weeks of treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tiotropium 5 Microgram (μg) | Change From Baseline After 6 Weeks of Treatment for Chronic Respiratory Questionnaire - Self Administered Individualized (CRQ-SAI) Dyspnoea Domain Score | 0.640 Unit on Scale | Standard Error 0.091 |
| Tiotropium + Olodaterol 5/5 μg | Change From Baseline After 6 Weeks of Treatment for Chronic Respiratory Questionnaire - Self Administered Individualized (CRQ-SAI) Dyspnoea Domain Score | 0.610 Unit on Scale | Standard Error 0.089 |
Comparison: The adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within-patient variation.p-value: 0.802595% CI: [-0.268, 0.208]Mixed Effect Model Repeated Measures
Secondary
Change From Baseline After 6 Weeks of Treatment for Chronic Respiratory Questionnaire - Self Administered Standardized (CRQ-SAS) Dyspnoea Domain Score
CRQ-SAS was questionnaire to assess patients' perception of COPD and measures the impact of COPD on their life. This version was derived from the original CRQ tool & therefore, is scored on 7-point Likert-type scale (1: maximum impairment to 7: no impairment) for each 4 domains covering: dyspnea, fatigue, emotional function & mastery. The CRQ-SAS refers to the CRQ-Self-administered standardized format & contains 20 questions. The first part of the questionnaire contains 5 standardized dyspnea questions and the patients must indicate how much shortness of breath they have experienced while performing each of these 5 activities. The scores for each question of each domain were added together and divided by the number of questions answered in each domain. The higher scores indicate better health-related quality of life in the respective domain. Measure type is actually Adjusted Mean Change from Baseline.
Time frame: Baseline and week 6
Population: FAS including participants with available data for change from baseline for CRQ-SAS questionnaire after 6 weeks of treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tiotropium 5 Microgram (μg) | Change From Baseline After 6 Weeks of Treatment for Chronic Respiratory Questionnaire - Self Administered Standardized (CRQ-SAS) Dyspnoea Domain Score | 0.325 Unit on Scale | Standard Error 0.088 |
| Tiotropium + Olodaterol 5/5 μg | Change From Baseline After 6 Weeks of Treatment for Chronic Respiratory Questionnaire - Self Administered Standardized (CRQ-SAS) Dyspnoea Domain Score | 0.415 Unit on Scale | Standard Error 0.087 |
Comparison: The adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within-patient variation.p-value: 0.363495% CI: [-0.106, 0.286]Mixed Effect Model Repeated Measures
Secondary
Change From Baseline After 6 Weeks of Treatment for Inspiratory Capacity Measured at the End of Exercise
Inspiratory Capacity (IC) is a standard measurement for the assessment of lung function. IC measurements were performed at the end of the 3min Constant Speed Shuttle Test (CSST). Measure type is actually Adjusted Mean Change from Baseline.
Time frame: Baseline and week 6
Population: FAS including participants with available data for change from baseline for inspiratory capacity measured end of exercise after 6 weeks of treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tiotropium 5 Microgram (μg) | Change From Baseline After 6 Weeks of Treatment for Inspiratory Capacity Measured at the End of Exercise | 0.256 Litre (L) | Standard Error 0.034 |
| Tiotropium + Olodaterol 5/5 μg | Change From Baseline After 6 Weeks of Treatment for Inspiratory Capacity Measured at the End of Exercise | 0.322 Litre (L) | Standard Error 0.034 |
Comparison: IC measured end of exercise, the adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within-patient variation.p-value: 0.085295% CI: [-0.009, 0.141]Mixed Effect Model Repeated Measures
Secondary
Change From Baseline After 6 Weeks of Treatment for Inspiratory Capacity Measured Prior to Exercise
Inspiratory Capacity (IC) is a standard measurement for the assessment of lung function. IC measurements were performed prior to the 3min Constant Speed Shuttle Test (CSST) (at rest). Measure type is actually Adjusted Mean Change from Baseline.
Time frame: Baseline and week 6
Population: FAS including participants with available data for change from baseline for inspiratory capacity measured prior to exercise after 6 weeks of treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tiotropium 5 Microgram (μg) | Change From Baseline After 6 Weeks of Treatment for Inspiratory Capacity Measured Prior to Exercise | 0.279 Litre (L) | Standard Error 0.04 |
| Tiotropium + Olodaterol 5/5 μg | Change From Baseline After 6 Weeks of Treatment for Inspiratory Capacity Measured Prior to Exercise | 0.464 Litre (L) | Standard Error 0.039 |
Comparison: IC measured prior to exercise, the adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within-patient variation.p-value: <0.000195% CI: [0.106, 0.265]Mixed Effect Model Repeated Measures
Secondary
Change From Baseline After 6 Weeks of Treatment for Intensity of Breathlessness (MBS-S) at 1, 2 and 2.5 Minute (Min) During the 3 Min Constant Speed Shuttle Test
At 1, 2 and 2.5 min during exercise, patients were asked to estimate the intensity of breathing discomfort that they were experiencing by matching their subjective estimate to descriptive phrases that best described the intensity of each sensation using the Modified Borg Scale (MBS-S). At 3 min or end of exercise (if 3 min not achieved), patients were asked to estimate the intensity of breathing discomfort that they were experiencing by matching their subjective estimate to descriptive phrases that best described the intensity of each sensation using the Modified Borg Scale (MBS-S). The modified Borg scale is 10-point subjective scoring system, in which a patient rates effort of exertion while performing a particular activity. The scale is 0 to 10, the higher the score, the greater the perceived difficulty. Measure type is actually Adjusted Mean Change from Baseline.
Time frame: Baseline and week 6
Population: FAS including participants with available data for MBS-S after 6 weeks of treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Tiotropium 5 Microgram (μg) | Change From Baseline After 6 Weeks of Treatment for Intensity of Breathlessness (MBS-S) at 1, 2 and 2.5 Minute (Min) During the 3 Min Constant Speed Shuttle Test | 1 min | -0.685 Unit on Scale | Standard Error 0.081 |
| Tiotropium 5 Microgram (μg) | Change From Baseline After 6 Weeks of Treatment for Intensity of Breathlessness (MBS-S) at 1, 2 and 2.5 Minute (Min) During the 3 Min Constant Speed Shuttle Test | 2 min | -0.839 Unit on Scale | Standard Error 0.102 |
| Tiotropium 5 Microgram (μg) | Change From Baseline After 6 Weeks of Treatment for Intensity of Breathlessness (MBS-S) at 1, 2 and 2.5 Minute (Min) During the 3 Min Constant Speed Shuttle Test | 2.5 min | -0.846 Unit on Scale | Standard Error 0.127 |
| Tiotropium + Olodaterol 5/5 μg | Change From Baseline After 6 Weeks of Treatment for Intensity of Breathlessness (MBS-S) at 1, 2 and 2.5 Minute (Min) During the 3 Min Constant Speed Shuttle Test | 1 min | -0.793 Unit on Scale | Standard Error 0.081 |
| Tiotropium + Olodaterol 5/5 μg | Change From Baseline After 6 Weeks of Treatment for Intensity of Breathlessness (MBS-S) at 1, 2 and 2.5 Minute (Min) During the 3 Min Constant Speed Shuttle Test | 2 min | -1.079 Unit on Scale | Standard Error 0.101 |
| Tiotropium + Olodaterol 5/5 μg | Change From Baseline After 6 Weeks of Treatment for Intensity of Breathlessness (MBS-S) at 1, 2 and 2.5 Minute (Min) During the 3 Min Constant Speed Shuttle Test | 2.5 min | -1.164 Unit on Scale | Standard Error 0.126 |
Comparison: 1 min, the adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within-patient variation.p-value: 0.264595% CI: [-0.3, 0.083]Mixed Effect Model Repeated Measures
Comparison: 2 min, the adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within-patient variation.p-value: 0.026795% CI: [-0.452, -0.028]Mixed Effect Model Repeated Measures
Comparison: 2.5 min, the adjusted means (SE) are obtained from fitting an Mixed-effects Model Repeated Measures (MMRM) model including treatment and period as fixed effects, patient as a random effect, and period baseline and patient baseline as covariates, compound symmetry covariance structure for within-patient variation.p-value: 0.025895% CI: [-0.596, -0.039]Mixed Effect Model Repeated Measures