Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The primary objectives of the study are to explore the effect of treatment with orally inhaled tiotropium + olodaterol fixed dose combination with and without exercise training, and tiotropium comparing to placebo, on top of behavioural modification in improving exercise capacity in patients with COPD
Interventions
DRUGplacebo to tiotropium + olodaterol
comparator
tiotropium 5 mcg once daily
DRUGtiotropium +olodaterol
olodaterol 5 mcg once daily fixed dose combination
DRUGtiotropium
tiotropium 5 mcg once daily fixed dose combination
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* All patients must sign an informed consent consistent with International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) - Good Clinical Practice (GCP) guidelines prior to participation in the trial, which includes medication washout and restrictions. * All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria: Patients must have relatively stable airway obstruction with a post-bronchodilator forced expiratory volume in one second \>=30% and \<80% of predicted normal; Global Initiative for Chronic Obstructive Lung Disease grade II - III, and a post-bronchodilator Tiffeneau index \<70% at Visit 1. * Male or female patients, aged \>=40 years and \<=75 years. * Patients must be current or ex-smokers with a smoking history of more than 10 pack years. Patients who have never smoked cigarettes must be excluded.
Exclusion criteria
* Patients with a significant disease other than chronic obstructive pulmonary disease. * Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis. * Patients with a history of asthma. * A diagnosis of thyrotoxicosis. * A diagnosis of paroxysmal tachycardia (\>100 beats per minute). * A history of myocardial infarction within 1 year of screening visit. * Unstable or life-threatening cardiac arrhythmia. * Hospitalized for heart failure within the past year. * Known active tuberculosis. * A malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years. * A history of life-threatening pulmonary obstruction and patients with chronic respiratory failure. * A history of cystic fibrosis. * Clinically evident bronchiectasis. * A history of significant alcohol or drug abuse. * Any contraindications for exercise testing. * Patients who have undergone thoracotomy with pulmonary resection. * Patients being treated with any oral ß-adrenergics. * Patients being treated with oral corticosteroid medication at unstable doses (i.e., less than six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day. * Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigators opinion will be unable to abstain from the use of oxygen therapy during clinic visits. * Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the screening visit or patients who are currently in a pulmonary rehabilitation program. * Patients who have a limitation of exercise performance as a result of factors other than fatigue or exertional dyspnoea, such as arthritis in the leg, angina pectoris or claudication or morbid obesity. * Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit. * Patients with known hypersensitivity to ß-adrenergics drugs, anticholinergic drugs, benzalkonium chloride, disodium edentat, or any other component of the Respimat® inhalation solution delivery system. * Pregnant or nursing women. * Women of childbearing potential not using highly effective methods of birth control. * Patients who have previously been randomized in this study or are currently participating in another study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 8 Weeks | Week 8 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Daily Walking Intensity Measured by the Activity Monitor in the Week Prior to 12 Weeks of Treatment | Week 12 | 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. |
| Perceived Difficulties as Evaluated With Functional Performance Inventory-Short Form (FPI-SF) Total Score at Week 12 | Week 12 | 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. |
| Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 12 Weeks | Week 12 | 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. |
| Average Daily Walking Time Measured by the Activity Monitor in the Week Prior to Week 12 | Week 12 | Average daily walking time measured by the activity monitor in the week prior to Week 12. |
| One Hour, Post-dose Forced Vital Capacity (FVC) After 8 Weeks of Treatment | Week 8 | One hour, Post-dose Forced Vital Capacity (FVC) after 8 weeks of treatment. |
| Resting Inspiratory Capacity (IC) Measured at 1.5 Hours Post Dose After 8 Weeks of Treatment | Week 8 | Resting inspiratory capacity (IC) measured at 1.5 hours post dose after 8 weeks of treatment. |
| One Hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 8 Weeks of Treatment | Week 8 | One hour, Post-dose Forced Expiratory Volume in One Second (FEV1) after 8 weeks of treatment. |
Countries
Australia, Austria, Belgium, Canada, Denmark, Germany, New Zealand, Poland, Portugal, United Kingdom, United States
Participant flow
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)
Participants by arm
| Arm | Count |
|---|---|
| Placebo With Behavioural Modification (BM) Placebo matching tiotropium + olodaterol FDC or tiotropium solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks. | 75 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM Tiotropium 5 μg solution was delivered to the patients orally once daily via RESPIMAT inhaler, with BM for 12 weeks. | 76 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM 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. | 76 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM 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. | 76 |
| Total | 303 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 5 | 4 | 5 |
| Overall Study | Not Treated | 1 | 0 | 0 | 0 |
| Overall Study | Other Reason | 1 | 0 | 1 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 4 | 0 | 3 |
Baseline characteristics
| Characteristic | 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 |
|---|---|---|---|---|---|
| Age, Continuous | 64.4 Years STANDARD_DEVIATION 6.6 | 65.1 Years STANDARD_DEVIATION 6.4 | 65.0 Years STANDARD_DEVIATION 6.9 | 64.7 Years STANDARD_DEVIATION 6.5 | 64.8 Years STANDARD_DEVIATION 6.6 |
| Gender Female | 23 Participants | 21 Participants | 28 Participants | 31 Participants | 103 Participants |
| Gender Male | 52 Participants | 55 Participants | 48 Participants | 45 Participants | 200 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 22 / 75 | 19 / 76 | 16 / 76 | 19 / 76 | 76 / 303 |
| serious Total, serious adverse events | 4 / 75 | 11 / 76 | 3 / 76 | 8 / 76 | 26 / 303 |
Outcome results
Primary
Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 8 Weeks
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
Population: 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 | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo With Behavioural Modification (BM) | Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 8 Weeks | 244.07 Second | Standard Error 17.666 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 8 Weeks | 254.18 Second | Standard Error 18.099 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 8 Weeks | 315.32 Second | Standard Error 21.671 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 8 Weeks | 355.73 Second | Standard Error 24.787 |
Comparison: This treatment comparison is the first one in the alpha-protected hierarchical testing chain.p-value: 0.000295% CI: [1.196, 1.777]ANCOVA
Comparison: This treatment comparison is the second one in the alpha-protected hierarchical testing chain.p-value: 0.010995% CI: [1.061, 1.573]ANCOVA
Comparison: 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.p-value: 0.689595% CI: [0.853, 1.272]ANCOVA
p-value: 0.218895% CI: [0.931, 1.368]ANCOVA
p-value: 0.030395% CI: [1.021, 1.507]ANCOVA
Secondary
Average Daily Walking Intensity Measured by the Activity Monitor in the Week Prior to 12 Weeks of Treatment
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo With Behavioural Modification (BM) | Average Daily Walking Intensity Measured by the Activity Monitor in the Week Prior to 12 Weeks of Treatment | 0.20 Multiple of 9.8*(meters / (second^2)) | Standard Error 0.003 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | Average Daily Walking Intensity Measured by the Activity Monitor in the Week Prior to 12 Weeks of Treatment | 0.20 Multiple of 9.8*(meters / (second^2)) | Standard Error 0.003 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | Average Daily Walking Intensity Measured by the Activity Monitor in the Week Prior to 12 Weeks of Treatment | 0.20 Multiple of 9.8*(meters / (second^2)) | Standard Error 0.003 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | Average Daily Walking Intensity Measured by the Activity Monitor in the Week Prior to 12 Weeks of Treatment | 0.20 Multiple of 9.8*(meters / (second^2)) | Standard Error 0.003 |
p-value: 0.518695% CI: [-0.01, 0.005]ANCOVA
p-value: 0.643695% CI: [-0.006, 0.009]ANCOVA
p-value: 0.108195% CI: [-0.014, 0.001]ANCOVA
p-value: 0.261295% CI: [-0.011, 0.003]ANCOVA
p-value: 0.036195% CI: [0.001, 0.015]ANCOVA
Secondary
Average Daily Walking Time Measured by the Activity Monitor in the Week Prior to Week 12
Average daily walking time measured by the activity monitor in the week prior to Week 12.
Time frame: Week 12
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo With Behavioural Modification (BM) | Average Daily Walking Time Measured by the Activity Monitor in the Week Prior to Week 12 | 4670.78 Second | Standard Error 211.798 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | Average Daily Walking Time Measured by the Activity Monitor in the Week Prior to Week 12 | 4145.85 Second | Standard Error 207.351 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | Average Daily Walking Time Measured by the Activity Monitor in the Week Prior to Week 12 | 4831.85 Second | Standard Error 202.261 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | Average Daily Walking Time Measured by the Activity Monitor in the Week Prior to Week 12 | 4338.80 Second | Standard Error 207.252 |
p-value: 0.263995% CI: [-916.015, 252.064]ANCOVA
p-value: 0.583795% CI: [-417.314, 739.459]ANCOVA
p-value: 0.078395% CI: [-1109.806, 59.954]ANCOVA
p-value: 0.0995% CI: [-1063.67, 77.575]ANCOVA
p-value: 0.018695% CI: [115.635, 1256.362]ANCOVA
Secondary
Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 12 Weeks
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
Population: 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 | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo With Behavioural Modification (BM) | Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 12 Weeks | 243.30 Second | Standard Error 18.68 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 12 Weeks | 255.67 Second | Standard Error 19.292 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 12 Weeks | 302.61 Second | Standard Error 21.691 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 12 Weeks | 324.21 Second | Standard Error 24.095 |
p-value: 0.007795% CI: [1.08, 1.645]ANCOVA
p-value: 0.03995% CI: [1.011, 1.53]ANCOVA
p-value: 0.645295% CI: [0.85, 1.299]ANCOVA
p-value: 0.504895% CI: [0.874, 1.313]ANCOVA
p-value: 0.106695% CI: [0.964, 1.453]ANCOVA
Secondary
One Hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 8 Weeks of Treatment
One hour, Post-dose Forced Expiratory Volume in One Second (FEV1) after 8 weeks of treatment.
Time frame: Week 8
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo With Behavioural Modification (BM) | One Hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 8 Weeks of Treatment | 1.375 Liter | Standard Error 0.027 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | One Hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 8 Weeks of Treatment | 1.550 Liter | Standard Error 0.027 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | One Hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 8 Weeks of Treatment | 1.731 Liter | Standard Error 0.026 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | One Hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 8 Weeks of Treatment | 1.705 Liter | Standard Error 0.026 |
p-value: <0.000195% CI: [0.255, 0.403]Mixed Models Analysis
p-value: <0.000195% CI: [0.282, 0.429]Mixed Models Analysis
p-value: <0.000195% CI: [0.099, 0.249]Mixed Models Analysis
p-value: 0.467795% CI: [-0.099, 0.045]Mixed Models Analysis
p-value: <0.000195% CI: [0.109, 0.255]Mixed Models Analysis
Secondary
One Hour, Post-dose Forced Vital Capacity (FVC) After 8 Weeks of Treatment
One hour, Post-dose Forced Vital Capacity (FVC) after 8 weeks of treatment.
Time frame: Week 8
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo With Behavioural Modification (BM) | One Hour, Post-dose Forced Vital Capacity (FVC) After 8 Weeks of Treatment | 2.974 Liter | Standard Error 0.047 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | One Hour, Post-dose Forced Vital Capacity (FVC) After 8 Weeks of Treatment | 3.259 Liter | Standard Error 0.046 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | One Hour, Post-dose Forced Vital Capacity (FVC) After 8 Weeks of Treatment | 3.504 Liter | Standard Error 0.044 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | One Hour, Post-dose Forced Vital Capacity (FVC) After 8 Weeks of Treatment | 3.452 Liter | Standard Error 0.045 |
p-value: <0.000195% CI: [0.35, 0.606]Mixed Models Analysis
p-value: <0.000195% CI: [0.403, 0.657]Mixed Models Analysis
p-value: <0.000195% CI: [0.157, 0.415]Mixed Models Analysis
p-value: 0.410795% CI: [-0.176, 0.072]Mixed Models Analysis
p-value: 0.000295% CI: [0.119, 0.37]Mixed Models Analysis
Secondary
Perceived Difficulties as Evaluated With Functional Performance Inventory-Short Form (FPI-SF) Total Score at Week 12
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo With Behavioural Modification (BM) | Perceived Difficulties as Evaluated With Functional Performance Inventory-Short Form (FPI-SF) Total Score at Week 12 | 2.191 Units on a scale | Standard Error 0.04 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | Perceived Difficulties as Evaluated With Functional Performance Inventory-Short Form (FPI-SF) Total Score at Week 12 | 2.207 Units on a scale | Standard Error 0.04 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | Perceived Difficulties as Evaluated With Functional Performance Inventory-Short Form (FPI-SF) Total Score at Week 12 | 2.335 Units on a scale | Standard Error 0.038 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | Perceived Difficulties as Evaluated With Functional Performance Inventory-Short Form (FPI-SF) Total Score at Week 12 | 2.268 Units on a scale | Standard Error 0.039 |
p-value: 0.172795% CI: [-0.034, 0.187]ANCOVA
p-value: 0.009795% CI: [0.035, 0.252]ANCOVA
p-value: 0.781595% CI: [-0.095, 0.126]ANCOVA
p-value: 0.218395% CI: [-0.174, 0.04]ANCOVA
p-value: 0.020395% CI: [0.02, 0.236]ANCOVA
Secondary
Resting Inspiratory Capacity (IC) Measured at 1.5 Hours Post Dose After 8 Weeks of Treatment
Resting inspiratory capacity (IC) measured at 1.5 hours post dose after 8 weeks of treatment.
Time frame: Week 8
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo With Behavioural Modification (BM) | Resting Inspiratory Capacity (IC) Measured at 1.5 Hours Post Dose After 8 Weeks of Treatment | 2.452 Liter | Standard Error 0.051 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | Resting Inspiratory Capacity (IC) Measured at 1.5 Hours Post Dose After 8 Weeks of Treatment | 2.627 Liter | Standard Error 0.05 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | Resting Inspiratory Capacity (IC) Measured at 1.5 Hours Post Dose After 8 Weeks of Treatment | 2.755 Liter | Standard Error 0.048 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | Resting Inspiratory Capacity (IC) Measured at 1.5 Hours Post Dose After 8 Weeks of Treatment | 2.771 Liter | Standard Error 0.049 |
p-value: <0.000195% CI: [0.179, 0.457]Mixed Models Analysis
p-value: <0.000195% CI: [0.165, 0.439]Mixed Models Analysis
p-value: 0.014595% CI: [0.035, 0.314]Mixed Models Analysis
p-value: 0.81595% CI: [-0.118, 0.151]Mixed Models Analysis
p-value: 0.064295% CI: [-0.008, 0.263]Mixed Models Analysis