Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
To compare the effects of BI 1744 CL versus placebo on exercise tolerance after 6 weeks of treatment in patients with Chronic Obstructive Pulmonary Disease
Interventions
Comparison of low and high doses on exercise endurance time in COPD patients
DRUGPlacebo
Comparison of low and high dose and placebo on exercise endurance time in COPD patients
Placebo that represents olodaterol
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent prior to participation. 2. Diagnosis of chronic obstructive pulmonary disease and post-bronchodilator FEV1(Forced Expiratory Volume in 1 sec) \<80% of predicted normal and post-bronchodilator FEV1(Forced Expiratory Volume in 1 sec)/FVC of \< 70% at Visit 1. 3. Male or female between 40 and 75 years of age. 4. Current or ex-smokers with smoking history of more than 10-pack years. 5. Able to perform technically acceptable pulmonary function tests, multiple exercise tests and able to maintain records. 6. Able to inhale medication in a competent manner from a metered-dose inhaler and Respimat inhaler.
Exclusion criteria
1. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with an SGOT \>x2 ULN, SGPT \>x2 ULN, bilirubin \>x2 ULN or creatinine \>x2 ULN. 2. Patients with a history of asthma and/or total blood eosinophil count of 600 cells/mm3. 3. Patients with thyrotoxicosis, paroxysmal tachycardia (\>100 beats per minute). 4. Patients with a history of myocardial infarction within 1 year of screening visit, unstable or life-threatening cardiac arrhythmia, hospitalization 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, life-threatening pulmonary obstruction, cystic fibrosis, clinically evident bronchiectasis, significant alcohol or drug abuse or contraindications to exercise. 5. Patients who have undergone thoracotomy with pulmonary resection. 6. Patients being treated with oral beta-adrenergics or 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. 7. Patients who regularly use daytime oxygen for more than one hour per day. 8. 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. 9. Patients who have a limitation of exercise performance as a result of factors other than fatigue or exertional dyspnea. 10. Pregnant or nursing women. 11. Women of childbearing potential not using two effective methods of birth control (one barrier and one non-barrier).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Endurance Time After 6 Weeks | 6 weeks | Primary endpoint was endurance time during constant work rate ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment. Mixed effects model on log10 transformation data. Adjusted means are back transformed to report as geometric means. Standard errors (SEs) are calculated using the delta method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Borg Scale of Breathing Discomfort at Isotime After 6 Weeks | 6 weeks | Isotime is defined as the endurance time of the constant work rate exercise test of shortest duration from Baseline visit, and Week 6 of each of the three treatment periods. Borg scale rates discomfort with breathing at rest, during exercise and at end-exercise on a scale from 0=Nothing at all to 10=Maximal discomfort. |
| Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks | 6 weeks | — |
| Adjusted Mean Inspiratory Capacity at End of Exercise After 6 Weeks | 6 weeks | — |
| Adjusted Mean Borg Scale of Breathing Discomfort at Pre-exercise After 6 Weeks | 6 weeks | Borg scale rates discomfort with breathing at rest, during exercise and at end-exercise on a scale from 0=Nothing at all to 10=Maximal discomfort. |
| Adjusted Mean Borg Scale of Breathing Discomfort at End of Exercise After 6 Weeks | 6 weeks | Borg scale rates discomfort with breathing at rest, during exercise and at end-exercise on a scale from 0=Nothing at all to 10=Maximal discomfort. |
| Adjusted Mean Functional Residual Capacity 30 Minutes Pre-dose After 6 Weeks | 6 weeks | — |
| Adjusted Mean Functional Residual Capacity 1 Hour Post-dose After 6 Weeks | 6 weeks | — |
| Adjusted Mean Inspiratory Capacity 30 Minutes Pre-dose After 6 Weeks | 6 weeks | Measured using body plethysmography |
| Adjusted Mean Inspiratory Capacity 1 Hour Post-dose After 6 Weeks | 6 weeks | Measured using body plethysmography |
| Adjusted Mean Total Lung Capacity 30 Minutes Pre-dose After 6 Weeks | 6 weeks | Measured using body plethysmography |
| Adjusted Mean Total Lung Capacity 1 Hour Post-dose After 6 Weeks | 6 weeks | — |
| Adjusted Mean Inspiratory Capacity at Isotime After 6 Weeks | 6 weeks | Isotime is defined as the endurance time of the constant work rate exercise test of shortest duration from Baseline visit, and Week 6 of each of the three treatment periods. |
| Adjusted Mean Forced Expiratory Volume in 1 Second, 1 Hour Post-dose After 6 Weeks | 6 weeks | — |
| Adjusted Mean Forced Vital Capacity, 30 Minutes Pre-dose After 6 Weeks | 6 weeks | — |
| Adjusted Mean Forced Vital Capacity, 1 Hour Post-dose After 6 Weeks | 6 weeks | — |
| Adjusted Mean Peak Expiratory Flow Rate, 30 Minutes Pre-dose After 6 Weeks | 6 weeks | — |
| Adjusted Mean Peak Expiratory Flow Rate, 1 Hour Post-dose After 6 Weeks | 6 weeks | — |
| Change From Baseline to Day 43 in Blood Pressure | Baseline and Week 6 | Change from Baseline to Day 43 in Blood Pressure with spirometry. Baseline is defined as mean of pre-treatment values at a given time point. |
| Change From Baseline to Day 43 in Pulse Rate | Baseline and Week 6 | Change from Baseline to Day 43 in Pulse rate with spirometry. Baseline is defined as mean of pre-treatment values at a given time point. |
| Number of Patients With Notable Changes in Heart Rate | Baseline and Week 6 | Number of Patients with notable changes in heart rate (HR). Notable HR increase defined as \>=25% increase and on-treatment HR \> 100 bpm; Notable HR decrease defined as \>=25% decrease and on-treatment HR \< 50 bpm. |
| Number of Patients With Notable Increase in PR Intervals | Baseline and Week 6 | Number of Patients with notable increase in PR intervals. Notable PR interval increase defined as \>=25% increase and on-treatment PR interval \> 200 ms. |
| Number of Patients With Notable Increase in QRS Intervals | Baseline and Week 6 | Number of Patients with notable increase in QRS intervals. Notable QRS interval increase defined as \>=10% increase and on-treatment QRS interval \> 110 ms. |
| Adjusted Mean Forced Expiratory Volume in 1 Second, 30 Minutes Pre-dose After 6 Weeks | 6 weeks | — |
Countries
Australia, Austria, Canada, France, Germany
Participant flow
Pre-assignment details
This was a randomised, double-blind, placebo-controlled, 3-way crossover trial. The duration of each treatment period was 6 weeks with a 14 day washout period between treatments.
Participants by arm
| Arm | Count |
|---|---|
| Study Total Total number of patients treated in the study. This was a randomised, double-blind, placebo-controlled, 3-way crossover trial. 151 patients were assigned randomly to one of 3 treatment sequences in which they received each of 3 treatments. The duration of each treatment period was 6 weeks with a 14 day washout period between treatments. | 151 |
| Total | 151 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 | 5 | 0 | 3 |
| Overall Study | Other reasons not listed above | 2 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 2 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Study Total |
|---|---|
| Age, Continuous | 60.6 years STANDARD_DEVIATION 7.7 |
| Sex: Female, Male Female | 35 Participants |
| Sex: Female, Male Male | 116 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 143 | 10 / 147 | 5 / 143 |
| serious Total, serious adverse events | 3 / 143 | 3 / 147 | 3 / 143 |
Outcome results
Primary
Adjusted Mean Endurance Time After 6 Weeks
Primary endpoint was endurance time during constant work rate ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment. Mixed effects model on log10 transformation data. Adjusted means are back transformed to report as geometric means. Standard errors (SEs) are calculated using the delta method.
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Endurance Time After 6 Weeks | 369.81 seconds | Standard Error 11.941 |
| Olo 5 mcg qd | Adjusted Mean Endurance Time After 6 Weeks | 421.58 seconds | Standard Error 13.459 |
| Olo 10 mcg qd | Adjusted Mean Endurance Time After 6 Weeks | 420.72 seconds | Standard Error 13.602 |
p-value: 0.000295% CI: [1.065, 1.221]Mixed Models Analysis
p-value: 0.000395% CI: [1.062, 1.219]Mixed Models Analysis
Secondary
Adjusted Mean Borg Scale of Breathing Discomfort at End of Exercise After 6 Weeks
Borg scale rates discomfort with breathing at rest, during exercise and at end-exercise on a scale from 0=Nothing at all to 10=Maximal discomfort.
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Borg Scale of Breathing Discomfort at End of Exercise After 6 Weeks | 6.978 Scores on a scale | Standard Error 0.143 |
| Olo 5 mcg qd | Adjusted Mean Borg Scale of Breathing Discomfort at End of Exercise After 6 Weeks | 6.890 Scores on a scale | Standard Error 0.141 |
| Olo 10 mcg qd | Adjusted Mean Borg Scale of Breathing Discomfort at End of Exercise After 6 Weeks | 7.234 Scores on a scale | Standard Error 0.143 |
p-value: 0.569895% CI: [-0.391, 0.216]Mixed Models Analysis
p-value: 0.100395% CI: [-0.05, 0.561]Mixed Models Analysis
Secondary
Adjusted Mean Borg Scale of Breathing Discomfort at Isotime After 6 Weeks
Isotime is defined as the endurance time of the constant work rate exercise test of shortest duration from Baseline visit, and Week 6 of each of the three treatment periods. Borg scale rates discomfort with breathing at rest, during exercise and at end-exercise on a scale from 0=Nothing at all to 10=Maximal discomfort.
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Borg Scale of Breathing Discomfort at Isotime After 6 Weeks | 5.870 Scores on a scale | Standard Error 0.185 |
| Olo 5 mcg qd | Adjusted Mean Borg Scale of Breathing Discomfort at Isotime After 6 Weeks | 5.104 Scores on a scale | Standard Error 0.182 |
| Olo 10 mcg qd | Adjusted Mean Borg Scale of Breathing Discomfort at Isotime After 6 Weeks | 5.235 Scores on a scale | Standard Error 0.185 |
p-value: 0.000795% CI: [-1.205, -0.326]Mixed Models Analysis
p-value: 0.005195% CI: [-1.077, -0.192]Mixed Models Analysis
Secondary
Adjusted Mean Borg Scale of Breathing Discomfort at Pre-exercise After 6 Weeks
Borg scale rates discomfort with breathing at rest, during exercise and at end-exercise on a scale from 0=Nothing at all to 10=Maximal discomfort.
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Borg Scale of Breathing Discomfort at Pre-exercise After 6 Weeks | 0.288 Scores on a scale | Standard Error 0.041 |
| Olo 5 mcg qd | Adjusted Mean Borg Scale of Breathing Discomfort at Pre-exercise After 6 Weeks | 0.185 Scores on a scale | Standard Error 0.04 |
| Olo 10 mcg qd | Adjusted Mean Borg Scale of Breathing Discomfort at Pre-exercise After 6 Weeks | 0.224 Scores on a scale | Standard Error 0.041 |
p-value: 0.044795% CI: [-0.204, -0.002]Mixed Models Analysis
p-value: 0.213295% CI: [-0.166, 0.037]Mixed Models Analysis
Secondary
Adjusted Mean Forced Expiratory Volume in 1 Second, 1 Hour Post-dose After 6 Weeks
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Forced Expiratory Volume in 1 Second, 1 Hour Post-dose After 6 Weeks | 1.473 liters | Standard Error 0.019 |
| Olo 5 mcg qd | Adjusted Mean Forced Expiratory Volume in 1 Second, 1 Hour Post-dose After 6 Weeks | 1.698 liters | Standard Error 0.019 |
| Olo 10 mcg qd | Adjusted Mean Forced Expiratory Volume in 1 Second, 1 Hour Post-dose After 6 Weeks | 1.699 liters | Standard Error 0.019 |
p-value: <0.000195% CI: [0.191, 0.258]Mixed Models Analysis
p-value: <0.000195% CI: [0.193, 0.259]Mixed Models Analysis
Secondary
Adjusted Mean Forced Expiratory Volume in 1 Second, 30 Minutes Pre-dose After 6 Weeks
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Forced Expiratory Volume in 1 Second, 30 Minutes Pre-dose After 6 Weeks | 1.475 liters | Standard Error 0.017 |
| Olo 5 mcg qd | Adjusted Mean Forced Expiratory Volume in 1 Second, 30 Minutes Pre-dose After 6 Weeks | 1.564 liters | Standard Error 0.017 |
| Olo 10 mcg qd | Adjusted Mean Forced Expiratory Volume in 1 Second, 30 Minutes Pre-dose After 6 Weeks | 1.576 liters | Standard Error 0.017 |
p-value: <0.000195% CI: [0.056, 0.123]Mixed Models Analysis
p-value: <0.000195% CI: [0.068, 0.134]Mixed Models Analysis
Secondary
Adjusted Mean Forced Vital Capacity, 1 Hour Post-dose After 6 Weeks
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Forced Vital Capacity, 1 Hour Post-dose After 6 Weeks | 3.187 liters | Standard Error 0.034 |
| Olo 5 mcg qd | Adjusted Mean Forced Vital Capacity, 1 Hour Post-dose After 6 Weeks | 3.471 liters | Standard Error 0.034 |
| Olo 10 mcg qd | Adjusted Mean Forced Vital Capacity, 1 Hour Post-dose After 6 Weeks | 3.477 liters | Standard Error 0.034 |
p-value: <0.000195% CI: [0.227, 0.342]Mixed Models Analysis
p-value: <0.000195% CI: [0.233, 0.348]Mixed Models Analysis
Secondary
Adjusted Mean Forced Vital Capacity, 30 Minutes Pre-dose After 6 Weeks
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Forced Vital Capacity, 30 Minutes Pre-dose After 6 Weeks | 3.212 liters | Standard Error 0.037 |
| Olo 5 mcg qd | Adjusted Mean Forced Vital Capacity, 30 Minutes Pre-dose After 6 Weeks | 3.319 liters | Standard Error 0.037 |
| Olo 10 mcg qd | Adjusted Mean Forced Vital Capacity, 30 Minutes Pre-dose After 6 Weeks | 3.310 liters | Standard Error 0.037 |
p-value: 0.000695% CI: [0.046, 0.167]Mixed Models Analysis
p-value: 0.001795% CI: [0.037, 0.158]Mixed Models Analysis
Secondary
Adjusted Mean Functional Residual Capacity 1 Hour Post-dose After 6 Weeks
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Functional Residual Capacity 1 Hour Post-dose After 6 Weeks | 4.950 liters | Standard Error 0.064 |
| Olo 5 mcg qd | Adjusted Mean Functional Residual Capacity 1 Hour Post-dose After 6 Weeks | 4.740 liters | Standard Error 0.063 |
| Olo 10 mcg qd | Adjusted Mean Functional Residual Capacity 1 Hour Post-dose After 6 Weeks | 4.577 liters | Standard Error 0.064 |
p-value: 0.001595% CI: [-0.339, -0.081]Mixed Models Analysis
p-value: <0.000195% CI: [-0.503, -0.243]Mixed Models Analysis
Secondary
Adjusted Mean Functional Residual Capacity 30 Minutes Pre-dose After 6 Weeks
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Functional Residual Capacity 30 Minutes Pre-dose After 6 Weeks | 4.977 liters | Standard Error 0.062 |
| Olo 5 mcg qd | Adjusted Mean Functional Residual Capacity 30 Minutes Pre-dose After 6 Weeks | 4.855 liters | Standard Error 0.061 |
| Olo 10 mcg qd | Adjusted Mean Functional Residual Capacity 30 Minutes Pre-dose After 6 Weeks | 4.862 liters | Standard Error 0.062 |
p-value: 0.078495% CI: [-0.258, 0.014]Mixed Models Analysis
p-value: 0.101395% CI: [-0.252, 0.023]Mixed Models Analysis
Secondary
Adjusted Mean Inspiratory Capacity 1 Hour Post-dose After 6 Weeks
Measured using body plethysmography
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Inspiratory Capacity 1 Hour Post-dose After 6 Weeks | 2.221 liters | Standard Error 0.04 |
| Olo 5 mcg qd | Adjusted Mean Inspiratory Capacity 1 Hour Post-dose After 6 Weeks | 2.427 liters | Standard Error 0.04 |
| Olo 10 mcg qd | Adjusted Mean Inspiratory Capacity 1 Hour Post-dose After 6 Weeks | 2.437 liters | Standard Error 0.04 |
p-value: <0.000195% CI: [0.136, 0.275]Mixed Models Analysis
p-value: <0.000195% CI: [0.146, 0.285]Mixed Models Analysis
Secondary
Adjusted Mean Inspiratory Capacity 30 Minutes Pre-dose After 6 Weeks
Measured using body plethysmography
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Inspiratory Capacity 30 Minutes Pre-dose After 6 Weeks | 2.170 liters | Standard Error 0.04 |
| Olo 5 mcg qd | Adjusted Mean Inspiratory Capacity 30 Minutes Pre-dose After 6 Weeks | 2.289 liters | Standard Error 0.04 |
| Olo 10 mcg qd | Adjusted Mean Inspiratory Capacity 30 Minutes Pre-dose After 6 Weeks | 2.262 liters | Standard Error 0.04 |
p-value: 0.000595% CI: [0.052, 0.185]Mixed Models Analysis
p-value: 0.007395% CI: [0.025, 0.159]Mixed Models Analysis
Secondary
Adjusted Mean Inspiratory Capacity at End of Exercise After 6 Weeks
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Inspiratory Capacity at End of Exercise After 6 Weeks | 1.887 liters | Standard Error 0.035 |
| Olo 5 mcg qd | Adjusted Mean Inspiratory Capacity at End of Exercise After 6 Weeks | 2.067 liters | Standard Error 0.035 |
| Olo 10 mcg qd | Adjusted Mean Inspiratory Capacity at End of Exercise After 6 Weeks | 2.024 liters | Standard Error 0.035 |
p-value: <0.000195% CI: [0.107, 0.252]Mixed Models Analysis
p-value: 0.000395% CI: [0.064, 0.21]Mixed Models Analysis
Secondary
Adjusted Mean Inspiratory Capacity at Isotime After 6 Weeks
Isotime is defined as the endurance time of the constant work rate exercise test of shortest duration from Baseline visit, and Week 6 of each of the three treatment periods.
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Inspiratory Capacity at Isotime After 6 Weeks | 1.917 liters | Standard Error 0.038 |
| Olo 5 mcg qd | Adjusted Mean Inspiratory Capacity at Isotime After 6 Weeks | 2.099 liters | Standard Error 0.038 |
| Olo 10 mcg qd | Adjusted Mean Inspiratory Capacity at Isotime After 6 Weeks | 2.091 liters | Standard Error 0.038 |
p-value: <0.000195% CI: [0.112, 0.252]Mixed Models Analysis
p-value: <0.000195% CI: [0.104, 0.245]Mixed Models Analysis
Secondary
Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks | 2.220 liters | Standard Error 0.032 |
| Olo 5 mcg qd | Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks | 2.478 liters | Standard Error 0.032 |
| Olo 10 mcg qd | Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks | 2.513 liters | Standard Error 0.032 |
p-value: <0.000195% CI: [0.191, 0.325]Mixed Models Analysis
p-value: <0.000195% CI: [0.226, 0.362]Mixed Models Analysis
Secondary
Adjusted Mean Peak Expiratory Flow Rate, 1 Hour Post-dose After 6 Weeks
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Peak Expiratory Flow Rate, 1 Hour Post-dose After 6 Weeks | 4.363 liters/second | Standard Error 0.063 |
| Olo 5 mcg qd | Adjusted Mean Peak Expiratory Flow Rate, 1 Hour Post-dose After 6 Weeks | 4.949 liters/second | Standard Error 0.063 |
| Olo 10 mcg qd | Adjusted Mean Peak Expiratory Flow Rate, 1 Hour Post-dose After 6 Weeks | 4.981 liters/second | Standard Error 0.063 |
p-value: <0.000195% CI: [0.502, 0.734]Mixed Models Analysis
p-value: <0.000195% CI: [0.47, 0.701]Mixed Models Analysis
Secondary
Adjusted Mean Peak Expiratory Flow Rate, 30 Minutes Pre-dose After 6 Weeks
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Peak Expiratory Flow Rate, 30 Minutes Pre-dose After 6 Weeks | 4.374 liters/second | Standard Error 0.059 |
| Olo 5 mcg qd | Adjusted Mean Peak Expiratory Flow Rate, 30 Minutes Pre-dose After 6 Weeks | 4.692 liters/second | Standard Error 0.059 |
| Olo 10 mcg qd | Adjusted Mean Peak Expiratory Flow Rate, 30 Minutes Pre-dose After 6 Weeks | 4.677 liters/second | Standard Error 0.059 |
p-value: <0.000195% CI: [0.192, 0.414]Mixed Models Analysis
p-value: <0.000195% CI: [0.207, 0.429]Mixed Models Analysis
Secondary
Adjusted Mean Total Lung Capacity 1 Hour Post-dose After 6 Weeks
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Total Lung Capacity 1 Hour Post-dose After 6 Weeks | 7.156 liters | Standard Error 0.066 |
| Olo 5 mcg qd | Adjusted Mean Total Lung Capacity 1 Hour Post-dose After 6 Weeks | 7.142 liters | Standard Error 0.066 |
| Olo 10 mcg qd | Adjusted Mean Total Lung Capacity 1 Hour Post-dose After 6 Weeks | 6.997 liters | Standard Error 0.067 |
p-value: 0.830295% CI: [-0.146, 0.118]Mixed Models Analysis
p-value: 0.020295% CI: [-0.292, -0.025]Mixed Models Analysis
Secondary
Adjusted Mean Total Lung Capacity 30 Minutes Pre-dose After 6 Weeks
Measured using body plethysmography
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and any evaluable post-dose data for the primary endpoint. Only patients who have baseline and at least one post-baseline measurement available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Total Lung Capacity 30 Minutes Pre-dose After 6 Weeks | 7.142 liters | Standard Error 0.064 |
| Olo 5 mcg qd | Adjusted Mean Total Lung Capacity 30 Minutes Pre-dose After 6 Weeks | 7.148 liters | Standard Error 0.063 |
| Olo 10 mcg qd | Adjusted Mean Total Lung Capacity 30 Minutes Pre-dose After 6 Weeks | 7.121 liters | Standard Error 0.064 |
p-value: 0.923995% CI: [-0.115, 0.127]Mixed Models Analysis
p-value: 0.736895% CI: [-0.144, 0.102]Mixed Models Analysis
Secondary
Change From Baseline to Day 43 in Blood Pressure
Change from Baseline to Day 43 in Blood Pressure with spirometry. Baseline is defined as mean of pre-treatment values at a given time point.
Time frame: Baseline and Week 6
Population: Treated set. Statistics only include patients with both a baseline and a post dose value.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to Day 43 in Blood Pressure | Systolic blood pressure | -3.5 mmHg | Standard Deviation 15.64 |
| Placebo | Change From Baseline to Day 43 in Blood Pressure | Diastolic blood pressure | -1.7 mmHg | Standard Deviation 7.9 |
| Olo 5 mcg qd | Change From Baseline to Day 43 in Blood Pressure | Systolic blood pressure | -2.7 mmHg | Standard Deviation 16.82 |
| Olo 5 mcg qd | Change From Baseline to Day 43 in Blood Pressure | Diastolic blood pressure | -1.8 mmHg | Standard Deviation 8.36 |
| Olo 10 mcg qd | Change From Baseline to Day 43 in Blood Pressure | Systolic blood pressure | -3.3 mmHg | Standard Deviation 16.47 |
| Olo 10 mcg qd | Change From Baseline to Day 43 in Blood Pressure | Diastolic blood pressure | -1.1 mmHg | Standard Deviation 9.16 |
Secondary
Change From Baseline to Day 43 in Pulse Rate
Change from Baseline to Day 43 in Pulse rate with spirometry. Baseline is defined as mean of pre-treatment values at a given time point.
Time frame: Baseline and Week 6
Population: Treated set. Statistics only include patients with both a baseline and a post dose value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Day 43 in Pulse Rate | -5.1 beats/min | Standard Deviation 13.63 |
| Olo 5 mcg qd | Change From Baseline to Day 43 in Pulse Rate | -5.1 beats/min | Standard Deviation 13.88 |
| Olo 10 mcg qd | Change From Baseline to Day 43 in Pulse Rate | -3 beats/min | Standard Deviation 12.61 |
Secondary
Number of Patients With Notable Changes in Heart Rate
Number of Patients with notable changes in heart rate (HR). Notable HR increase defined as \>=25% increase and on-treatment HR \> 100 bpm; Notable HR decrease defined as \>=25% decrease and on-treatment HR \< 50 bpm.
Time frame: Baseline and Week 6
Population: Treated set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients With Notable Changes in Heart Rate | 30 min pre-dose: increase (N=138, 139, 140) | 0.7 percentage of participants |
| Placebo | Number of Patients With Notable Changes in Heart Rate | 30 min pre-dose: decrease (N=138, 139, 140) | 1.4 percentage of participants |
| Placebo | Number of Patients With Notable Changes in Heart Rate | 30 min pre-dose: no change (N=138, 139, 140) | 97.8 percentage of participants |
| Placebo | Number of Patients With Notable Changes in Heart Rate | 40 min post-dose: increase (N=138, 141, 138) | 2.2 percentage of participants |
| Placebo | Number of Patients With Notable Changes in Heart Rate | 40 min post-dose: decrease (N=138, 141, 138) | 4.3 percentage of participants |
| Placebo | Number of Patients With Notable Changes in Heart Rate | 40 min post-dose: no change (N=138, 141, 138) | 93.5 percentage of participants |
| Olo 5 mcg qd | Number of Patients With Notable Changes in Heart Rate | 40 min post-dose: no change (N=138, 141, 138) | 93.6 percentage of participants |
| Olo 5 mcg qd | Number of Patients With Notable Changes in Heart Rate | 30 min pre-dose: increase (N=138, 139, 140) | 0.7 percentage of participants |
| Olo 5 mcg qd | Number of Patients With Notable Changes in Heart Rate | 40 min post-dose: increase (N=138, 141, 138) | 1.4 percentage of participants |
| Olo 5 mcg qd | Number of Patients With Notable Changes in Heart Rate | 40 min post-dose: decrease (N=138, 141, 138) | 5.0 percentage of participants |
| Olo 5 mcg qd | Number of Patients With Notable Changes in Heart Rate | 30 min pre-dose: decrease (N=138, 139, 140) | 2.9 percentage of participants |
| Olo 5 mcg qd | Number of Patients With Notable Changes in Heart Rate | 30 min pre-dose: no change (N=138, 139, 140) | 96.4 percentage of participants |
| Olo 10 mcg qd | Number of Patients With Notable Changes in Heart Rate | 30 min pre-dose: decrease (N=138, 139, 140) | 2.1 percentage of participants |
| Olo 10 mcg qd | Number of Patients With Notable Changes in Heart Rate | 30 min pre-dose: no change (N=138, 139, 140) | 97.1 percentage of participants |
| Olo 10 mcg qd | Number of Patients With Notable Changes in Heart Rate | 40 min post-dose: no change (N=138, 141, 138) | 90.6 percentage of participants |
| Olo 10 mcg qd | Number of Patients With Notable Changes in Heart Rate | 40 min post-dose: increase (N=138, 141, 138) | 2.9 percentage of participants |
| Olo 10 mcg qd | Number of Patients With Notable Changes in Heart Rate | 30 min pre-dose: increase (N=138, 139, 140) | 0.7 percentage of participants |
| Olo 10 mcg qd | Number of Patients With Notable Changes in Heart Rate | 40 min post-dose: decrease (N=138, 141, 138) | 6.5 percentage of participants |
Secondary
Number of Patients With Notable Increase in PR Intervals
Number of Patients with notable increase in PR intervals. Notable PR interval increase defined as \>=25% increase and on-treatment PR interval \> 200 ms.
Time frame: Baseline and Week 6
Population: Treated set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients With Notable Increase in PR Intervals | 30 min pre-dose: increase (N=137, 137, 139) | 0.0 percentage of participants |
| Placebo | Number of Patients With Notable Increase in PR Intervals | 30 min pre-dose: no increase (N=137, 137, 139) | 100.0 percentage of participants |
| Placebo | Number of Patients With Notable Increase in PR Intervals | 40 min post-dose: increase (N=137, 140, 137) | 0.0 percentage of participants |
| Placebo | Number of Patients With Notable Increase in PR Intervals | 40 min post-dose: no increase (N=137, 140, 137) | 100.0 percentage of participants |
| Olo 5 mcg qd | Number of Patients With Notable Increase in PR Intervals | 40 min post-dose: no increase (N=137, 140, 137) | 100.0 percentage of participants |
| Olo 5 mcg qd | Number of Patients With Notable Increase in PR Intervals | 30 min pre-dose: increase (N=137, 137, 139) | 0.7 percentage of participants |
| Olo 5 mcg qd | Number of Patients With Notable Increase in PR Intervals | 40 min post-dose: increase (N=137, 140, 137) | 0.0 percentage of participants |
| Olo 5 mcg qd | Number of Patients With Notable Increase in PR Intervals | 30 min pre-dose: no increase (N=137, 137, 139) | 99.3 percentage of participants |
| Olo 10 mcg qd | Number of Patients With Notable Increase in PR Intervals | 40 min post-dose: no increase (N=137, 140, 137) | 99.3 percentage of participants |
| Olo 10 mcg qd | Number of Patients With Notable Increase in PR Intervals | 30 min pre-dose: no increase (N=137, 137, 139) | 100.0 percentage of participants |
| Olo 10 mcg qd | Number of Patients With Notable Increase in PR Intervals | 40 min post-dose: increase (N=137, 140, 137) | 0.7 percentage of participants |
| Olo 10 mcg qd | Number of Patients With Notable Increase in PR Intervals | 30 min pre-dose: increase (N=137, 137, 139) | 0.0 percentage of participants |
Secondary
Number of Patients With Notable Increase in QRS Intervals
Number of Patients with notable increase in QRS intervals. Notable QRS interval increase defined as \>=10% increase and on-treatment QRS interval \> 110 ms.
Time frame: Baseline and Week 6
Population: Treated set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients With Notable Increase in QRS Intervals | 30 min pre-dose: increase (N=138, 139, 140) | 0.7 percentage of participants |
| Placebo | Number of Patients With Notable Increase in QRS Intervals | 30 min pre-dose: no increase (N=138, 139, 140) | 99.3 percentage of participants |
| Placebo | Number of Patients With Notable Increase in QRS Intervals | 40 min post-dose: increase (N=138, 141, 138) | 0.7 percentage of participants |
| Placebo | Number of Patients With Notable Increase in QRS Intervals | 40 min post-dose: no increase (N=138, 141, 138) | 99.3 percentage of participants |
| Olo 5 mcg qd | Number of Patients With Notable Increase in QRS Intervals | 40 min post-dose: no increase (N=138, 141, 138) | 99.3 percentage of participants |
| Olo 5 mcg qd | Number of Patients With Notable Increase in QRS Intervals | 30 min pre-dose: increase (N=138, 139, 140) | 0.7 percentage of participants |
| Olo 5 mcg qd | Number of Patients With Notable Increase in QRS Intervals | 40 min post-dose: increase (N=138, 141, 138) | 0.7 percentage of participants |
| Olo 5 mcg qd | Number of Patients With Notable Increase in QRS Intervals | 30 min pre-dose: no increase (N=138, 139, 140) | 99.3 percentage of participants |
| Olo 10 mcg qd | Number of Patients With Notable Increase in QRS Intervals | 40 min post-dose: no increase (N=138, 141, 138) | 99.3 percentage of participants |
| Olo 10 mcg qd | Number of Patients With Notable Increase in QRS Intervals | 30 min pre-dose: no increase (N=138, 139, 140) | 100.0 percentage of participants |
| Olo 10 mcg qd | Number of Patients With Notable Increase in QRS Intervals | 40 min post-dose: increase (N=138, 141, 138) | 0.7 percentage of participants |
| Olo 10 mcg qd | Number of Patients With Notable Increase in QRS Intervals | 30 min pre-dose: increase (N=138, 139, 140) | 0.0 percentage of participants |