Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The primary objective of this study is to compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination (2.5/5 µg; 5/5 µg) with placebo on exercise tolerance after 12 weeks of treatment in patients with COPD.
Interventions
DEVICERespimat inhaler
Respimat inhaler
DRUGtiotropium+olodaterol (low dose)
2.5 µg tiotropium + 5 µg olodaterol
DRUGtiotropium + olodaterol (high dose)
5 µg tiotropium + 5 µg olodaterol
DRUGplacebo to tiotropium+olodaterol
comparator
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions. 2. 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, at visit 1: a post-bronchodilator 30% \<= FEV1 \<80% of predicted normal (ECSC) and a post-bronchodilator FEV1/FVC \<70% at Visit 1 3. Male or female patients, between 40 and 75 years (inclusive) of age on day of signing informed consent. 4. 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. 5. Patients must be able to perform technically acceptable pulmonary function tests (spirometry), must be able to complete multiple symptom-limited cycle ergometry tests (and for a subset also shuttle walk tests), as required in the protocol. 6. Patients must be able to inhale medication in a competent manner from the RESPIMAT inhaler and from a metered dose inhaler (MDI).
Exclusion criteria
1. Patients with a significant disease other than COPD 2. 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 will be excluded regardless of clinical condition 3. Patients with a history of asthma 4. A diagnosis of thyrotoxicosis 5. A diagnosis of paroxysmal tachycardia (\>100 beats per minute) 6. A history of myocardial infarction within 1 year of screening visit (Visit 1) 7. Unstable or life-threatening cardiac arrhythmia 8. Hospitalized for heart failure within the past year 9. Known active tuberculosis 10. A malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years 11. A history of life-threatening pulmonary obstruction and patients with chronic respiratory failure 12. A history of cystic fibrosis 13. Clinically evident bronchiectasis 14. A history of significant alcohol or drug abuse 15. Any contraindications for exercise testing 16. Patients who have undergone thoracotomy with pulmonary resection 17. Patients being treated with any oral ß-adrenergics 18. 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 19. Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigator's opinion will be unable to abstain from the use of oxygen therapy during clinic visits 20. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the screening visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program 21. Patients who have a limitation of exercise performance as a result of factors other than fatigue or exertional dyspnoea or morbid obesity 22. Patients with an endurance time \>=25 minutes during the training (Visit 2) or baseline (Visit 3) constant work rate cycle ergometry 23. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit (Visit 1) 24. Patients with known hypersensitivity to ß-adrenergic drugs, anticholinergic drugs, BAC, EDTA or any other component of the RESPIMAT inhalation solution delivery system 25. Pregnant or nursing women 26. Women of childbearing potential not using a highly effective method of birth control. Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years 27. Patients who have previously been randomized in this study or are currently participating in another study 28. Patients who are unable to comply with pulmonary medication restrictions prior to randomization At sites performing the shuttle walk tests, patients with the following criteria will be excluded from the shuttle walk tests: 29. Patients who complete level 12 at the incremental shuttle walk test at visit 1a. 30. Patients with an endurance time \>=15 minutes during the training (Visit 2a) or baseline (visit 3a) endurance shuttle walk test.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 12 Weeks | 12 weeks | Primary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 12 weeks of treatment. The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Inspiratory Capacity at Pre-exercise After 12 Weeks | 12 weeks | Secondary endpoint was pre-exercise inspiratory capacity (IC) before constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap) after 12 weeks of treatment. |
| Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) on Day 1 | 1 day | Secondary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity on Day 1. Analysis of covariance model on log10 transformation data. Adjusted means are back transformed to report in original units. Standard errors (SEs) are calculated using the delta method. |
| Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 6 Weeks Treatment | 6 weeks | Secondary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment.The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean. |
| Adjusted Mean Inspiratory Capacity at Pre-exercise After 1 Day | 1 day | Secondary endpoint was pre-exercise inspiratory capacity (IC) during constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap) on Day 1. |
| Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks | 6 weeks | Secondary endpoint was pre-exercise inspiratory capacity (IC) during constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap) after 6 weeks of treatment. |
| Adjusted Mean Endurance Time During Endurance Shuttle Walk Test (ESWT) After 12 Weeks | 12 weeks | Key secondary endpoint was endurance time during endurance shuttle walk test to symptom limitation at 85% of predicted maximum oxygen consumption (VO2) peak after 12 weeks of treatment. The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean. |
| Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 6 | 6 weeks | Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment. The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates favorable results. |
| Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 12 | 12 weeks | Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 12 weeks of treatment. The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates favorable results. |
| Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) on Day 1 | 1 day | Secondary endpoint was adjusted mean 1-hour, post-dose Forced Expiratory Volume in one second (FEV1) observed on day 1 |
| Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 6 Weeks | 6 weeks | Secondary endpoint was adjusted mean 1-hour, post-dose Forced Expiratory Volume in one second (FEV1) observed after 6 weeks of treatment |
| Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 12 Weeks | 12 weeks | Secondary endpoint was adjusted mean 1-hour, post-dose Forced Expiratory Volume in one second (FEV1) observed after 12 weeks of treatment |
| Adjusted Mean Slope of the Intensity of Breathing Discomfort on Day 1 | 1 day | Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 1 day of treatment. The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates slowing down in decline in breathing, i.e., favorable results. |
Countries
Argentina, Canada, Finland, France, Germany, Hungary, Italy, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
This was a randomised, placebo-controlled, double-blind, parallel-group comparison of once daily treatment with orally inhaled Tiotropium+Olodaterol Fixed Dose Combination (FDC) (2.5/5.0 µg; 5.0/5.0 µg) with placebo over 12 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Placebo once daily 2 puffs, solution for inhalation Respimat
placebo to tiotropium+olodaterol: comparator | 132 |
| Tio+Olo 2.5 / 5.0 µg Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning. | 133 |
| Tio+Olo 5.0 / 5.0 µg Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning. | 139 |
| Total | 404 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 7 | 5 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Other reason not described above | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Tio+Olo 2.5 / 5.0 µg | Tio+Olo 5.0 / 5.0 µg | Total |
|---|---|---|---|---|
| Age, Continuous | 60.8 years STANDARD_DEVIATION 7.6 | 61.9 years STANDARD_DEVIATION 7.3 | 63.1 years STANDARD_DEVIATION 7.5 | 62.0 years STANDARD_DEVIATION 7.5 |
| Sex: Female, Male Female | 45 Participants | 46 Participants | 44 Participants | 135 Participants |
| Sex: Female, Male Male | 87 Participants | 87 Participants | 95 Participants | 269 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 | 25 / 132 | 25 / 133 | 16 / 139 |
| serious Total, serious adverse events | 5 / 132 | 9 / 133 | 4 / 139 |
Outcome results
Primary
Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 12 Weeks
Primary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 12 weeks of treatment. The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean.
Time frame: 12 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 12 Weeks | 463.63 seconds | Standard Error 18.813 |
| Tio+Olo 2.5 / 5.0 µg | Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 12 Weeks | 503.64 seconds | Standard Error 19.642 |
| Tio+Olo 5.0 / 5.0 µg | Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 12 Weeks | 527.51 seconds | Standard Error 20.154 |
Comparison: Treatment ratio between Tio+Olo 5.0/5.0 and placebo. This treatment comparison is the first one in the alpha-protected hierarchical testing chain.p-value: 0.020995% CI: [1.02, 1.269]Mixed Models Analysis
Comparison: Treatment ratio between Tio+Olo 2.5/5.0 and placebo. This treatment comparison is the second 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: 0.141995% CI: [0.973, 1.213]Mixed Models Analysis
Comparison: Treatment ratio between Tio+Olo 5.0/5.0 and Tio+Olo 2.5/5.0. This treatment comparison is not included in the alpha-protected hierarchical testing chain.p-value: 0.39795% CI: [0.941, 1.166]Mixed Models Analysis
Secondary
Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 12 Weeks
Secondary endpoint was adjusted mean 1-hour, post-dose Forced Expiratory Volume in one second (FEV1) observed after 12 weeks of treatment
Time frame: 12 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 12 Weeks | 1.527 liters | Standard Error 0.02 |
| Tio+Olo 2.5 / 5.0 µg | Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 12 Weeks | 1.784 liters | Standard Error 0.019 |
| Tio+Olo 5.0 / 5.0 µg | Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 12 Weeks | 1.778 liters | Standard Error 0.019 |
p-value: <0.000195% CI: [0.196, 0.305]Mixed Models Analysis
p-value: <0.000195% CI: [0.202, 0.312]Mixed Models Analysis
p-value: 0.815695% CI: [-0.06, 0.047]Mixed Models Analysis
Secondary
Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 6 Weeks
Secondary endpoint was adjusted mean 1-hour, post-dose Forced Expiratory Volume in one second (FEV1) observed after 6 weeks of treatment
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 6 Weeks | 1.517 liters | Standard Error 0.02 |
| Tio+Olo 2.5 / 5.0 µg | Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 6 Weeks | 1.790 liters | Standard Error 0.019 |
| Tio+Olo 5.0 / 5.0 µg | Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 6 Weeks | 1.763 liters | Standard Error 0.019 |
p-value: <0.000195% CI: [0.192, 0.3]Mixed Models Analysis
p-value: <0.000195% CI: [0.218, 0.328]Mixed Models Analysis
p-value: 0.323695% CI: [-0.08, 0.027]Mixed Models Analysis
Secondary
Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) on Day 1
Secondary endpoint was adjusted mean 1-hour, post-dose Forced Expiratory Volume in one second (FEV1) observed on day 1
Time frame: 1 day
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) on Day 1 | 1.509 liters | Standard Error 0.02 |
| Tio+Olo 2.5 / 5.0 µg | Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) on Day 1 | 1.693 liters | Standard Error 0.019 |
| Tio+Olo 5.0 / 5.0 µg | Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) on Day 1 | 1.679 liters | Standard Error 0.019 |
p-value: <0.000195% CI: [0.116, 0.224]Mixed Models Analysis
p-value: <0.000195% CI: [0.129, 0.239]Mixed Models Analysis
p-value: 0.610595% CI: [-0.067, 0.04]Mixed Models Analysis
Secondary
Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 6 Weeks Treatment
Secondary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment.The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean.
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 6 Weeks Treatment | 427.74 seconds | Standard Error 17.093 |
| Tio+Olo 2.5 / 5.0 µg | Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 6 Weeks Treatment | 522.26 seconds | Standard Error 20.232 |
| Tio+Olo 5.0 / 5.0 µg | Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 6 Weeks Treatment | 525.62 seconds | Standard Error 19.99 |
Comparison: Treatment ratio between Tio+Olo 5.0/5.0 and placebo. Hypothesis test is descriptivep-value: 0.000295% CI: [1.103, 1.37]Mixed Models Analysis
Comparison: Treatment ratio between Tio+Olo 2.5/5.0 and placebo. Hypothesis test is descriptive.p-value: 0.000495% CI: [1.095, 1.362]Mixed Models Analysis
Comparison: Treatment ratio between Tio+Olo 5.0/5.0 and Tio+Olo 2.5/5.0. Hypothesis test is descriptive.p-value: 0.906295% CI: [0.905, 1.12]Mixed Models Analysis
Secondary
Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) on Day 1
Secondary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity on Day 1. Analysis of covariance model on log10 transformation data. Adjusted means are back transformed to report in original units. Standard errors (SEs) are calculated using the delta method.
Time frame: 1 day
Population: Visit 4 Set. All randomized patients dispensed medication, were documented to have taken any dose of study medication, and had evaluable measurements of endurance time at Baseline (Visit 3) and at Visit 4 (Day 1) during CWRCE. Patients were assigned to the Visit 4 set after implementation of data handling rules that set measurements to missing.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) on Day 1 | 478.59 seconds | Standard Error 17.861 |
| Tio+Olo 2.5 / 5.0 µg | Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) on Day 1 | 527.69 seconds | Standard Error 19.67 |
| Tio+Olo 5.0 / 5.0 µg | Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) on Day 1 | 538.76 seconds | Standard Error 19.715 |
Comparison: Treatment ratio between Tio+Olo 5.0/5.0 and placebop-value: 0.024595% CI: [1.015, 1.248]ANCOVA
Comparison: Treatment ratio between Tio+Olo 2.5/5.0 and placebop-value: 0.065595% CI: [0.994, 1.223]ANCOVA
Comparison: Treatment ratio between Tio+Olo 5.0/5.0 and Tio+Olo 2.5/5.0p-value: 0.691295% CI: [0.921, 1.132]ANCOVA
Secondary
Adjusted Mean Endurance Time During Endurance Shuttle Walk Test (ESWT) After 12 Weeks
Key secondary endpoint was endurance time during endurance shuttle walk test to symptom limitation at 85% of predicted maximum oxygen consumption (VO2) peak after 12 weeks of treatment. The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean.
Time frame: 12 weeks
Population: Endurance shuttle walk test (ESWT) substudy set - This patient set included all patients in the Treated Set who had given informed consent for participating in the ESWT substudy and had a baseline and at least one post-baseline measurement during ESWT before or at Week 12 for the key secondary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Endurance Time During Endurance Shuttle Walk Test (ESWT) After 12 Weeks | 311.41 seconds | Standard Error 22.519 |
| Tio+Olo 2.5 / 5.0 µg | Adjusted Mean Endurance Time During Endurance Shuttle Walk Test (ESWT) After 12 Weeks | 377.20 seconds | Standard Error 25.942 |
| Tio+Olo 5.0 / 5.0 µg | Adjusted Mean Endurance Time During Endurance Shuttle Walk Test (ESWT) After 12 Weeks | 376.39 seconds | Standard Error 25.033 |
Comparison: Treatment ratio between Tio+Olo 5.0/5.0 and placebo. Since the hierarchical testing chain has been broken, even though this treatment comparison is included as the 3rd one in the alpha-protected hierarchical testing chain, this hypothesis test is descriptive only.p-value: 0.055295% CI: [0.996, 1.467]Mixed Models Analysis
Comparison: Treatment ratio between Tio+Olo 2.5/5.0 and placebop-value: 0.056295% CI: [0.995, 1.475]Mixed Models Analysis
Comparison: Treatment ratio between Tio+Olo 5.0/5.0 and Tio+Olo 2.5/5.0. This treatment comparison is not included in the alpha-protected hierarchical testing chain.p-value: 0.982295% CI: [0.826, 1.205]Mixed Models Analysis
Secondary
Adjusted Mean Inspiratory Capacity at Pre-exercise After 12 Weeks
Secondary endpoint was pre-exercise inspiratory capacity (IC) before constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap) after 12 weeks of treatment.
Time frame: 12 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Inspiratory Capacity at Pre-exercise After 12 Weeks | 2.390 liters | Standard Error 0.038 |
| Tio+Olo 2.5 / 5.0 µg | Adjusted Mean Inspiratory Capacity at Pre-exercise After 12 Weeks | 2.597 liters | Standard Error 0.036 |
| Tio+Olo 5.0 / 5.0 µg | Adjusted Mean Inspiratory Capacity at Pre-exercise After 12 Weeks | 2.624 liters | Standard Error 0.035 |
p-value: <0.000195% CI: [0.133, 0.336]Mixed Models Analysis
p-value: <0.000195% CI: [0.105, 0.309]Mixed Models Analysis
p-value: 0.589295% CI: [-0.072, 0.126]Mixed Models Analysis
Secondary
Adjusted Mean Inspiratory Capacity at Pre-exercise After 1 Day
Secondary endpoint was pre-exercise inspiratory capacity (IC) during constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap) on Day 1.
Time frame: 1 day
Population: Visit 4 Set. All randomized patients dispensed medication, were documented to have taken any dose of study medication, and had evaluable measurements of endurance time at Baseline (Visit 3) and at Visit 4 (Day 1) during CWRCE. Patients were assigned to the Visit 4 set after implementation of data handling rules that set measurements to missing.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Inspiratory Capacity at Pre-exercise After 1 Day | 2.440 liters | Standard Error 0.041 |
| Tio+Olo 2.5 / 5.0 µg | Adjusted Mean Inspiratory Capacity at Pre-exercise After 1 Day | 2.642 liters | Standard Error 0.041 |
| Tio+Olo 5.0 / 5.0 µg | Adjusted Mean Inspiratory Capacity at Pre-exercise After 1 Day | 2.605 liters | Standard Error 0.041 |
p-value: 0.000695% CI: [0.088, 0.316]ANCOVA
p-value: 0.004995% CI: [0.051, 0.279]ANCOVA
p-value: 0.516295% CI: [-0.151, 0.076]ANCOVA
Secondary
Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks
Secondary endpoint was pre-exercise inspiratory capacity (IC) during constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap) after 6 weeks of treatment.
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks | 2.402 liters | Standard Error 0.037 |
| Tio+Olo 2.5 / 5.0 µg | Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks | 2.589 liters | Standard Error 0.036 |
| Tio+Olo 5.0 / 5.0 µg | Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks | 2.627 liters | Standard Error 0.035 |
p-value: <0.000195% CI: [0.124, 0.326]Mixed Models Analysis
p-value: 0.000395% CI: [0.086, 0.288]Mixed Models Analysis
p-value: 0.454195% CI: [-0.061, 0.137]Mixed Models Analysis
Secondary
Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 12
Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 12 weeks of treatment. The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates favorable results.
Time frame: 12 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 12 | 0.015 units / seconds | Standard Error 0.001 |
| Tio+Olo 2.5 / 5.0 µg | Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 12 | 0.013 units / seconds | Standard Error 0.001 |
| Tio+Olo 5.0 / 5.0 µg | Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 12 | 0.013 units / seconds | Standard Error 0.001 |
p-value: 0.059895% CI: [-0.004, 0]Mixed Models Analysis
p-value: 0.021895% CI: [-0.005, 0]Mixed Models Analysis
p-value: 0.654995% CI: [-0.002, 0.003]Mixed Models Analysis
Secondary
Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 6
Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment. The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates favorable results.
Time frame: 6 weeks
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline and at least one post-baseline measurement before or at Week 12 for the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 6 | 0.016 units / seconds | Standard Error 0.001 |
| Tio+Olo 2.5 / 5.0 µg | Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 6 | 0.013 units / seconds | Standard Error 0.001 |
| Tio+Olo 5.0 / 5.0 µg | Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 6 | 0.013 units / seconds | Standard Error 0.001 |
p-value: 0.008195% CI: [-0.005, -0.001]Mixed Models Analysis
p-value: 0.009995% CI: [-0.005, -0.001]Mixed Models Analysis
p-value: 0.962695% CI: [-0.002, 0.002]Mixed Models Analysis
Secondary
Adjusted Mean Slope of the Intensity of Breathing Discomfort on Day 1
Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 1 day of treatment. The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates slowing down in decline in breathing, i.e., favorable results.
Time frame: 1 day
Population: Visit 4 Set. All randomized patients dispensed medication, were documented to have taken any dose of study medication, and had evaluable measurements of endurance time at Baseline (Visit 3) and at Visit 4 (Day 1) during CWRCE. Patients were assigned to the Visit 4 set after implementation of data handling rules that set measurements to missing.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Slope of the Intensity of Breathing Discomfort on Day 1 | 0.014 units / seconds | Standard Error 0.001 |
| Tio+Olo 2.5 / 5.0 µg | Adjusted Mean Slope of the Intensity of Breathing Discomfort on Day 1 | 0.012 units / seconds | Standard Error 0.001 |
| Tio+Olo 5.0 / 5.0 µg | Adjusted Mean Slope of the Intensity of Breathing Discomfort on Day 1 | 0.012 units / seconds | Standard Error 0.001 |
p-value: 0.046895% CI: [-0.004, 0]ANCOVA
p-value: 0.01895% CI: [-0.005, 0]ANCOVA
p-value: 0.685695% CI: [-0.002, 0.002]ANCOVA