Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The primary objective of this trial is to investigate the effect of 6 weeks treatment with tiotropium + olodaterol fixed dose combination inhalation solution on lung hyperinflation and exercise tolerance in patients with COPD.
Interventions
DEVICERespimat
Respimat inhaler
DRUGPlacebo
placebo matching tiotropium + olodaterol
Tiotropium 2.5 mcg + olodaterol 5 mcg once daily
tiotropium 5 mcg + olodaterol 5 mcg once daily
DRUGTiotropium
tiotropium
DRUGOlodaterol
Olodaterol 5 mcg once daily
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. 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 a post-bronchodilator FEV1 \<80% of predicted normal and a post-bronchodilator FEV1/FVC \<70% at Visit 1. 3. Male or female patients, between 40 and 75 years of age (inclusive) on day of signing informed consent. 4. Patients must be current or ex-smokers with a smoking history of more than 10 pack years.
Exclusion criteria
1. Patients with a significant disease other than COPD; a significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, (ii) influence the results of the study, or (iii) cause concern regarding the patient's ability to participate in the study 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. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma. Patients with any of the following conditions: 4. A diagnosis of thyrotoxicosis (due to the known class side effect profile of ß2-agonists) 5. A diagnosis of paroxysmal tachycardia (\>100 beats per minute) (due to the known class side effect profile of ß2-agonists) 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 (patients with treated basal cell carcinoma are allowed) 11. A history of life-threatening pulmonary obstruction 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 (patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1) 17. Patients being treated with any oral ß-adrenergics 18. Patients being treated with oral corticosteroid medication at unstable doses 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 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, such as arthritis in the leg, angina pectoris or claudication or morbid obesity. 22. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit 23. Patients with known hypersensitivity to ß-adrenergics drugs, anticholinergic drugs, BAC, EDTA or any other component of the Respimat® inhalation solution delivery system 24. Pregnant or nursing women 25. Women of childbearing potential not using highly effective methods of birth control.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity | 6 weeks | Inspiratory capacity (IC) at rest before constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap). Wcap was defined as the maximum work rate achieved for at least 30 seconds during the incremental cycle ergometry performed at Visit 1. The presented means are adjusted means from the MMRM (Mixed Effects Model Repeated Measures) model. |
| Endurance Time During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap | 6 weeks | Endurance time during constant work rate cycle ergometry (CWRCE) to symptom limitation at 75% Wcap Wcap was defined as the maximum work rate achieved for at least 30 seconds during the incremental cycle ergometry performed at Visit 1. The presented means are adjusted mean from the MMRM model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Slope of the Intensity of Breathing Discomfort (Borg Scale) During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap | 6 weeks | Slope of the intensity of breathing discomfort (Borg Scale) during CWRCE to symptom limitation at 75% Wcap. The intensity of breathing discomfort was rated using the modified Borg scale with ratings from 0 (nothing at all) to 10 (maximal). Slope is defined as : (intensity of breathing discomfort at the end of exercise minus intensity of breathing discomfort at rest) / endurance time. A decrease in slope indicates improvement. The presented means are adjusted means from MMRM model. |
| FEV1 (1 Hour Post-dose) | 6 weeks | Forced Expiratory Volume in 1 Second (FEV1) (one hour post-dose). The presented means are adjusted means from MMRM model. |
Countries
Argentina, Austria, Canada, Germany, Netherlands, Russia, Sweden, United States
Participant flow
Pre-assignment details
This was a randomised, 4-period incomplete block cross-over trial. 291 patients were randomized to one of five treatments sequences and treated. It was a double-blind trial in which each treatment period lasted 6 weeks with a washout period of 21 days between each.
Participants by arm
| Arm | Count |
|---|---|
| Overall Study A randomised, double-blind, placebo controlled, 5 treatment, 4-period, incomplete, crossover study. Each treatment period was separated by a washout period of 21 days. The treatments administered, by oral inhalation delivered once daily in the morning, via the respimat inhaler, were:
* Oral inhalation of placebo
* Tiotropium fixed dose 5 µg
* Olodaterol fixed dose 5 µg
* Fixed dose combination (FDC) of Tiotropium 2.5 µg and Olodaterol 5 µg
* Fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 5 µg
Treatment sequence is not considered as a factor which may affect the treatment effect due to sufficient washout period added between treatment cycles. As a result, we only display baseline characteristics as a whole population, but not by treatment sequence | 291 |
| Total | 291 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 7 | 1 | 5 | 3 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Other reason not defined above | 1 | 0 | 1 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 2 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 4 | 5 | 2 | 4 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 61.2 years STANDARD_DEVIATION 7.9 |
| Sex: Female, Male Female | 87 Participants |
| Sex: Female, Male Male | 204 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 | 41 / 214 | 42 / 218 | 48 / 218 | 36 / 219 | 40 / 224 |
| serious Total, serious adverse events | 3 / 214 | 3 / 218 | 8 / 218 | 3 / 219 | 4 / 224 |
Outcome results
Primary
Endurance Time During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap
Endurance time during constant work rate cycle ergometry (CWRCE) to symptom limitation at 75% Wcap Wcap was defined as the maximum work rate achieved for at least 30 seconds during the incremental cycle ergometry performed at Visit 1. The presented means are adjusted mean from the MMRM model.
Time frame: 6 weeks
Population: FAS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Endurance Time During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap | 410.77 seconds | Standard Error 12.009 |
| Olodaterol 5 µg | Endurance Time During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap | 419.06 seconds | Standard Error 12.207 |
| Tiotropium 5 µg | Endurance Time During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap | 446.50 seconds | Standard Error 12.958 |
| Tiotropium + Olodaterol 2.5/5 | Endurance Time During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap | 460.66 seconds | Standard Error 13.31 |
| Tiotropium + Olodaterol 5/5 | Endurance Time During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap | 465.68 seconds | Standard Error 13.359 |
p-value: <0.000195% CI: [1.065, 1.206]Mixed Models Analysis
p-value: 0.000995% CI: [1.045, 1.182]Mixed Models Analysis
p-value: 0.180795% CI: [0.981, 1.109]Mixed Models Analysis
p-value: 0.000395% CI: [1.054, 1.193]Mixed Models Analysis
p-value: 0.002995% CI: [1.033, 1.17]Mixed Models Analysis
p-value: 0.32495% CI: [0.97, 1.098]Mixed Models Analysis
Primary
Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity
Inspiratory capacity (IC) at rest before constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap). Wcap was defined as the maximum work rate achieved for at least 30 seconds during the incremental cycle ergometry performed at Visit 1. The presented means are adjusted means from the MMRM (Mixed Effects Model Repeated Measures) model.
Time frame: 6 weeks
Population: Full Analysis Set (FAS) : This patient set included all patients in the TS who had the study baseline and at least 1 evaluable post-dose measurement for 1 of the primary endpoints. Assignment to the FAS was done after implementation of any data handling rules,which set measurements to missing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity | 2.502 Litres | Standard Error 0.026 |
| Olodaterol 5 µg | Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity | 2.687 Litres | Standard Error 0.025 |
| Tiotropium 5 µg | Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity | 2.679 Litres | Standard Error 0.025 |
| Tiotropium + Olodaterol 2.5/5 | Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity | 2.776 Litres | Standard Error 0.025 |
| Tiotropium + Olodaterol 5/5 | Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity | 2.767 Litres | Standard Error 0.025 |
p-value: <0.000195% CI: [0.215, 0.315]Mixed Models Analysis
p-value: 0.001595% CI: [0.031, 0.129]Mixed Models Analysis
p-value: 0.000595% CI: [0.039, 0.137]Mixed Models Analysis
p-value: <0.000195% CI: [0.224, 0.324]Mixed Models Analysis
p-value: 0.000495% CI: [0.039, 0.138]Mixed Models Analysis
p-value: 0.000195% CI: [0.047, 0.147]Mixed Models Analysis
Secondary
FEV1 (1 Hour Post-dose)
Forced Expiratory Volume in 1 Second (FEV1) (one hour post-dose). The presented means are adjusted means from MMRM model.
Time frame: 6 weeks
Population: All patients in FAS with available FEV1 data at baseline and week 6 are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 (1 Hour Post-dose) | 1.548 Litres | Standard Error 0.016 |
| Olodaterol 5 µg | FEV1 (1 Hour Post-dose) | 1.742 Litres | Standard Error 0.016 |
| Tiotropium 5 µg | FEV1 (1 Hour Post-dose) | 1.741 Litres | Standard Error 0.016 |
| Tiotropium + Olodaterol 2.5/5 | FEV1 (1 Hour Post-dose) | 1.852 Litres | Standard Error 0.016 |
| Tiotropium + Olodaterol 5/5 | FEV1 (1 Hour Post-dose) | 1.876 Litres | Standard Error 0.016 |
p-value: <0.000195% CI: [0.294, 0.364]Mixed Models Analysis
p-value: <0.000195% CI: [0.099, 0.169]Mixed Models Analysis
p-value: <0.000195% CI: [0.1, 0.17]Mixed Models Analysis
p-value: <0.000195% CI: [0.269, 0.34]Mixed Models Analysis
p-value: <0.000195% CI: [0.075, 0.145]Mixed Models Analysis
p-value: <0.000195% CI: [0.076, 0.146]Mixed Models Analysis
Secondary
Slope of the Intensity of Breathing Discomfort (Borg Scale) During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap
Slope of the intensity of breathing discomfort (Borg Scale) during CWRCE to symptom limitation at 75% Wcap. The intensity of breathing discomfort was rated using the modified Borg scale with ratings from 0 (nothing at all) to 10 (maximal). Slope is defined as : (intensity of breathing discomfort at the end of exercise minus intensity of breathing discomfort at rest) / endurance time. A decrease in slope indicates improvement. The presented means are adjusted means from MMRM model.
Time frame: 6 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Slope of the Intensity of Breathing Discomfort (Borg Scale) During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap | 0.018 units on a scale / s | Standard Error 0.001 |
| Olodaterol 5 µg | Slope of the Intensity of Breathing Discomfort (Borg Scale) During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap | 0.017 units on a scale / s | Standard Error 0.001 |
| Tiotropium 5 µg | Slope of the Intensity of Breathing Discomfort (Borg Scale) During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap | 0.015 units on a scale / s | Standard Error 0.001 |
| Tiotropium + Olodaterol 2.5/5 | Slope of the Intensity of Breathing Discomfort (Borg Scale) During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap | 0.014 units on a scale / s | Standard Error 0.001 |
| Tiotropium + Olodaterol 5/5 | Slope of the Intensity of Breathing Discomfort (Borg Scale) During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap | 0.015 units on a scale / s | Standard Error 0.001 |
p-value: <0.000195% CI: [-0.004, -0.002]Mixed Models Analysis
p-value: 0.003395% CI: [-0.003, -0.001]Mixed Models Analysis
p-value: 0.230695% CI: [-0.002, 0.001]Mixed Models Analysis
p-value: <0.000195% CI: [-0.005, -0.002]Mixed Models Analysis
p-value: 0.00195% CI: [-0.004, -0.001]Mixed Models Analysis
p-value: 0.120695% CI: [-0.002, 0]Mixed Models Analysis