E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Obstructive Pulmonary Disease (COPD) |
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E.1.1.1 | Medical condition in easily understood language |
Chronic obstructive pulmonary disease (COPD) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010952 |
E.1.2 | Term | COPD |
E.1.2 | System Organ Class | 100000004855 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. Exercise tolerance will be assessed by measurement of symptom-limited endurance time during constant work rate cycle ergometry. |
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E.2.2 | Secondary objectives of the trial |
- to compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination (2.5/5 μg; 5/5 μg) with placebo on endurance time during endurance shuttle walk test after 12 weeks of treatment (subset of patients).
- to compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination with placebo on lung hyperinflation (inspiratory capacity) during constant work rate cycle ergometry after 12 weeks of treatment.
- to compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination with placebo on the intensity of breathing discomfort (Borg Category-Ratio Scale) experienced during constant work rate cycle ergometry after 12 weeks of treatment.
- to compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination with placebo on the intensity of breathing discomfort and lung hyperinflation during endurance shuttle walk test after 12 weeks of treatment.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
to compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination (2.5/5 µg; 5/5 µg) with placebo on endurance time during endurance shuttle walk test after 12 weeks of treatment in patients with COPD |
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E.3 | Principal 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).
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E.4 | Principal 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
3. Patients with a history of asthma.
Patients with any of the following conditions:
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
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 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 (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 β-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, such as arthritis in the leg, angina pectoris or claudication or morbid obesity
22. Patients with an endurance time more than 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 β-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.
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 more than 15 minutes during the training (Visit 2a) or baseline (visit 3a) endurance shuttle walk test.
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E.5 End points |
E.5.1 | Primary end point(s) |
endurance time during constant work rate cycle ergometry at 75% Wcap (maximal work capacity). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Inspiratory capacity (IC) during constant work rate cycle ergometry: pre-exercise.
2. Endurance time during constant work rate cycle ergometry.
3. Slope of the intensity of breathing discomfort (Borg Category-Ratio Scale) during constant work rate cycle ergometry.
4. 1-hour post-dose FEV1.
5. IC during constant work rate cycle ergometry: isotime and end-exercise.
6. Intensity of breathing discomfort (Borg Category-Ratio Scale) during constant work rate cycle ergometry: pre-exercise, isotime, and end-exercise.
7. Intensity of leg discomfort (Borg Category-Ratio Scale) during constant work rate cycle ergometry: pre-exercise, isotime, and end-exercise.
8. Locus of symptom limitation (breathing discomfort, leg discomfort, breathing and leg discomfort) during constant work rate cycle ergometry.
9. Trough FEV1 and trough FVC.
10. 1-hour post-dose FVC.
11. Endurance time during endurance shuttle walk test.
12. IC during endurance shuttle walk test: pre-exercise, isotime and end-exercise.
13. Slope of the intensity of breathing discomfort during endurance shuttle walk test.
14. Intensity of breathing discomfort (Borg Category-Ratio Scale) during endurance shuttle walk: pre-exercise, isotime, and end-exercise.
15. Intensity of leg discomfort (Borg Category-Ratio Scale) during endurance shuttle walk test: pre-exercise, isotime, and end-exercise.
16. Locus of symptom limitation (breathing discomfort, leg discomfort, breathing and leg discomfort, other) during endurance shuttle walk test.
17. On Day 1, a subset of patients - not participating in the endurance shuttle walk substudy - take the constant work rate cycle ergometry and record measurements of endurance time, IC, intensity of breathing discomfort and leg discomfort, as well as locus of symptom limitation. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Endpoints 1, 3 to 8, and 10 on Day 1 as well as after 6 and 12 weeks of treatment.
Endpoint 2 on Day 1 and after 6 weeks of treatment.
Endpoint 11 after 6 weeks of treatment.
Endpoints 9 and 12 to 16 after 6 and 12 weeks of treatment.
Endpoint 17 on Day 1 of treatment.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 42 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Canada |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |