| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| COPD, Chronic Obstructive Pulmonary Disease, Chronic bronchitis, emphysema |
|
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009033 |
| E.1.2 | Term | Chronic obstructive pulmonary disease |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009032 |
| E.1.2 | Term | Chronic obstructive lung disease |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 objectives of this study are:
1) To compare the effects of orally inhaled tiotropium + olodaterol fixed
dose combination (2.5 / 5 μg ; 5 / 5 μg) with tiotropium (5 μg),
olodaterol (5 μg) and placebo on lung hyperinflation during constant
work rate exercise in patients with COPD. Lung hyperinflation will be
assessed by measurement of inspiratory capacity (IC).
2) To compare the effects of orally inhaled tiotropium + olodaterol fixed
dose combination (2.5 / 5 μg ; 5 / 5 μg) with tiotropium (5 μg),
olodaterol (5 μg) and placebo on constant work rate exercise tolerance
after 6 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. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary 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 tiotropium (5 μg), olodaterol (5 μg) and placebo on the
intensity of breathing discomfort experienced during constant work rate
exercise in patients with COPD. The intensity of breathing discomfort will
be rated by the patients using the Borg Category-Ratio Scale. |
|
| E.2.3 | Trial contains a sub-study | No |
| 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 pulmonarydisease and must meet the following spirometric criteria:
Patients must have relatively stable airway obstruction with a postbronchodilator 30% ≤ FEV1 <80% of predicted normal (ECSC) ; GOLD II - III and a postbronchodilator FEV1/FVC <70% at Visit 1 (ECSC predicted normal
equations)
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.
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 during the study period as required in the
protocol. |
|
| 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; all patients with an SGOT >x2 ULN, SGPT
>x2 ULN, bilirubin >x2 ULN or creatinine >x2 ULN will be excluded
regardless of clinical condition (a repeat laboratory evaluation will not
be conducted in these patients)
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. If a patient has a total blood eosinophil count greater
than or equal to 600/mm3, source documentation is required to verify
that the increased eosinophil count is related to a non-asthmatic
condition.
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 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 as outlined in protocol
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 greater than 25 minutes during the
training (Visit 1) or baseline constant work rate cycle ergometry at Visit
2
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-adrenergics 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 highly effective methods
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
* as per ICH M3(R2): a highly effective method of birth control is defined
as those which result in a low failure rate (i.e. less than 1% per year)
when used consistently and correctly.
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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Two primary endpoints are defined:
• inspiratory capacity (IC) at isotime during constant work rate cycle
ergometry to symptom limitation at 75% Wcap after 6 weeks of
treatment.
• endurance time during constant work rate cycle ergometry to
symptom limitation at 75% Wcap* (maximal work capacity) after 6
weeks of treatment.
* Wcap (maximal work capacity) is the maximum work rate achieved for
at least 30 seconds during the incremental cycle ergometry performed at
Visit 1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 6 weeks treatment. For IC, this will be measured at isotime where
for each individual subject, isotime is defined as the endurance time of
the constant work rate exercise test of shortest duration from Visit 2,
Visit 4, Visit 6, Visit 8 and Visit 10. |
|
| E.5.2 | Secondary end point(s) |
The following key secondary endpoint will also be assessed during the
constant work rate cycle ergometry:
- intensity of breathing discomfort at isotime during constant work rate
cycle ergometry to symptom limitation at 75% Wcap after 6 weeks of
treatment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 6 weeks treatment. For BORG breathing discomfort this will be
measured at isotime where for each individual subject, isotime is defined
as the endurance time of the constant work rate exercise test of shortest
duration from Visit 2, Visit 4, Visit 6, Visit 8 and Visit 10. |
|
| 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 | No |
| 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 | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| Austria |
| Canada |
| Colombia |
| Germany |
| Netherlands |
| Russian Federation |
| Sweden |
| United States |
|
| 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
|
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 3 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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