A Study to Determine the Effect of Tiotropium + Olodaterol Fixed Dose Combination on Exercise Endurance Time During Constant Work Rate Cycle Ergometry Test in COPD

A Randomised, Double-blind, Placebo-controlled, Parallel Group Study to Determine the Effect of 12 Weeks Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (2.5/5 µg and 5/5 µg) Delivered by the Respimat® Inhaler, on Exercise Endurance Time During Constant Work Rate Cycle Ergometry in Patients With Chronic Obstructive Pulmonary Disease (COPD)[Torracto (TM)]

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.

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.