Clinical trial NCT02172794 (phase 3, status: completed)
Conditions: pulmonary disease, chronic obstructive
ICD codes: J44.9, J44.1, J44.0
Drugs: tiotropium, placebo to tiotropium, salmeterol, placebo to salmeterol
SMILES: [H][C@]12O[C@@]1([H])[C@]1([H])C[C@@]([H])(C[C@@]2([H])[N+]1(C)C)OC(=O)C(O)(C1=CC=CS1)C1=CC=CS1, [H][C@]12O[C@@]1([H])[C@]1([H])C[C@@]([H])(C[C@@]2([H])[N+]1(C)C)OC(=O)C(O)(C1=CC=CS1)C1=CC=CS1, OCC1=C(O)C=CC(=C1)C(O)CNCCCCCCOCCCCC1=CC=CC=C1, OCC1=C(O)C=CC(=C1)C(O)CNCCCCCCOCCCCC1=CC=CC=C1
Eligibility criteria:

        Inclusion Criteria:

          1. All patients had to sign an informed consent consistent with ICH-GCP guidelines prior
             to participation in the trial, which includes medication washout and restrictions.

          2. Male or female patients 40 years of age or older.

          3. All patients had to have a diagnosis of chronic obstructive pulmonary disease and must
             meet the following spirometric criteria:

             Patients had to have moderate to severe airway obstruction with a postbronchodilator
             FEV1/FVC ≤ 70% and FEV1 ≤ 60% predicted (Visit 1).

          4. FEV1 % predicted and/or forced vital capacity (FVC) increases >5% after inhalation
             with 480 μg salbutamol and 80 μg ipratropium

          5. Patients had to be current or ex-smokers with a smoking history of more than 10
             pack-years.

          6. Patients had to be able to perform technically acceptable pulmonary function tests and
             had to be able to maintain records (Patient Daily Record) during the study period as
             required in the protocol.

          7. Patients had to be able to inhale medication from the HandiHaler, and from an
             inhalation aerosol.

          8. Patients should have had a ventilatory limitation of maximal exercise capacity:

             Increase in arterial carvon dioxide tension (PaCO2) during incremental bicycle test
             and/or increase in minute ventilation (VE) max > 80% (FEV1 x 37.5)

          9. Patients should have had a Wmax ≥ 40 Watt during maximal incremental bicycle test.

        Exclusion Criteria:

          1. Increase of blood lactate > 10 mmol/L at peak exercise

          2. Increase of blood lactate >2.5 mmol/L at ≥ 50% of Wmax

          3. Decrease of oxygen saturation below 90% at ≥ 50% of Wmax

          4. Patients with significant diseases other than COPD had to be excluded. A significant
             disease was defined as a disease which in the opinion of the investigator may either
             put the patient at risk because of participation in the study or a disease which may
             influence the results of the study or the patient's ability to participate in the
             study.

          5. Patients with clinically relevant abnormal haemoglobulin, leukocytes, thrombocytes,
             glucose, sodium, potassium.

          6. Patients with a recent history (i.e., six months or less) of myocardial infarction.

          7. Patients with any cardiac arrhythmia requiring drug therapy or who have been
             hospitalised for heart failure within the past three years.

          8. Patients with known active tuberculosis.

          9. Patients on oxygen therapy.

         10. Patients with a history of cystic fibrosis, bronchiectasis, interstitial lung disease,
             or pulmonary thromboembolic disease.

         11. Patients who have undergone thoracotomy with pulmonary resection. Patients with a
             history of thoracotomy for other reasons should be evaluated as per exclusion 4.

         12. Patients with any respiratory infection in the six weeks prior to the Screening Visit
             (Visit 1) or during the baseline period. The enrolment of these patients was to be
             postponed for at least six weeks.

         13. Patients who have frequent exacerbations (at least three in the preceding year) which
             could be expected to interfere with the patient's ability to participate in the trial
             should be excluded.

         14. Patients with known hypersensitivity to anticholinergic drugs, beta adrenergics,
             lactose or any other components of the inhalation capsule delivery system.

         15. Patients with a history of cancer within the last three years. Patients with treated
             basal cell carcinoma were allowed. Patients with successfully treated cancers greater
             than five years prior to entry were allowed.

         16. Patients with known symptomatic prostatic hypertrophy or bladder neck obstruction.

         17. Patients with known narrow-angle glaucoma.

         18. Patients who were being treated with cromolyn sodium or nedocromil sodium.

         19. Patients who were being treated with antihistamines (H1 receptor antagonists).

         20. Patients who were being treated with theophyllines

         21. Patients who were currently on β-blocker therapy.

         22. Patients using 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.

         23. Pregnant or nursing women or women of childbearing potential not using a medically
             approved means of contraception for the previous 3 months (i.e. oral contraceptives,
             intrauterine devices, diaphragm or subdermal implants e.g. Norplant).

         24. Patients with a history of asthma or allergic rhinitis or who have a total blood
             eosinophil count ≥600 /mm3. A repeat eosinophil count was not conducted in these
             patients (Criterion modified by Protocol Amendment 2).

         25. Patients with significant alcohol or drug abuse within the past two years.

         26. Patients who had taken an investigational drug within one month or six half lives
             (whichever is greater) prior to Screening Visit (Visit 1).