Pharmacokinetics and Safety Comparison of Tiotropium Inhalation Powder Administered as the Bromide Salt From Hard Polyethylene Capsule Via the HandiHaler® 2 and Spiriva® HandiHaler® in Patients With Chronic Obstructive Pulmonary Disease (COPD)
Pharmacokinetics and Safety Comparison of Tiotropium Inhalation Powder Administered as the Bromide Salt From Hard Polyethylene Capsule Via the HandiHaler® 2 and Spiriva® HandiHaler® in Patients With Chronic Obstructive Pulmonary Disease (COPD)
The primary objective of this trial was to establish non-inferiority of lung function
 response to tiotropium 10 μg, formulated as inhalation powder in the polyethylene hard
 capsule and delivered via the HandiHaler® 2, compared to tiotropium 18 μg, formulated as
 inhalation powder in the hard gelatine capsule and delivered via the HandiHaler® (Spiriva®)
 following single dose inhalation in patients with COPD. A hard polyethylene (PE) capsule with
 half the strength (tiotropium 5 μg) was included to investigate a dose ordering effect.

 The secondary objectives were to characterize the pharmacokinetics of tiotropium inhalation
 powder hard PE capsule (delivered via HandiHaler® 2) and tiotropium inhalation powder hard
 gelatine capsule (delivered via HandiHaler®) and to compare the safety of the two
 pharmaceutical formulations.
Inclusion Criteria:

 1. All patients must sign an informed consent consistent with International Conference on
 Harmonization Good Clinical Practice (ICH-GCP) guidelines and local legislations prior
 to any study-related procedures, 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 pre-dose FEV1 <= 60%
 of predicted normal and FEV1 <= 70% of FVC at Visits 1 and 2.

 -  * The randomization of patients with any respiratory infection or COPD
 exacerbation in the 6 weeks prior to the Screening Visit (Visit 1) or during the
 baseline period should be postponed. Patients may be randomized 6 weeks following
 recovery from the infection or exacerbation

 3. At Visit 1, patients must demonstrate an improvement in FEV1 of >= 12% over the
 baseline FEV1 value 45 minutes after inhalation of 4 puffs of 20 µg ipratropium
 bromide (Atrovent® MDI)

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

 5. Patients must be current or ex-smokers with a smoking history of more than 10
 pack-years (Patients who had never smoked cigarettes had to be excluded)

 6. Patients must be able to perform technically acceptable pulmonary function tests
 during the study period as required in the protocol

 7. Patients must be able to inhale medication in a competent manner from the HandiHaler®
 2 and the HandiHaler® devices

 Exclusion Criteria:

 1. Patients with significant diseases other than COPD will be excluded. A significant
 disease is 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

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

 3. Patients who have been hospitalized for heart failure (NYHA class III or IV) within
 the past year

 4. Patients with any unstable or life threatening cardiac arrhythmia or cardiac
 arrhythmia requiring intervention or a change in drug therapy within the past year

 5. Patients with malignancy for which the patient has undergone resection, radiation
 therapy or chemotherapy within the last five years. Patients with treated basal cell
 carcinoma are allowed

 6. Patients with a history of asthma, allergic rhinitis or atopy or who have a total
 blood eosinophil count ≥600/mm3. A repeat eosinophil count will not be conducted in
 these patients

 7. Patients with a history of life threatening pulmonary obstruction, or a history of
 cystic fibrosis or clinically evident bronchiectasis

 8. Patients with known active tuberculosis

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

 10. 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

 11. 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 that will not be maintained throughout the duration of the
 study

 12. 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

 13. Patients who are being treated with antihistamines (H1 receptor antagonists),
 antileukotrienes or leukotriene receptor antagonists for asthma or excluded allergic
 conditions. See exclusion criterion No 6

 14. Patients who are being treated with cromolyn sodium or nedocromil sodium

 15. 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

 16. Patients with known hypersensitivity to anticholinergic drugs, lactose or any other
 components of the inhalation capsule delivery system (Spiriva® HandiHaler®; tiotropium
 HandiHaler 2)

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

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

 19. Patients who have been treated with oral beta-adrenergics within one month prior to
 Visit 1 or during the run-in period

 20. Patients who have been treated with theophylline preparations within one month prior
 to Visit 1 or during the run-in period

 21. Patients who have been treated with the long-acting anticholinergic tiotropium
 (Spiriva®) within one month prior to Visit 1 or during the run-in period

 22. Patients with any respiratory infections in the six weeks prior to the Screening Visit
 (Visit 1) or during the run-in period. In the case of a respiratory infection during
 the run-in period the latter may be extended up to six weeks

 23. Patients who are currently participating in another study23. The randomisation of
 patients with any respiratory infection or COPD exacerbation in the six weeks prior to
 the Screening Visit (Visit 1) or during the baseline period should be postponed.
 Patients may be randomised six weeks following recovery from the infection or
 exacerbation