Effect of inhalation of tiotropium once daily 18 mcg versus salmeterol twice daily 50 mcg on time to first exacerbation in COPD patients (a randomized, double-blind, double-dummy, parallel group, one year study)

Several drug therapies have been shown to reduce exacerbations. Inhaled
long-acting ß2-agonists such as salmeterol and formoterol have somewhat
conflicting data regarding effects on exacerbations while the long-acting
anticholinergic tiotropium appears to consistently reduce exacerbation rates
[P99-01272, P03-01576, P03-01593, P04-00293, P05-09172, R07-0368].
Nevertheless, both are recommended in international guidelines for the
treatment of COPD as maintenance therapy [P05-12781]. In clinical trials,
tiotropium has been shown to improve lung function, health-related quality of
life, dyspnoea, exercise tolerance and to prevent exacerbations [P02-01288,
P02-01290, P03-04061, P04-1571]. However, it is still unclear whether
tiotropium can be demonstrated in a randomized, blinded clinical trial to be
more effective in reducing exacerbations compared with long-acting ß2-agonists
such as salmeterol.

To demonstrate superiority of tiotropium vs. salmeterol in reducing
exacerbations which are an important patient outcome because they are a major
cause of morbidity from COPD. In addition, they are associated with a more
rapid decline in lung function over time and contribute to decline of
health-related quality of life

One year randomized, double-blind, double-dummy, parallel group design.
Study consists of 6 visits (Screening, study start, 2, 4, 8 and 12 months) and
8 telephone calls monthly between the visits. Patients randomized by IVRS into
2 groups: tiotropium 18 mcg once daily via the HandiHaler® + placebo MDI twice
daily or salmeterol 50 mcg twice daily + placebo capsules once daily via the
HandiHaler®.

Pharmacogenetic sub-study: Participation is voluntary and is not a prerequisite
for participation in the study. One blood sample will be taken from patients
who have signed separate informed consent.

Subjects will be randomly assigned to 1 of 2 treatment groups: tiotropium 18
mcg once daily via the HandiHaler® + placebo MDI twice daily or salmeterol 50
mcg twice daily + placebo capsules once daily via the HandiHaler®.
Subjects who are at screening treated with tiotropium will be switched to
ipatropium first due to the long elimination half-life of tiotropium.

Tiotropium is indicated as a maintenance bronchodilator treatment to relieve
symptoms of patients with chronic obstructive pulmonary disease (COPD) [see
SPC].
Salmeterol is a selective β2-agonist indicated for reversible airways
obstruction in patients with asthma and chronic obstructive pulmonary disease
(COPD) [see SPC].
In the present clinical trial, both medications will be studied within their
approved indications.

Safety evaluations:
1. Serious adverse events
2. Adverse events leading to treatment discontinuation
3. All-cause mortality during treatment with study medication
4. All-cause mortality including follow-up of vital status from patients who
prematurely discontinue treatment
5. Physical examination

Health economic analysis: For the purpose of a separate health economic
analysis (for example cost-effectiveness analysis including the clinical
endpoint as the effectiveness parameter), health care resource utilization
(HCRU) data will be collected.

Pharmacogenetic sub-study: Participation is voluntary and is not a prerequisite
for participation in the study. One blood sample will be taken from patients
who have signed separate informed consent.