Add-on Effects of Tiotropium Over Formoterol in Exercise Tolerance on Chronic Obstructive Pulmonary Disease Patients

Phase 4

Completed

Conditions: Chronic Bronchitis
Pulmonary Disease, Chronic Obstructive
Pulmonary Emphysema

Interventions: Drug: Formoterol plus Tiotropium
Drug: Formoterol plus Placebo (Tiotropium)

Brief Summary: The primary objective is to comparatively evaluate the isolated effects of a long-acting beta2-adrenergic (formoterol fumarate 12µg b.i.d. via Aeroliser) and combined with a long-acting anti-cholinergic (tiotropium bromide 18µg o.d via Handihaler) on breathlessness, dynamic hyperinflation and exercise tolerance in patients with advanced, but stable, chronic obstructive pulmonary disease. The study hypothesis is that combining long acting bronchodilators with different action mechanisms would promote synergistic effects on clinical outcomes.

Detailed Description: This will be a single center, randomized, double-blind study consisting of two 2-week treatment periods separated by a 5-7 days washout phase without long-acting bronchodilators. Eligible patients who complete the one week screening phase will be randomized to one of two treatment sequences: 1) Formoterol --\> Formoterol + Tiotropium or 2) Formoterol + Tiotropium --\> Formoterol. During the treatment periods, patients will be allowed to use a short-acting beta2-adrenergic+short-acting anticholinergic as rescue medication (salbutamol+ipratropium via MDI)

Recruitment & Eligibility

Inclusion Criteria

COPD patients aged ≥ 40 years with stable moderate-to-severe airflow obstruction (FEV1 < 70% and FEV1/FVC ≤ 70% of predicted normal value) post-bronchodilator
presenting with a long history of smoking (> 20 pack-years) and chronic breathlessness (Baseline Dyspnoea Index total score < 9)

Exclusion Criteria

significant cardiovascular disease, hospitalization for COPD exacerbation or presence of a respiratory tract infection within 1 month of screening
current or childhood asthma
a history of allergic rhinitis or other atopic disease
inability to interrupt usual bronchodilator medication
use of oral steroids within a month before screening
need for long-term oxygen therapy, arterial oxygen saturation < 85% at rest anemia, hypo- and hyperthyroidism, hyperadrenergic state
uncontrolled insulin dependent diabetes mellitus, malignancy, or any disease or condition which limits exercise performance other than COPD
change in inhaled corticosteroid or theophylline use within 1 month prior to screening

Arm && Interventions

Group	Intervention	Description
2	Formoterol plus Tiotropium	Formoterol plus Tiotropium
1	Formoterol plus Placebo (Tiotropium)	Formoterol plus Placebo (Tiotropium)

Primary Outcome Measures

Name	Time	Method
Percentage Change in Exercise Tolerance From Baseline at 2 Weeks	Baseline and after 2 weeks with each treatment	Percentage change from baseline in time to the limit of tolerance on a high intensity constant-speed treadmill exercise test (with a speed corresponding to 80% of that obtained during incremental test)

Secondary Outcome Measures

Name	Time	Method
Mean Score on the Transitional Dyspnea Index (TDI)	After 2 week of each treatment	TDI is a multidimensional clinical instrument developed to provide a comprehensive assessment of change in dyspnea after an intervention, considering three components (functional impairment, magnitude of task, and magnitude of effort). It ranges from -9 (major deterioration) to +9 (major improvement).