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

Study Overview
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Brief Summary
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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
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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)

Official Title
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Randomised Cross-over Study to Compare the Effect of Formoterol Plus Tiotropium Versus Formoterol Monotherapy on Breathlessness, Dynamic Hyperinflation and Exercise Tolerance in Moderate-to-severe Stable COPD Patients

Conditions
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Pulmonary Disease, Chronic Obstructive, Chronic Bronchitis, Pulmonary Emphysema

Intervention / Treatment
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* Drug: Formoterol plus Placebo (Tiotropium)
* Drug: Formoterol plus Tiotropium


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Formoterol plus Placebo (Tiotropium) | Drug: Formoterol plus Placebo (Tiotropium)<br>* Formoterol 12mcg-capsules (2x/d) + Placebo (Tiotropium) (1x/d). Double-blind medication will be dispensed in HandiHalers and Aerolisers during 2 weeks.<br>|
| Experimental: 2<br>Formoterol plus Tiotropium | Drug: Formoterol plus Tiotropium<br>* Formoterol 12mcg-capsule (2x/dia) + Tiotropium 18mcg-capsule (1x/d). Double-blind medication will be dispensed in HandiHalers and Aerolisers during 2 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in Exercise Tolerance From Baseline at 2 Weeks | 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) | Baseline and after 2 weeks with each treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Score on the Transitional Dyspnea Index (TDI) | 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). | After 2 week of each treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Disease, Chronic Obstructive, Tiotropium, Formoterol, Bronchodilator Agents, Exercise Tolerance, Randomized Controlled Trial [Publication Type], COPD