Tiotropium Once Daily 18 Mcg Versus Salmeterol Twice Daily 50 Mcg on Time to First Exacerbation in COPD Patients.

Study Overview
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Brief Summary
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This is a randomised, double-blind, double-dummy, multinational, multicentre, parallel group trial comparing tiotropium (18 mcg) inhalation capsule via HandiHaler and salmeterol (50 mcg) via MDI in patients with COPD. There will be a two-week run-in period followed by a 52-week randomised treatment phase. Patients who withdraw prematurely from trial medication will be encouraged to remain in the trial and participate in follow-up telephone contacts until their predicted normal exit date from the trial (i.e. 52 weeks after taking the first dose of randomised treatment). The phone calls will be made at all scheduled visits. The primary objective of this study is to compare the effect of tiotropium (18 mcg) inhalation capsule via HandiHaler with that of salmeterol (50 mcg) via MDI on COPD exacerbations. The primary endpoint is time to first COPD exacerbation during the 52 week randomised treatment period. A COPD exacerbation will be defined as a complex of respiratory events / symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing, dyspnoea or chest tightness with at least one symptom lasting at least three days requiring treatment with antibiotics and/or systemic steroids and/or hospitalisation. The onset of an exacerbation is defined as the onset of the first new or increased reported symptom. The end of the exacerbation should be recorded as defined by the investigator. Only COPD exacerbations with onset during randomised treatment will be included in the analysis.

Official Title
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Effect of Inhalation of Tiotropium Once Daily 18 Mcg Versus Salmeterol Twice Daily 50 Mcg on Time to First Exacerbation in COPD Patients (a Randomised, Double-blind, Double-dummy, Parallel Group, One-year Study).

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Tiotropium bromide
* Drug: Salmeterol
* Drug: Placebo Salmeterol
* Drug: Placebo Tiotropium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must have a diagnosis of chronic obstructive pulmonary disease (COPD) and must meet the following criteria at Visit 1: Patients must have relatively stable, moderate to very severe airway obstruction with a post-bronchodilator FEV1 <=70% of predicted normal and FEV1 <=70% of FVC post-bronchodilator (i.e. 30 minutes after inhalation of 4 puffs of 100 µg salbutamol or equivalent SABA). Predicted normal values will be calculated according to ECSC. For Height measured in inches Males: FEV1 predicted (L) = 4.30 x (height (inches) / 39.37)-0.029 x age (yrs) - 2.49 Females:FEV1 predicted (L) = 3.95 x (height (inches) / 39.37)-0.025 x age (yrs) - 2.60 For Height measured in metres Males: FEV1 predicted (L) = 4.30 x (height (metres)) - 0.029 x age (years) - 2.49 Females: FEV1 predicted (L) = 3.95 x (height (metres)) - 0.025 x age (years) - 2.60 All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial. Male or female patients 40 years of age or older. Patients with a history of at least one exacerbation within the past year requiring treatment with either antibiotics and/or systemic steroids and/or hospitalisation. Patients must be current or ex-smokers with a smoking history of >= 10 pack-years. (Patients who have never smoked cigarettes must be excluded.) Patients must be able to perform all study-related procedures including technically acceptable pulmonary function tests (PFTs). Patients must be able to inhale medication in a competent manner from the HandiHaler and a metered dose inhaler (MDI). Patients must be able to maintain records (patient daily diary card) during the study period as required in the protocol. Exclusion Criteria: Significant diseases other than COPD. A significant disease is defined as a disease or condition which, in the opinion of the investigator, may put the patient at risk because of participation in the study or may influence either the results of the study or the patients' ability to participate in the study. Patients with a diagnosis of asthma. Patients with a life-threatening pulmonary obstruction, or a history of cystic fibrosis. Patients with known active tuberculosis. Patients with a known symptomatic prostatic hyperplasia or bladder neck obstruction. Patients with symptomatically-controlled prostatic hyperplasia on medication may be included and should continue their medication. Patients with known narrow-angle glaucoma. Patients with a history of myocardial infarction within the year prior to Visit 1. Patients with a history of hospital admission for heart failure within the year prior to Visit 1. Patients with cardiac arrhythmia requiring medical or surgical treatment. Patients with severe cardiovascular disorders. Patients with a known hypersensitivity to anticholinergic drugs, beta-adrenergics, lactose or any other component of the medication delivery system. Patients with known moderate or severe renal insufficiency (known creatinine clearance of <= 50 mL/min). Patients with untreated known hypokalaemia. Patients with untreated known thyrotoxicosis. Patients with brittle/unstable diabetes mellitus. Patients with a history of and/or active significant alcohol or drug abuse. See exclusion criterion 1. Patients who have taken an investigational drug within 30 days or six half-lives (whichever is greater) prior to Screening Visit (Visit 1). Use of systemic corticosteroid medication at unstable doses (i.e less than six weeks on stable dose) or at doses in excess of the equivalent of 10 mg prednisolone per day or 20 mg every other day. Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception (i.e oral contraceptives, intrauterine devices, diaphragm or subdermal implants e.g Norplant) for at least three months prior to, and for the duration of the trial. Previous participation (receipt of randomised treatment) in this study. Patients who are currently participating in another study. Patients with any respiratory infection or COPD exacerbation in the four weeks prior to the Screening Visit (Visit 1) or during the run-in period should be postponed. In the case of a respiratory infection or COPD exacerbation during the run-in period, the latter may be extended up to four weeks.

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tiotropium + Placebo<br>patients inhale Tiotropium 18mcg once daily via HandiHaler and Placebo MDI twice daily | Drug: Tiotropium bromide<br>* 18 mcg/daily<br>Drug: Placebo Salmeterol<br>* Placebo identical to Salmeterol device<br>|
| Active Comparator: Salmeterol + Placebo<br>patients inhale Salmeterol 50mcg twice daily via MDI and Placebo HandiHaler once daily | Drug: Salmeterol<br>* 100 mcg/daily<br>Drug: Placebo Tiotropium<br>* Placebo identical to Tiotropium device<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| First Occurrence of (Moderate or Severe) COPD Exacerbation | First occurrence analysed by Cox regression as time to first exacerbation and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| COPD Exacerbations Per Patient-year Leading to Hospitalisation | An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). | 52 weeks | 
| Number of Participants With at Least One COPD Exacerbation | An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). | 52 weeks | 
| COPD Exacerbations Per Patient-year |  | 52 weeks | 
| First Occurrence of COPD Exacerbation Leading to Hospitalization | First occurrence analysed by Cox regression as time to first exacerbation leading to hospitalisation and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). | 52 weeks | 
| Number of Participants With at Least One COPD Exacerbation Leading to Hospitalisation | An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). | 52 weeks | 
| Occurrence of Premature Discontinuation of Trial Medication | Occurrence analysed by Cox regression as time to premature discontinuation of trial medication and reported as hazard ratio | 52 weeks | 
| Number of Participants With Premature Discontinuation of Trial Medication |  | 52 weeks | 
| First Occurrence of COPD Exacerbation or Discontinuation of Trial Medication Because of Worsening of Underlying Disease, Whichever Comes First | First occurrence analysed by Cox regression as time to first exacerbation or discontinuation of trial medication because of worsening of underlying disease, whichever comes first and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). | 52 weeks | 
| First Occurrence of COPD Exacerbations Treated With Systemic Steroids | First occurrence analysed by Cox regression as time to first exacerbation treated with systemic steroids and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). | 52 weeks | 
| First Occurrence of COPD Exacerbations Treated With Antibiotics | First occurrence analysed by Cox regression as time to first exacerbation treated with antibiotics and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). | 52 weeks | 
| First Occurrence of COPD Exacerbations Treated With Systemic Steroids and Antibiotics | First occurrence analysed by Cox regression as time to first exacerbation treated with systemic steroids and antibiotics and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). | 52 weeks | 
| COPD Exacerbations Treated With Systemic Steroids Per Patient-year | An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). | 52 weeks | 
| COPD Exacerbations Treated With Antibiotics Per Patient-year | An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). | 52 weeks | 
| COPD Exacerbations Treated With Systemic Steroids and Antibiotics Per Patient-year | An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). | 52 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 1 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 2 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 3 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 4 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 5 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 6 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 7 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 8 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 9 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 10 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 11 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 12 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 13 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 14 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 15 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks | 
| Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 16 | PEFR means peak expiratory flow rate and is measured in liter per minute | 16 weeks |