Efficacy and Safety of Tiotropium Compared to Salmeterol and Placebo in Patients With Chronic Obstructive Bronchitis (COPD)

Study Overview
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Brief Summary
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The objective of this study is to compare the long-term (six month) bronchodilator efficacy and safety of tiotropium inhalation capsules, salmeterol inhalation aerosol and placebo inpatients with COPD.

Official Title
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A Multiple Dose Comparison of Tiotropium Inhalation Capsules, Salmeterol Inhalation Aerosol and Placebo in a Six-Month, Double-Blind, Double-Dummy, Safety and Efficacy Study in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Tiotropium inhalation powder capsules
* Drug: Salmeterol inhalation aerosol
* Drug: Placebo inhalation aerosol
* Drug: Placebo inhalation powder capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 40 years. A diagnosis of relatively stable, moderate to severe COPD with: Screening FEV1 ≤ 60% of predicted normal value (calculated according to European Community for Coal and Steel (ECCS) criteria and screening FEV1/FVC ≤ 70% Smoking history ≥ 10 pack-years (a pack-year is 20 cigarettes per day for one year or equivalent) Ability to be trained in the proper use of the HandiHaler® device and Metered Dose Inhaler (MDI). Ability to perform all study related tests including the Shuttle Walking Test, acceptable pulmonary function tests, including Peak expiratory flow rate (PEFR) measurements, and maintenance of diary card records. Ability to give written informed consent in accordance with Good Clinical Practice and local regulations. Exclusion Criteria: Clinically significant diseases other than COPD. Patients with clinically relevant abnormal baseline haematology, blood chemistry or urinalysis, if the abnormality defines a disease listed as an exclusion criterion, will be excluded. All patients with a serum glutamic oxaloacetic transaminase (SGOT) > 80 IU/L, serum glutamic pyruvic transaminase (SGPT) > 80 IU/L, bilirubin >2.0 mg/dL or creatinine > 2.0 mg/dL will be excluded regardless of clinical condition. A recent history (i.e., one year or less) of myocardial infarction. Any cardiac arrhythmia requiring drug therapy or hospitalisation for heart failure within the past three years. Inability to abstain from regular daytime use of oxygen therapy for more than 1 hour per day. Known active tuberculosis. History of cancer within the last five years (excluding basal cell carcinoma) History of life-threatening pulmonary obstruction, or a history of cystic fibrosis or bronchiectasis. Patients who have undergone thoracotomy with pulmonary resection. Any upper respiratory infection in the past six weeks prior to the screening visit or during the run-in period. Current participation in a pulmonary rehabilitation programme or completion of a pulmonary rehabilitation programme in the six week prior to the screening visit. Known hypersensitivity to anticholinergic drugs, salmeterol, or any of the components of the lactose powder capsule or MDI delivery systems. Known symptomatic prostatic hypertrophy or bladder neck obstruction. Patients with known narrow-angle glaucoma. Current treatment with cromolyn sodium or nedocromil sodium. Current treatment with antihistamines (H1 receptor antagonists). 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 prednisolone per day or 20 mg every other day. Current use of β-blocker medication. Current treatment with monoamine oxidase inhibitors or tricyclic antidepressants. Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception. Patients with a history of asthma, allergic rhinitis or atopy or who have a total blood eosinophil count > 600mm3. History of and/or active significant alcohol or drug abuse. Concomitant or recent use of an investigational drug within one month or six half lives (whichever is greater) prior to the screening visit. Changes in the pulmonary therapeutic plan within the six weeks prior to the screening visit. Inability to comply with the medication restrictions specified in Section 4.2 of the trial protocol

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 |
| --- | --- |
| Experimental: Tiotropium<br> | Drug: Tiotropium inhalation powder capsules<br> <br> Drug: Placebo inhalation aerosol<br> <br> |
| Active Comparator: Salmeterol<br> | Drug: Salmeterol inhalation aerosol<br> <br> Drug: Placebo inhalation powder capsules<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo inhalation aerosol<br> <br> Drug: Placebo inhalation powder capsules<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough forced expiratory volume in one second (FEV1) response |  | 6 months | 
| Transition Dyspnoea Index (TDI) focal score |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average FEV1 response |  | 30 and 60 min prior to and 30 and 60 min, 2 and 3 h post treatment on day 1, week 2, 8, 16, 24 | 
| Peak FEV1 response |  | 30 and 60 min prior to and 30 and 60 min, 2 and 3 h post treatment on day 1, week 2, 8, 16, 24 | 
| Trough FVC (forced vital capacity) response |  | 30 and 60 min prior to and 30 and 60 min, 2 and 3 h post treatment on day 1, week 2, 8, 16, 24 | 
| Average FVC (forced vital capacity) response |  | 30 and 60 min prior to and 30 and 60 min, 2 and 3 h post treatment on day 1, week 2, 8, 16, 24 | 
| Peak FVC (forced vital capacity) response |  | 30 and 60 min prior to and 30 and 60 min, 2 and 3 h post treatment on day 1, week 2, 8, 16, 24 | 
| Individual FEV1 measurement |  | Day 1, weeks 2, 8, 16, 24 | 
| Individual FVC measurement |  | Day 1, weeks 2, 8, 16, 24 | 
| Patient peak expiratory flow rates (PEFR) twice daily |  | 27 weeks | 
| Physician's global evaluation on an 8-point-scale |  | 27 weeks | 
| COPD symptom scores (wheezing, shortness of breath, coughing and tightness of chest) |  | 27 weeks | 
| Amount of salbutamol therapy used during the treatment period |  | 27 weeks | 
| Number and length of exacerbations of COPD |  | 27 weeks | 
| Number and length of hospitalizations for respiratory disease |  | 27 weeks | 
| Changes from baseline in St. George's Hospital Respiratory Questionnaire (SGRQ) |  | Day 1, week 8, 16, 24 and 27 | 
| Changes from baseline in Mahler Dyspnoea Index (Baseline Dyspnoea Index /Transitional Dyspnoea Index (BDI/TDI)) |  | Baseline, week 8, 16, 24, 27 | 
| Health resource utilisation |  | 27 weeks | 
| Patient preference measures | patient satisfaction questionnaire score | Day 1 and week 24 | 
| Changes from baseline in Shuttle walking tests (SWT) and Borg dyspnea score |  | Day 1, week 8, 16, 24, 27 | 
| Occurrence of Adverse Events |  | 27 weeks | 
| Changes from baseline in pulse rate and blood pressure in conjunction with spirometry |  | baseline, Day 1, week 2, 8, 16 and 24 | 
| Changes from baseline in physical examination and ECG |  | baseline and week 24 | 
| Changes from baseline in laboratory tests |  | baseline and week 24 |