Pharmacodynamic and Pharmacokinetic Dose Ranging Study of Tiotropium Bromide Administered Via Respimat Device in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Inclusion criteria

• Age: ≥ 40 years;
• Diagnosis of COPD and met the following criteria:

• Relatively stable, moderate to severe airway obstruction,
• Baseline 30% ≤ FEV1 ≤ 65% of predicted normal value, predicted normal values are based on the guidelines for standardized lung function testing of the European Community for Coal and Steel (ECCS) ,
• Baseline FEV1/ forced expiratory vital capacity (FEVC) ≤ 70%;
• Smoking history ≥ 10 pack-years (p.y.). A p.y. is defined as the equivalent of smoking one pack of cigarettes per day for one year;
• Male of female;
• Ability to be trained in the proper use of Respimat and Handihaler;
• Ability to be trained in the performance of technically satisfactory pulmonary function tests;
• Ability to provide written informed consent
• Patient affiliated to the Social Security System

Exclusion criteria

• History of asthma, allergic rhinitis or atopy or who have a blood eosinophil count above 600/mm³
• Changes in the therapeutic (pulmonary) plan within the last six weeks prior to the Screening Visit;
• Treatment by cromolyn/nedocromil sodium;
• Treatment by antihistamines (H1 receptor antagonists);
• A lower respiratory tract infection or any exacerbation in the past six weeks prior to the Screening Visit;
• Regular use of daytime oxygen therapy;
• Treatment by oral corticosteroid medication if initiated or modified within the last six weeks or if daily dose > 10 mg prednisone equivalent;
• History of life threatening pulmonary obstruction, cystic fibrosis or bronchiectasis
• Patients who have undergone thoracotomy with pulmonary resection;
• History of clinically significant cardiovascular, renal neurologic, liver or endocrine dysfunction. A clinically significant disease was defined as one which in the opinion of the investigator may either put the patient at risk because of participation in the study or a disease which may influence the results of the study or the patient's ability to participate in the study.
• Patients with a recent (≤ one year) history of myocardial infarction, of heart failure or patients with any cardiac arrhythmia requiring drug therapy;
• Tuberculosis with indication for treatment;
• History of cancer within the last five years. Patients with treated basal cell carcinoma were allowed:
• Current psychiatric disorders;
• Patients with known symptomatic prostatic hypertrophy or bladder neck obstruction;
• Patients with any history of glaucoma or increased intra-ocular pressure;
• Patients with clinically significant abnormal baseline haematology or blood chemistry, if the abnormality defines a disease listed as an exclusion criterion;
• Patients with

• glutamyl-oxalo-acetic transaminase/glutamyl-pyruvic transaminase (SGOT/SGPT): > 200% of the upper limit of the normal range (ULN, )
• bilirubin: > 150% of the ULN,
• creatinine: > 125% of the ULN;
• Intolerance to aerosolised anticholinergic containing products, and/or hypersensitivity to benzalkonium chloride, to lactose or any other components of the inhalation capsule delivery system;
• Beta-blocker medication;
• Concomitant or recent (within the last month) use of investigational drugs;
• History of drug abuse and/or alcoholism;
• Pregnant or nursing women and women of childbearing potential not using a medically approved means of contraception ( urinary pregnancy test at screening);
• Previous participation in this study (i.e. having been allocated a randomised treatment number);
• Patients deprived of their freedom by a judicial or administrative decision;
• Minors, adults under guardianship;
• Persons in medical or social establishments;
• Patients in emergency situations