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

Study Overview
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Brief Summary
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This pharmacodynamic and pharmacokinetic dose-ranging study aims to determine the optimal dose of tiotropium inhaled as a solution from a Respimat device once a day for three weeks in patients with COPD.

Official Title
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Pharmacodynamic and Pharmacokinetic Dose Ranging Study of Tiotropium Bromide Administered Via Respimat Device in Patients With Chronic Obstructive Pulmonary Disease (COPD): a Randomized, 3-week Multiple-dose, Placebo Controlled, Intraformulation Double-blind, Parallel Group Study

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Tiotropium 0.625 mcg/puff
* Drug: Tiotropium 1.25 mcg/puff
* Drug: Tiotropium 2.5 mcg/puff
* Drug: Tiotropium 5 mcg/puff
* Drug: Placebo solution
* Drug: Tiotropium-18 lactose powder
* Drug: Placebo lactose powder
* Drug: Tiotropium 10 mcg/puff
* Device: Respimat
* Device: Handihaler


Participation Criteria
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Eligibility Criteria
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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

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-1.25 Respimat<br>Two puffs of tiotropium inhalation solution from a Respimat device, 0.625 mcg/puff | Drug: Tiotropium 0.625 mcg/puff<br> <br> Device: Respimat<br> <br> |
| Experimental: Tiotropium-2.5 Respimat<br>Two puffs of tiotropium inhalation solution from a Respimat device, 1.25 mcg/puff | Drug: Tiotropium 1.25 mcg/puff<br> <br> Device: Respimat<br> <br> |
| Experimental: Tiotropium-5 Respimat<br>Two puffs of tiotropium inhalation solution from a Respimat device, 2.5 mcg/puff | Drug: Tiotropium 2.5 mcg/puff<br> <br> Device: Respimat<br> <br> |
| Experimental: Tiotropium-10 Respimat<br>Two puffs of tiotropium inhalation solution from a Respimat device, 5 mcg/puff | Drug: Tiotropium 5 mcg/puff<br> <br> Device: Respimat<br> <br> |
| Experimental: Tiotropium-20 Respimat<br>Two puffs of tiotropium inhalation solution from a Respimat device, 10 mcg/puff | Drug: Tiotropium 10 mcg/puff<br> <br> Device: Respimat<br> <br> |
| Placebo Comparator: Placebo Respimat<br> | Drug: Placebo solution<br> <br> Device: Respimat<br> <br> |
| Active Comparator: Tiotropium-18 lactose powder Handihaler<br> | Drug: Tiotropium-18 lactose powder<br> <br> Device: Handihaler<br> <br> |
| Placebo Comparator: Placebo lactose powder Handihaler<br> | Drug: Placebo lactose powder<br> <br> Device: Handihaler<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced expiratory volume in one second (FEV1) with emphasis on the last two hours of the 24-hour dosing interval (trough FEV1) |  | last two hours of the 24-hour dosing interval | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced expiratory volume in one second (FEV1) |  | during the first four hours post dose | 
| Forced Vital Capacity (FVC) |  | during first four hours post dose | 
| Pharmacokinetic evaluation: 2-hours urine sampling pre- and post-dose (10 patients per group) |  | before and after last drug administration at day7,14 and 21. | 
| Chronic obstructive pulmonary disease symptom scores, physician's global evaluation, sleep question and use of rescue medication |  | 3 weeks treatment period | 
| Changes in ECG, pulse rate (PR) and blood pressure (BP) from the pre-dose values recorded on test day |  | Day 0, day 7, day 14, day 21 | 
| Changes in ECG, physical examination, haematology and biochemistry recorded before and after the trial |  | Screening, 24 to 28 days after treatment | 
| Occurrence of adverse events |  | up to 28 days |