Study to Assess the Safety of Ipratropium Bromide, in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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Study to assess the safety of two-week administration of 80 and 160 mcg of ipratropium bromide as delivered by the RESPIMAT® device and as determined by 24 hours ambulatory ECG monitoring in COPD patients. To assess the overall safety of the two doses of ipratropium bromide as delivered by the RESPIMAT® device when administered over a two-week period.

Official Title
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A Double-blind, Placebo Controlled Trial to Assess the Safety of Two-week Administration of 80 mcg q.i.d. and 160 mcg q.i.d. of Ipratropium Bromide, as Delivered by the RESPIMAT® Device, in Patients With Chronic Obstructive Pulmonary Disease

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Ipratropium Bromide low dose
* Drug: Placebo
* Drug: Ipratropium Bromide high dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must have a diagnosis of COPD and must meet the following spirometric criteria: Patients must have relatively stable, moderate to severe airway obstruction with an FEV1 <=65% of predicted normal and FEV1 <=70% of forced vital capacity (FVC). Predicted normal value will be calculated according to Morris Males: FEV1 = 0.093 (Height in inches)-0.032 (age)-1.343 Females: FEV1 = 0.085 (Height. in inches)-0.025(age)-1.692 Male or female patients 40 years of age or older Patients must have a smoking history of more than 10 pack-years. A pack-year is defined as the equivalent of smoking one pack of 20 cigarettes per day for a year Patients must be able to perform pulmonary function tests (PFTs) and maintain records during the study period as required in the protocol Patients must be able to be trained in the proper use of an inhalation aerosol and the RESPIMAT™ device Patients must have a baseline electrocardiogram (ECG) with no clinical relevant arrhythmias or conduction system disease (e.g. right or left bundle branch block, second degree AV block or higher) Patients must have an oxygen saturation of >=90% for >=92% of the recording time on overnight oximetry All patients must sign an Informed Consent Form prior to participation in the trial (i.e., at least 24 hours (h) prior to the screening visit (Visit 1)) Exclusion Criteria: Patients with clinically relevant diseases other than COPD will be excluded. A clinically relevant disease is defined as a disease which in the opinion of the investigator may either put the patient at risk because of participation in the study or a disease with may influence the results of the study or patient's ability to participate in the study Patients with a recent history (i.e. one year or less) of myocardial infarction Patients with a recent history (i.e. one year or less) of heart failure or patients with any past history or active cardiac arrhythmia requiring drug therapy Patients who have a pacemaker Patients with clinically relevant abnormal baseline hematology, blood chemistry or urinalysis. If the abnormality defines a disease listed as an exclusion criterion the patient is excluded All patients with serum glutamic oxaloacetic transaminase / Aspartate aminotransferase (SGOT/AST) >80 IU/L, serum glutamic pyruvic transaminase / Alanine transaminase (SGPT/ALT) >80 IU/L, bilirubin >2.0 mg/dl, or creatinine >2.0 mg/dl will be excluded regardless of the clinical condition. Repeat laboratory evaluation will be not be conducted in these subjects Patients who have a blood eosinophil count >=600/mm3. A Repeat eosinophil count will be not be conducted in these patients Patients with a history of cancer, other than treated basal cell carcinoma, within the last 5 years Patients with a history of life-threatening pulmonary obstruction, or a history of cystic fibrosis or bronchiectasis Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reason should be evaluated per exclusion criterion No. 1 Patients with a history of asthma, allergic rhinitis or atopy Patients with a history of and/or active alcohol or drug abuse Patients with known active tuberculosis Patients with an upper respiratory tract infection or COPD exacerbation in the past 6 weeks prior to the screening visit (Visit 1) or during the baseline period Patients with known symptomatic prostatic hypertrophy or bladder neck obstruction Patients with known narrow-angle glaucoma Patients with current significant psychiatric disorders Patients with regular use of daytime oxygen therapy Patients who are being treated with cromolyn sodium or nedocromil sodium Patients who are being treated with antihistamines Patients using oral corticosteroid medication at unstable doses (i.e. less than six weeks on a stable dose) or at a dose in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day Patients who are being treated with beta-blocker medication Patients who have had changes in their therapeutic plan within the last six weeks prior to the screening visit (visit 1) Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception (e.g., oral contraceptive, intrauterine devices, diaphragm or Norplant®) Patients with known hypersensitivity to ant cholinergic drugs or any other components of the ATROVENT® RESPIMAT™ solution including bacteriostatic agent benzalkonium chlorid (BAC) and edetic acid (EDTA) Patients who have taken an investigational drug within 1 month or 6 half-lives (whichever is longer) prior to the screening visit (visit1) Previous participation in this study

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: Ipratropium Bromide low<br>delivered via RESPIMAT® | Drug: Ipratropium Bromide low dose<br> <br> |
| Experimental: Ipratropium Bromide high<br>delivered via RESPIMAT® | Drug: Ipratropium Bromide high dose<br> <br> |
| Placebo Comparator: Placebo<br>delivered via RESPIMAT® | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of clinical significant findings in 24-hour ambulatory ECG monitoring |  | Pre-treatment, on Day 7 and 13 | 
| Number of patients with adverse events |  | Up to 15 days after first drug administration | 
| Number of patients with clinical significant findings in ECG |  | Up to 15 days after first drug administration | 
| Number of patients with clinical significant findings in vital signs |  | Up to 15 days after first drug administration | 
| Number of patients with clinical significant findings in laboratory tests |  | Up to day 15 after drug administration | 
| Number of patients with paradoxical bronchospasm |  | Up to 15 days after first drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 (forced expiratory volume in the first second) AUC0-4 (Area under the curve from 0 to 4 hours) |  | Pre-treatment, up to 4 h after drug administration on Day 1 and 14 | 
| Peak FEV1 |  | On Day 1 and 14 | 
| Onset of therapeutic FEV1 response |  | On Day 1 and 14 | 
| Time to peak FEV1 response |  | On Day 1 and 14 | 
| AUC(0-6h) (Area under the plasma concentration-time curve from 0 to 6 h) |  | Day 14 | 
| Cmax (maximum plasma concentration) |  | Day 14 | 
| Cmin(0h) (minimum plasma concentration before inhalation) |  | Day 14 | 
| Cmin(6h) (minimum plasma concentration at 6 hours after inhalation) |  | Day 14 | 
| Ae(0-2h) (urine excretion between 0 to 2 h) |  | Day 14 | 
| Ae(0-6h) (urine excretion between 0 to 6 h) |  | Day 14 |