Comparison of Safety and Efficacy of COMBIVENT HFA to COMBIVENT (CFC) in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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To compare the long-term (one-year) bronchodilator efficacy and safety of COMBIVENT hydrofluoroalkane (HFA) Inhalation Aerosol to COMBIVENT chlorofluorocarbon (CFC) Inhalation Aerosol and Placebo formulations of each in patients with COPD. In addition, steady state pharmacokinetics over one dosing interval following four weeks of therapy will be characterized.

Official Title
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A One-year Randomized, Double-blind, Placebo and Active-controlled Parallel Design Safety and Efficacy Comparison of COMBIVENT HFA Inhalation Aerosol to COMBIVENT (CFC) Inhalation Aerosol in Patients With COPD

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: COMBIVENT HFA
* Drug: Placebo HFA
* Drug: COMBIVENT CFC
* Drug: Placebo CFC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must have a diagnosis of COPD Male or female patients 40 years of age or older Patients must have a smoking history of more than ten 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 technically satisfactory pulmonary function tests Patients must be able to be trained in the proper use of a metered dose inhalator (MDI) All patients must sign an Informed Consent Form prior to participation in the trial i.e. prior to pre-study washout of their usual pulmonary medications Patients must be on at least one regular aerosol bronchodilator for control of their COPD symptoms and have symptoms of bronchospasm (wheeze or shortness of breath) present OR Patients must be on at least two classes of prescribed bronchodilators on a regular basis for control of their COPD symptoms for the three month period immediately preceding the screening visit. Exclusion Criteria: Patients with significant disease other than COPD will be excluded. A significant 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 which may influence the results of the study or the patient's ability to participate in the study 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 a serum aspartate amino transferase (ASAT/SGOT) > 80 IU/L, serum alanine amino transferase (ALAT/SGPT) > 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 not be conducted in these patients. Patients who have a total bood eosinophil count >= 600 mm**3. A repeat eosinophil count will not be conducted in these patients Patients with a recent history (i.e. one year or less) of myocardial infarction Patients with a recent history (i.e. three years or less) of heart failure or patients with any cardiac arrhythmia requiring drug therapy Patients with a history of cancer, other than treated basal cell carcinoma, within the last five 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 wth a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1 Patients with a history of asthma, allergic rhinitis or atopy. Patients with a history of or active alcohol or drug abuse Patients with known active tuberculosis Patients with an upper respiratory tract infection or COPD exacerbation in the six 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 beta-blocker medications, monoamine oxidase (MAO) inhibitors or tricyclic antidepressants 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 or at a dose in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day Patients who have been treated with oral beta-adrenergics or long-acting beta-adrenergics in the two weeks prior to the Screening Visit or during the baseline period Patients who have had changes in their therapeutic plan within the last six weeks prior to the Screening Visit or during the baseline period, excluding changes from long acting or oral beta-adrenergics to short acting inhaled beta-adrenergics for purposes of this trial Pregnant of nursing women or woman of childbearing potential not using a medically approved means of contraception Patients with known hypersensitivity to anticholinergic or beta-agonist drugs or any other component of either COMBIVENT formulation Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to Screening visit 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: COMBIVENT HFA<br> | Drug: COMBIVENT HFA<br> <br> |
| Placebo Comparator: Placebo HFA<br> | Drug: Placebo HFA<br> <br> |
| Active Comparator: COMBIVENT (CFC)<br> | Drug: COMBIVENT CFC<br> <br> |
| Placebo Comparator: Placebo CFC<br> | Drug: Placebo CFC<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve from 0 to 6 hours (AUC0-6) of forced expiratory volume in the first second (FEV1) |  | after 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak FEV1 response |  | 28 weeks | 
| Onset of therapeutic FEV1 response |  | 28 weeks | 
| Duration of therapeutic FEV1 response |  | 28 weeks | 
| Time to peak FEV1 response |  | 28 weeks | 
| Average FEV1 response as area under the curve from 0 - 6 hours divided by six (TAUC0-6) |  | 28 weeks | 
| Average forced vital capacity (FVC) response area under the curve from 0 - 6 hours divided by six (AUC0-6) |  | 28 weeks | 
| Number of participants requiring test-day rescue therapy |  | 28 weeks | 
| Peak expiratory flow rate (PEFR) |  | 28 weeks | 
| Daily COPD symptom scores |  | 28 weeks | 
| Number of puffs of rescue medication |  | 28 weeks | 
| Number and length of COPD exacerbations |  | 28 weeks | 
| Average FEV1 response as area under the curve from 0 - 8 hours divided by six (TAUC0-8) |  | 28 weeks | 
| Number of adverse events including paradoxical bronchoconstrictions |  | 28 weeks | 
| Number of patients with clinically significant changes in pulse rate and blood pressure |  | 28 weeks | 
| Plasma ipratropium concentration |  | pre-treatment, 5, 15, 30 min; 1, 2, 4 and 8 hours | 
| Plasma albuterol concentration |  | pre-treatment, 5, 15, 30 min; 1, 2, 4 and 8 hours | 
| Renal excretion of ipratropium fractions |  | pre-treatment, 0 - 2 hours, 2 - 8 hours | 
| Renal excretion of albuterol fractions |  | pre-treatment, 0 - 2 hours, 2 - 8 hours | 
| Physician's global evaluation on an 8-point scale |  | 28 weeks | 
| Peak FVC response |  | 28 weeks | 
| Number of patients with clinically significant changes in laboratory tests |  | 28 weeks | 
| Number of patients with abnormal findings in physical examination |  | 28 weeks | 
| Number of patients with clinically significant changes in electrocardiogram |  | 28 weeks |