Ipratropium Bromide/Salbutamol Delivered by the Respimat® Inhaler Compared to Ipratropium Bromide Respimat®, COMBIVENT® Inhalation Aerosol and Placebo in Adults With Chronic Obstructive Pulmonary Disease

Study Overview
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Brief Summary
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The primary objective of this study was to compare the long-term (12-week) bronchodilator efficacy and safety of ipratropium bromide / salbutamol combination administered by the Respimat® 40 mcg / 200 mcg (one inhalation q.i.d.) to COMBIVENT Inhalation Aerosol (two inhalations q.i.d.), ipratropium bromide Respimat® (one inhalation q.i.d.) and Placebo formulations of each in patients with Chronic Obstructive Pulmonary Disease (COPD). An additional objective was to show the superiority of Combivent Respimat as compared to ipratropium bromide (40 mcg) Respimat. Steady state pharmacokinetics over one dosing interval following four weeks of therapy were also characterized.

Official Title
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A Comparison of Ipratropium Bromide/Salbutamol (40 mcg / 200 mcg, One Inhalation) Delivered by the Respimat ® Inhaler to COMBIVENT Inhalation Aerosol (Two Inhalations), Ipratropium Bromide Respimat ® and Placebo of Each Formulation in a 12-week, Double-blind, Safety and Efficacy Study in Adults With Chronic Obstructive Pulmonary Disease

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Ipratropium bromide / Salbutamol
* Drug: Placebo Inhalation solution
* Drug: Ipratropium bromide
* Drug: COMBIVENT Inhalation Aerosol
* Drug: Placebo Inhalation Aerosol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must have a diagnosis of COPD and the following spirometric criteria: Visit 1 (Screening) and Visit 2: Patients must have relatively stable, moderate to severe airway obstruction with an FEV1 ≤65% of predicted normal and FEV1 ≤70% of FVC 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 pulmonary function tests 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 MDI (metered dose inhaler) and the Respimat® inhaler All patients must sign an Informed Consent Form prior to participation in the trial Exclusion Criteria: Patients with significant diseases 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 SGOT (serum glutamic oxaloacetic transaminase) >80 IU/L, SGPT (serum glutamic pyruvic transaminase) >80 IU/L, bilirubin >2.0 mg/dL or creatinine >2.0 mg/dL will be excluded regardless of the clinical condition Patients who have a total blood eosinophil count ≥600/mm3 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 5 years Patients with a history of life-threatening pulmonary obstruction, or a history of cystic fibrosis or clinically evident bronchiectasis Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of a thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1 Patients with a history of asthma or allergic rhinitis Patients with a history of and/or active alcohol or drug abuse Patients with known active tuberculosis Patients with an upper or lower respiratory tract infection or COPD exacerbation in the 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 who regularly use daytime oxygen therapy for more than one hour per day and in the investigator's opinion will be unable to abstain from the use of oxygen therapy Patients who are being treated with cromolyn sodium or nedocromil sodium Patients who are being treated with antihistamines for any excluded allergic conditions Patients using oral corticosteroid medication at unstable doses (i.e., less than 6 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 initiated use of an inhaled steroid or changed doses less than 6 weeks prior to the Screening Visit (Visit 1) or during the baseline period Patients who are being treated with beta-blocker medications, MAO (monoamine oxidase) inhibitors or tricyclic antidepressants. Beta blocker eye medications (e.g., Betoptic) for treatment of non-narrow angle glaucoma are allowed Patients who have had changes in their therapeutic plan within the last 6 weeks prior to the Screening Visit (Visit 1) or during the baseline period Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception Patients with known hypersensitivity to anticholinergic drugs or any component of the ipratropium bromide/salbutamol Respimat® solution (including BAC (Benzalkonium chloride) and EDTA (Ethylenediaminetetraacetic acid)) or the ipratropium bromide/salbutamol MDI components Previous participation in this study Patients who are currently participating in another 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 / Salbutamol Inhalation solution<br> | Drug: Ipratropium bromide / Salbutamol<br> <br> |
| Placebo Comparator: Placebo Inhalation solution<br> | Drug: Placebo Inhalation solution<br> <br> |
| Experimental: Ipratropium bromide Inhalation solution<br> | Drug: Ipratropium bromide<br> <br> |
| Active Comparator: COMBIVENT Inhalation Aerosol (ipratropium bromide/salbutamol)<br> | Drug: COMBIVENT Inhalation Aerosol<br> <br> |
| Placebo Comparator: Placebo Inhalation Aerosol<br> | Drug: Placebo Inhalation Aerosol<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 TAUC0-6 (Total area under the FEV1 (forced expiratory volume in one second) curve from 0 to 6 hours divided by six) |  | Day 85 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 TAUC0-6 |  | Days 1, 29 and 57 | 
| FEV1 TAUC0-8 |  | Days 1, 29, 57 and 85 | 
| Peak FEV1 post treatment over two hours |  | Days 1, 29, 57 and 85 | 
| Change from baseline in Peak FEV1 response |  | Days 1, 29, 57 and 85 | 
| Area under the FEV1 curve from 0 to 6 hours above test-day baseline divided by six for normalization (AUC0-6) |  | Days 1, 29, 57 and 85 | 
| Onset of therapeutic FEV1 response |  | Days 1, 29, 57 and 85 | 
| Duration of therapeutic FEV1 response |  | Days 1, 29, 57 and 85 | 
| Time to peak FEV1 response |  | Days 1, 29, 57 and 85 | 
| TAUC0-6, TAUC0-8 and peak FVC (Forced vital capacity) |  | Days 1, 29, 57 and 85 | 
| Amount of beta agonist therapy used as rescue medication during the treatment period |  | up to day 85 | 
| Number of patients using concomitant medication including corticosteroids during the treatment period |  | up to day 85 | 
| Weekly means of daily symptom scores over the treatment period |  | up to day 85 | 
| Number of patients with at least one COPD exacerbation |  | up to day 85 | 
| Number of COPD exacerbations during the treatment period |  | up to day 85 | 
| Physician's Global Evaluation |  | Days 1, 29, 57 and 85 | 
| Trough PEFR (peak expiratory flow rate) measured by the patient at home once daily |  | up to day 85 | 
| Number of patients with adverse events |  | up to day 85 | 
| Incidence of paradoxical bronchoconstriction on the test day |  | up to day 85 | 
| Number of COPD exacerbation days |  | up to day 85 | 
| Number of patients with clinically significant changes in vital signs |  | Baseline, days 1, 29, 57 and 85 | 
| Number of patients with abnormal changes in laboratory parameters |  | Days 29 and 85 | 
| Number of patients with abnormal changes in 12-lead electrocardiogram (ECG) parameters |  | pre-treatment and 1 hour post-treatment on days 1, 29 and 85 | 
| Plasma ipratropium and salbutamol concentrations |  | pre-treatment, 5, 15, 30 and 60 minutes and 2, 4 and 8 hours after inhalation of test drug on day 29 | 
| Renal excretion amounts of ipratropium and salbutamol |  | 0-2 hours, 2-8 hours at day 29 | 
| Length of COPD exacerbations during the treatment period |  | up to day 85 |