4 Week 2 Way Crossover Double Blind Treatment Phase With Combivent CFC Versus Albuterol Followed by a 4 Week Open Label Combivent Respimat When All Drugs Are Used for Symptom Relief as Needed in Pts With Moderate to Severe Asthma

Study Overview
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Brief Summary
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The primary goal of this trial is to compare the efficacy and safety of COMBIVENT CFC MDI with albuterol HFA MDI, the current standard reliever medication in asthma. In the first cross-over part of the study (Treatment Phases 1 and 2) the marketed product, COMBIVENT CFC MDI will be used. In the second, parallel group part of the trial (Treatment Phase 3) COMBIVENT RESPIMAT will be tested for acute bronchodilator efficacy in a blinded manner at the clinic visits. During the third 4-week treatment phase open label COMBIVENT RESPIMAT will be used for symptom relief as needed.

Official Title
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A Multicenter Randomized Study Starting With a 4 Week 2 Way Crossover Double Blind Treatment Phase Comparing the Efficacy and Safety of Combivent CFC MDI to Albuterol HFA MDI Followed by a 4 Week Open Label Combivent Respimat Treatment Phase When All Study Drugs Are Used for Symptom Relief as Needed in Pts With Moderate to Severe Asthma (GINA 2007 Treatment Steps 3-5)

Conditions
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Asthma

Intervention / Treatment
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* Drug: Combivent CFC MDI
* Drug: Albuterol HFA MDI
* Drug: Respimat Combivent


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must sign and date an Informed Consent consistent with International Conference on Harmonization Good Clinical Practices (ICH GCP) guidelines and local regulations prior to participation in the trial (i.e., prior to any study procedures, including washout of any medication) at Visit 1. Male or female patients greater to or equal to 18 years of age. Physician diagnosis of moderate-to-severe asthma (GINA Guidelines) existing for >1 year. Reversible airway obstruction (more than or equal to 12 % or at least 200 mL improvement in FEV1 post bronchodilator after 4 puffs of albuterol HFA MDI). Pre-bronchodilator clinic measured FEV1 ≤80% of predicted normal value (measured greater to or equal to 6 hours of the last use of short acting bronchodilator and greater to or equal to 12 hours after the last use of LABA if applicable). Continuous treatment with inhaled corticosteroids (ICS) with or without long-acting beta agonists (LABA) and other controller medication(s) for at least 6 weeks prior to screening (GINA 2007 Treatment Steps 3 to 5). No change in dos or regimen of ICS and LABA or other controller medications (including oral corticosteroids [OCS] if applicable), for at least 2 weeks prior to Visit 2. Use of short acting bronchodilator at least three times a week for symptom relief in the 2 weeks prior to Visit 1. Score of ≥1.5 points on the Asthma Control Questionnaire (ACQ) (see Appendix 10.6). Able to perform technically acceptable pulmonary function tests at the clinic and peak flow measurements with the eDiary/Peak Expiratory Flow Meter. Able to perform all necessary recordings (symptoms and as needed medication use) in the electronic diary, which is a part of the eDiary/Peak Expiratory Flow Meter. Investigator assessment of patients ability to inhale medication from a metered dose inhaler and RESPIMAT inhaler. Exclusion Criteria: Significant disease other than asthma not limited to diagnosis of COPD, such as, active tuberculosis, cystic fibrosis, alpha 1 antitrypsin deficiency, clinically significant bronchiectasis, interstitial lung disease, allergic bronchopulmonary aspergillosis, or constrictive bronchiolitis. A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, or (ii) influence the results of the study, or (iii) cause concern regarding the patient ability to participate in the study. History of thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion 1. History of life-threatening asthma attack. Worsening of asthma that required treatment with an addition or increase in OCS dose (steroid burst) in the 4- week period prior to Visit 2. Current or ex-smokers who quit <1 year before enrollment. Ex-smokers who quit less than 1 year from enrollment must have a cigarette smoking history of less than 10 pack years. Pack years = Number of cigarettes/day x years of smoking 20 Use of oral beta-adrenergic agents within 4 weeks prior to screening. Treatment with inhaled ipratropium, ipratropium/albuterol combination, or nasal ipratropium within 1week of Visit 2. Treatment with inhaled tiotropium within 4 weeks of Visit 2. Known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC), ethylenediaminetetracetic acid (EDTA) or any other components of the tiotropium inhalation solution or MDI. Known narrow-angle glaucoma. Clinically relevant abnormal hematology or blood chemistry at screening if the abnormality defines a significant disease as defined in exclusion criterion 1. Recent history (i.e., one year less) of myocardial infarction. Cardiac arrhythmias, newly diagnosed arrhythmias and/or any arrhythmia requiring an intervention (i.e., hospitalization, cardio version, pacemaker placement, and automatic implantable cardiac defibrillator placement) or a change in drug therapy during the last year. Hospitalization for cardiac failure during the past year. Malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years, with the exception of treated basal cell carcinoma. Unwillingness or inability to use a highly effective method of birth control by women of childbearing potential. Highly effective methods of birth control are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner. Barrier methods of contraception are accepted if condom or occlusive cap is used together with spermicides (e.g., foam or gel). Female patients will be considered to be of childbearing potential unless surgically sterilized by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years. Pregnancy or nursing. Any investigational drug taken within 30 days or six half-lives (whichever is greater) prior to Visit 2. Previous randomization in this study or current participation in another study. Symptomatic prostate hypertrophy or bladder neck obstruction. Patients with symptomatically controlled prostate hypertrophy on medications may be included and should continue their medications. Use of monoamine oxidase inhibitors or tricyclic antidepressants. Examples include but are not limited to the following for monoamine oxidase inhibitors nardil, parnate, marplan and for tricyclic antidepressants: amitriptyline, norpramine, and pamelor. History of and/or active alcohol or drug abuse. Patient who have been treated with beta-blocker medication during the screening of the study. Topical cardio-selective beta-blocker eye medications for treatment of acute angle glaucoma are allowed.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Crossover Assignment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Combivent CFC MDI|nan|
|Drug: Albuterol HFA MDI|nan|
|Drug: Respimat Combivent|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 AUC0-6 Response (Crossover Part of the Study) | Change from baseline after 4 weeks in Forced Expiratory Volume Area Under (FEV1 AUC) the Curve from 0 to 6 hours. | Test day baseline and test day FEV1 AUC 0-6, after 4 weeks | 
| Peak FEV1 Response (Crossover Part of the Study) | Change from baseline after 4 weeks in peak Forced Expiratory Volume response | Test day baseline and test day peak FEV1, after 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mini Asthma Quality of Life Questionnaire (Crossover Part of the Study) | Change from baseline after 4 weeks in Mini-AQLQ score. Worst score - 1 (most severe), best score - 7 (less severe) | Baseline, 4 weeks | 
| Asthma Control Questionnaire (Crossover Part of the Study) | Change from baseline after 4 weeks in ACQ score. Worst score - 6(most severe), best score - 0 (no symptoms) | Baseline, 4 weeks | 
| Puffs Study Medication Used During Day (Crossover Part of the Study) | Change from baseline in weekly mean of puffs of blinded study medication (albuterol HFA or combivent CFC) used during day | Baseline, 4 weeks | 
| Puffs Study Medication Used During Night (Crossover Part of the Study) | Change from baseline in weekly mean of puffs of blinded study medication (albuterol HFA or combivent CFC) used during night | Baseline, 4 weeks | 
| Puffs Open-label Albuterol Used During Day (Crossover Part of the Study) | Change from baseline in weekly mean of puffs of open-label albuterol used during day | Baseline, 4 weeks | 
| Puffs Open-label Albuterol Used During Night (Crossover Part of the Study) | Change from baseline in weekly mean of puffs of open-label albuterol used during night | Baseline, 4 weeks | 
| FEV1 AUC0-6 Response (Parallel Part of the Study) | Change from baseline after 4 weeks in Forced Expiratory Volume Area Under the Curve from 0 to 6 hours | Test day baseline and test day FEV1 AUC 0-6, after 4 weeks | 
| Peak FEV1 Response | Change from baseline after 4 weeks in peak Forced Expiratory Volume response | Test day baseline and test day peak FEV1, after 4 weeks |