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
Condition: Asthma
MeSH terms: Asthma
Intervention: Combivent CFC MDI; Albuterol HFA MDI; Respimat Combivent
Intervention MeSH terms: Albuterol
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Crossover Assignment
Enrollment: 226.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. 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.

          2. Male or female patients greater to or equal to 18 years of age.

          3. Physician diagnosis of moderate-to-severe asthma (GINA Guidelines) existing for >1
             year.

          4. 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).

          5. 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).

          6. 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).

          7. 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.

          8. Use of short acting bronchodilator at least three times a week for symptom relief in
             the 2 weeks prior to Visit 1.

          9. Score of ≥1.5 points on the Asthma Control Questionnaire (ACQ) (see Appendix 10.6).

         10. Able to perform technically acceptable pulmonary function tests at the clinic and peak
             flow measurements with the eDiary/Peak Expiratory Flow Meter.

         11. 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.

         12. Investigator assessment of patients ability to inhale medication from a metered dose
             inhaler and RESPIMAT inhaler.

        Exclusion Criteria:

          1. 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.

          2. History of thoracotomy with pulmonary resection. Patients with a history of
             thoracotomy for other reasons should be evaluated as per exclusion criterion 1.

          3. History of life-threatening asthma attack.

          4. 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.

          5. 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

          6. Use of oral beta-adrenergic agents within 4 weeks prior to screening.

          7. Treatment with inhaled ipratropium, ipratropium/albuterol combination, or nasal
             ipratropium within 1week of Visit 2.

          8. Treatment with inhaled tiotropium within 4 weeks of Visit 2.

          9. Known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC),
             ethylenediaminetetracetic acid (EDTA) or any other components of the tiotropium
             inhalation solution or MDI.

         10. Known narrow-angle glaucoma.

         11. Clinically relevant abnormal hematology or blood chemistry at screening if the
             abnormality defines a significant disease as defined in exclusion criterion 1.

         12. 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.

         13. Hospitalization for cardiac failure during the past year.

         14. 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.

         15. 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.

         16. Pregnancy or nursing.

         17. Any investigational drug taken within 30 days or six half-lives (whichever is greater)
             prior to Visit 2.

         18. Previous randomization in this study or current participation in another study.

         19. Symptomatic prostate hypertrophy or bladder neck obstruction. Patients with
             symptomatically controlled prostate hypertrophy on medications may be included and
             should continue their medications.

         20. 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.

         21. History of and/or active alcohol or drug abuse.

         22. 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.