A 12-Month Study Comparing Fluticasone Propionate/Salmeterol (ADVAIR) DISKUS Combination Product 250/50mcg Twice Daily To Fluticasone Propionate (FLOVENT) DISKUS 250 mcg Twice Daily In Symptomatic Patients With Asthma

A 52-week, Randomized, Double-Blind, Parallel-Group Study of Fluticasone Propionate/Salmeterol DISKUS Combination Product (FSC) 250/50 mcg BID and Fluticasone Propionate (FP) DISKUS 250 mcg BID in Treatment of Subjects With Asthma

This purpose of this study is to show the superiority and long term safety and efficacy of adding a long acting beta agonist (salmeterol) to constant dose of an inhaled corticosteroid (fluticasone propionate) in symptomatic subjects with asthma. The 12-month assessment of asthma control will provide key information on the efficacy and safety of the combination therapy. The safety measure will be an assessment of adverse events

Inclusion Criteria:

• Subjects eligible for enrollment in the study must meet all of the following criteria:

  1. Consent: A signed and dated written informed consent must be obtained from the subject and/or subject's legally acceptable representative prior to study participation.
  2. Type of Subject: Outpatient
  3. Gender: Male or female Females are eligible to participate only if they are currently non-pregnant and non-lactating.

A female is eligible to enter and participate in the study if she is:

1. of non-child-bearing potential; OR

2. of child-bearing potential but has a negative urinary pregnancy test at Screening (Visit 1 and when specified in Appendix 1) and agrees to take contraceptive precautions (including abstinence) which are adequate to prevent pregnancy during the study.

   Acceptable methods of contraception [Hatcher, 2004] are:

   - Abstinence

   • oral contraceptive (either combined or progestogen only)

   • injectable progestogen

   • implants of levonorgestrel

   • estrogenic vaginal ring

   • percutaneous contraceptive devices

   • intrauterine device (IUD) or intrauterine system (IUS) with published data showing that the lowest expected failure rate is less than 1% per year

   • male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study and is the sole sexual partner for that female subject

   • double barrier method: condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent

     1. Age: A subject must be 12 years of age at Visit 1 (screening).
     2. Asthma Diagnosis: A documented diagnosis of persistent asthma, for at least six months, as defined by the following American Thoracic Society definition:

   Asthma is a clinical syndrome characterized by increased responsiveness of the airways to a variety of stimuli. The major symptoms of asthma are episodes of dyspnea, wheezing, and cough, which may vary from mild and almost undetectable to severe and unremitting (status asthmaticus). The primary physiological manifestation of this hyperresponsiveness is variable airway obstruction. This can take the form of spontaneous fluctuations in the severity of obstruction, substantial improvements in the severity of obstruction following bronchodilators or corticosteroids, or increased obstruction caused by drugs or other stimuli [American Thoracic Society, 1987].

   1. Asthma Medication History: A subject must be using a low to medium dose of an ICS (Table 1) OR a combination of controller medications (Table 2), containing a low (total daily) dose ICS (as defined in Table 1) for at least 4 weeks preceding screening.

   Table 1 (ICS Dosage Table) Inhaled Corticosteroid (Dosage (mcg/day))(LowMedium) Beclomethasone dipropionate CFC (168 = 504> 504 = 840) Beclomethasone dipropionate HFA (80 = 240>240 = 640) Triamcinolone acetonide (400 = 1000>1000 = 2000) Flunisolide (500 = 1000> 1000 = 2000) Fluticasone propionate inhalation aerosol (176 = 220> 220 = 440) Fluticasone propionate inhalation powder (100 = 250> 250 = 500) Budesonide1 (200 = 600> 600 =1200) Mometasone (200 = 400> 400 = 800) Ciclesonide (80 = 160>160 = 320)

   1.Respules are allowed at a dosage of 250-500mcg/day.

   Table 2 (Asthma Controller Medications) Asthma Controller Medication(s) Low dose ICS + Leukotriene modifiers Low dose ICS + Theophylline products Low Dose ICS + Inhaled anticholinergics or combination products (e.g., Atrovent or Combivent) Low Dose ICS + Long acting inhaled anticholinergic (e.g. Spiriva) Low dose ICS+ long acting beta agonist or combination products containing a low dose ICS and a long-acting beta-agonists (e.g. ADVAIR™/SERETIDE™1 100/50 mcg BID or Symbicort 160/9 mcg BID (i.e 80/4.5 mcg two inhalations BID)

   1.ADVAIR/SERETIDE =250/50 mcg BID or Symbicort 320/9 mcg BID (i.e 160/4.5 mcg two inhalation BID) are not permitted.

   1. Pulmonary function: A pre-albuterol (salbutamol) FEV1 of 50% and 85% of predicted normal value at screening (Visit 1) after withholding asthma medications as detailed in the protocol (Section 6.8.1). Predicted FEV1 will be based on the National Health and Nutrition Examination Survey (NHANES III) predicted normal values for ages 8 years and older [Hankinson, 1999].
   2. Reversibility: An increase in FEV1 of 12% over the pre-albuterol (salbutamol) FEV1 within 30 minutes after the inhalation of 2-4 puffs of albuterol (salbutamol). Historical documentation of reversibility will not be permitted.
   3. Asthma symptom criteria: Each subject must have experienced asthma symptoms requiring albuterol (salbutamol) use within the 4 weeks preceding screening (Visit 1).

   Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the investigational product that may impact subject eligibility is provided in the IB and the product labels.

   Exclusion Criteria:

   • Subjects meeting any of the following criteria must not be enrolled in the study:

     1.Life-Threatening Asthma: A subject must not have life-threatening asthma. Life-threatening asthma is defined for this protocol as a history of significant asthma episode(s) requiring intubation associated with hypercapnia, respiratory arrest, or hypoxic seizures, or asthma-related syncopal episode(s) within the 12 months prior to screening (Visit 1).

     2.Worsening of Asthma: A subject must not have experienced a worsening of asthma which involved an ER visit, hospitalization or use of oral/parenteral corticosteroids within 4 weeks of screening (Visit 1).

     3.Intermittent, Seasonal, or Exercise-Induced Asthma Alone: Subjects with only intermittent or seasonal or exercise-induced asthma are excluded from participation in this study.

     4.Concurrent Respiratory Disease: A subject must not have current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, or other respiratory abnormalities other than asthma.

     5.Concurrent Conditions/Diseases: A subject with historical or current evidence of any clinically significant, co-morbid or uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or would confound the interpretation of the results if the condition/disease exacerbated during the study.

   The list of excluded conditions/diseases includes, but is not limited to:

   congestive heart failure known aortic aneurysm clinically significant coronary clinically significant cardiac arrhythmia heart disease stroke within 3 months of screening (Visit 1) uncontrolled hypertension coronary artery disease hematologic, hepatic, or renal disease cystic fibrosis poorly controlled peptic ulcer dyspnea by any other cause than asthma gastroesophageal reflux disease (GERD) not controlled by pharmacotherapy and may be causing/contributing to subject's respiratory symptoms thyrotoxicosis hypokalemia immunologic compromise current malignancy1 tuberculosis (current or quiescent) Cushing's or Addison's disease pneumonia, pneumothorax, chronic bronchitis or atelectasis uncontrolled diabetes mellitus recent history of drug or alcohol abuse 1.history of malignancy is acceptable only if subject has been in remission for one year prior to screening (Visit 1; remission = no treatment for the malignancy in the 12 months prior to screening [Visit 1])

   1. Drug Allergy: A subject must not have had any immediate or delayed hypersensitivity to any beta2-agonist; sympathomimetic drug; any intranasal; inhaled or systemic corticosteroid therapy; lactose; or have a severe milk protein allergy.

   2. Respiratory Tract Infections: A subject must not have had any sinus, middle ear, oropharyngeal, upper or lower respiratory tract infection symptoms that have not resolved at least 7 days immediately preceding screening (Visit 1).

   3. Asthma Medications: Asthma medications listed below must not have been used prior to screening (Visit 1) for the required exclusion period as indicated below:

      Medication (Exclusion Period Prior to screening (Visit 1)) Oral or parenteral systemic corticosteroids (4 weeks) Omalizumab (Xolair) (6 months)

   1. Concurrent Medications: A subject must not have the concurrent use of any of the following medications that interact with any of the study drugs used in this study, or that may affect the course of asthma or interact with sympathomimetic amines, such as:

      - beta-adrenergic receptor blocking agents

      - monoamine oxidase (MAO) inhibitors

      - tricyclic antidepressants

      - ritonavir

      • ketoconazole

   2. Concurrent use of asthma medications: Concurrent use of all asthma medications (other than protocol defined study and rescue medications and oral/parenteral corticosteroids) are prohibited during the study.

   3. Concomitant use of leukotriene modifiers (LTM) for allergies is prohibited. A subject must not be on LTM for treatment of nasal allergies that requires regular maintenance therapy. Substitution with any other antihistamine is permitted.

   4. Immunosuppressive Medications: A subject must not be using, or require the use of, immunosuppressive medications during the study.

   5. Immunotherapy for the treatment of allergies is not allowed during the study unless the subject has used a constant dose for 4 weeks prior to Screening (Visit 1) and the same dose will be continued throughout the study.

   6. Tobacco Use: >10 pack year history or use of any tobacco products within 1 year of screening (Visit 1). This includes cigarettes, cigars, pipe, chewing tobacco, and snuff.

   7. Questionable Validity of Consent: A subject must not have any infirmity or disability that would limit the subject's consent.

   8. Positive Pregnancy Test (for all females who have had menarche): A current positive pregnancy test.

   9. Investigational Medications: A subject must not have had use of any investigational drug within 30 days of screening (Visit 1).

   10. Site Affiliation: A subject may not participate if he/she is a participating investigator, sub-investigator, study coordinator, employee of a participating investigator or is in any way associated with the administration of the study. Immediate family members of these individuals are also excluded.

   11. Compliance with Study Requirements: A subject may not participate if, in the opinion of the investigator, there are present or anticipated circumstances that will prohibit the subject from being compliant with study visits and procedures (e.g. geographic location that will prohibit subject from required clinic visit schedule).