Advair HFA For Chronic Obstructive Pulmonary Disease(COPD)

Inclusion criteria:

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

• Signed and dated written informed consent obtained from the subject and/or subject's legally acceptable representative prior to study participation.
• Males or females ≥ 40 years of age.

A female is eligible to participate in this study if she is of:

1. non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal [i.e., >1 year without menses in the absence of hormone replacement therapy]); or,

2. child-bearing potential, has a negative pregnancy test (urine) at screen, and one of the following applies:

   • Abstinence from intercourse, or,
   • Male partner was sterile prior to the female subject's entry into the study, or,
   • Use of implants of levonorgestrel; or,
   • Injectable progesterone; or,
   • Oral contraceptive (combined or progesterone only), contraceptive patch, vaginal ring; or,
   • Any intrauterine device (IUD) with published data showing that the highest expected failure rate is less than 1% per year (e.g., Paragard), or,

   • Double barrier technique simultaneously using two of the following: spermicide, male condom, diaphragm, or female condom

     • An established clinical history of COPD (including chronic bronchitis and/or emphysema) in accordance with the following definition by the American Thoracic Society:

COPD is a preventable and treatable disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences [Celli, 2004].

• A post-albuterol FEV1/FVC ratio of ≤ 0.70
• A post-albuterol FEV1 ≥ 0.70L and ≤ 70% of predicted normal OR a post-albuterol FEV1 of ≤ 0.70L and ≥40% of predicted normal but still ≤70% of predicted normal based on NHANES III reference values [Hankinson, 1999].
• Current or previous smokers with a cigarette smoking history of ≥ 10 pack-years. [number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 10 pack-years is equal to 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years]. Former-smokers are defined as subjects who have discontinued smoking for ≥ 6 months prior to Visit 1. Subjects who decide to stop smoking at Visit 1 will not be eligible for participation in the study.

Exclusion Criteria:

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

• A current diagnosis of asthma.
• Any clinically significant and uncontrolled disease, including but not limited to the following: neurological, psychiatric, renal, immunological, endocrine/metabolic (including uncontrolled diabetes, hypokalemia or thyroid disease), cardiovascular, neuromuscular, hepatic, gastric, or hematological abnormalities, or peripheral vascular disease. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or would affect the efficacy analysis if the disease/condition exacerbated during the study.
• A respiratory diagnosis other than COPD (e.g., lung cancer, bronchiectasis, sarcoidosis, tuberculosis, lung fibrosis), including subjects with a diagnosis of alpha-1-antitrypsin deficiency. Allergic rhinitis is not exclusionary.
• An abnormal and clinically significant chest x-ray or computed tomography (CT) scan not believed to be due to the presence of COPD. A chest x-ray must be taken if the subject has not had one within 6 months of Visit 1.

• An abnormal and clinically significant 12-lead electrocardiogram (ECG). For the purposes of this study, an abnormal ECG is defined as a 12-lead tracing which is interpreted with (but not limited to) any of the following:

  • Myocardial ischemia
  • Clinically significant conduction abnormalities (e.g., left bundle branch block, Wolff-Parkinson-White syndrome)
  • Clinically significant arrhythmias (e.g., atrial fibrillation, ventricular tachycardia) The study investigator will determine the clinical significance of any ECG abnormality and determine if a subject is precluded from entering the study.
• Previously diagnosed cancer unless it is in complete clinical remission (no evidence of any tumor burden) at Visit 1. Localized carcinomas of the skin that have been resected for cure are not considered exclusionary.
• Any immediate or delayed hypersensitivity to any beta-agonist, sympathomimetic drug, or intranasal, inhaled, or oral corticosteroid including any components of the formulations (e.g. lactose or milk protein).
• Initiation of systemic beta-blocker medications within 30 days of Visit 1.
• Use of products containing the protease inhibitor ritonavir (Norvir, Kaletra).
• Use of the following medications within the defined times prior to Visit 1:

Medication (Exclusion Prior to Visit 1) Short-acting beta-agonists (e.g., albuterol) (6 hours) Ipratropium (6 hours) Ipratropium/albuterol combination product (6 hours) Oral beta-agonists (48 hours) Salmeterol and formoterol (48 hours) Theophylline preparations (48 hours) Tiotropium (48 hours) Long-acting beta-agonist/inhaled corticosteroid combination products (e.g., ADVAIR™ or Symbicort) (30 days) Inhaled corticosteroids (30 days) Oral or parenteral corticosteroids (30 days) Any investigational drug (30 days)

• Lung resection surgery (e.g., lung volume reduction surgery, or lobectomy) within 1 year of Visit 1.
• A COPD exacerbation and/or infection of the upper or lower respiratory tract requiring treatment with systemic (oral or parenteral) corticosteroids and/or antibiotics that has not resolved within 30 days of Visit 1
• A COPD exacerbation that resulted in hospitalization that has not resolved within 3 months of Visit 1.
• Use of nocturnal positive pressure [e.g., continuous positive airway pressure or bi-level positive airway pressure].
• A body mass index (BMI) of ≥ 40kg/m².
• Subject is a study investigator, sub-investigator, study coordinator, or employee of a participating investigator or immediate family members of the aforementioned.
• Any intellectual deficiency including illiteracy, history of substance abuse in the two years prior to Visit 1 (including drug and alcohol), or other conditions, which will limit the validity of informed consent to participate in the study.

• Supplemental oxygen, with the following exceptions:

  • Use at high altitude (> 5000 feet) provided subject does not require a flow rate of > 2 L/minute
  • Use for exertion provided subject does not require > 2 hours per day of oxygen and does not require a flow rate of > 2L/minute
  • Use for nocturnal therapy provided subject does not require a flow rate of > 2L/minute