Chronic Obstructive Pulmonary Disease (COPD) Post-hospitalization Study

A Randomized, Double-Blind, Parallel Group, Multicenter Study of the Effects of Fluticasone Propionate/Salmeterol Combination Product 250/50mcg BID (ADVAIR DISKUS™) in Comparison to Salmeterol 50mcg BID (SEREVENT DISKUS™) on the Rate of Exacerbations of COPD Following Hospitalization

This trial is a randomized, double-blind, parallel-group, multicenter study to be conducted in the United States. The purpose of the study is to evaluate the rate of exacerbations of chronic obstructive pulmonary disease (COPD) following hospital discharge for an acute exacerbation of COPD, in patients receiving either fluticasone propionate/salmeterol combination product 250/50mcg BID or salmeterol 50mcg BID via DISKUS™ over 29 weeks. The study population will include patients hospitalized for an acute exacerbation of COPD. The target enrolment is 720 subjects at 80 study centers. The primary endpoint is the rate of exacerbation requiring hospitalization that occur more than 21 days post-discharge, emergency room visit or physician's office visit for an exacerbation of COPD requiring treatment with oral corticosteroids or oral corticosteroids and antibiotics. The secondary endpoint is the rate of COPD exacerbation requiring treatment with oral corticosteroids, antibiotics, and/or hospitalization (alone and in combination). Related efficacy endpoints include, time to first exacerbation of COPD requiring treatment with oral corticosteroids, antibiotics, and/or hospitalization (alone and in combination), pre-dose AM FEV1, the probability of premature withdrawal of subject from the study, and supplemental albuterol use, change in biomarkers of inflammation, including, surfactant protein D (SP-D), clara cell secretory protein 16 (CC-16) and high sensitivity C-reactive protein (hs-CRP). Health outcome assessments include domain scores evaluation for fatigue, dyspnea, emotional function and mastery, measured with the Chronic Respiratory Disease Questionnaire self-administered standardized format (CRQ-SAS); and symptoms (congestion, cough, phlegm, mucus, chest discomfort, shortness of breath and sleep disturbance), assessed by the EXAcerbations of Chronic pulmonary disease Tool (EXACT). Albuterol will be supplied to study subjects for use as-needed throughout the study. Safety will be assessed by monitoring of adverse events.

Inclusion Criteria:

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

• Male or female of at least 40 years of age at screening.

To be eligible for entry into the study, females of childbearing potential must commit to the consistent and correct use of an acceptable method of birth control starting on the day of visit 1, throughout the clinical trial, and for a period after the trial to account for elimination of the drug (minimum of six days), as defined by any one of the following:

• Abstinence Females of childbearing potential who are not sexually active must commit to complete abstinence from intercourse
• Oral contraceptive (either combined estrogen/progestin or progestin only)
• Injectable progestogen
• Implants of levonorgestrel or etonogestrel
• Percutaneous contraceptive patches
• Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year,
• Male partner who is sterile (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, or
• Double-barrier method; condom or occlusive cap (diaphragm or cervical /vault caps) plus spermicide.
• Current or former smokers with a >10 pack-year cigarette smoking history [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 those who have quit smoking for at least 3 months prior to the screening visit.
• Any of the following populations:
• Patients hospitalized for a duration not exceeding 10 days due to an acute exacerbation of COPD, and who must be randomized within 10 days post-discharge.
• Patients with COPD who were treated and held for observation in the emergency department (i.e. emergency room, ER) for at least 24 hours due to an acute exacerbation of COPD, and who must be randomized within 10 days post-discharge.
• Patients who received oral corticosteroids or oral corticosteroids and antibiotics for treatment of an exacerbation of COPD during a physician's office visit and who must be randomized within 10 days of the visit, and who have been hospitalized within the previous six months due to an acute exacerbation of COPD.
• Clinical diagnosis of COPD (for at least 6 months). The following definition of COPD from the American Thoracic Society (ATS) will be used: COPD is a disease state characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema; the airflow obstruction is generally progressive, may be accompanied by airway hyper-reactivity, and may be partially reversible [American Thoracic Society, 1995].
• Documented evidence (within a year prior to Visit 1) in the medical chart of spirometry confirming the diagnosis of COPD and/or spirometry performed prior to randomization (Visit 2) that confirms pre-bronchodilator FEV1/FVC ratio less than or equal to 0.70 and pre-bronchodilator FEV1 <70% of predicted.
• Review and subject's completion of written informed consent: a subject-signed and dated written informed consent (form) must be obtained prior to any study procedure, and the subject must be willing to comply with all the requirements of the study protocol.
• Subject must be able to read, comprehend, and record information in English or Spanish.

Exclusion Criteria:

• Subjects meeting any of the following criteria must not be enrolled in the study:
• Diagnosis of pneumonia, congestive heart failure (CHF), or other complicating co-morbid condition while hospitalized within the last 6 months for an exacerbation of COPD.
• Historical or current evidence of clinically significant uncontrolled disease including, but not limited to, those listed below. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subjects at risk through study participation, or which would affect the safety analysis or other analyses if the disease/condition exacerbated during the study.
• A previous lung resection surgery (e.g. lobectomy, pneumonectomy, etc) within the year preceding Visit 1 (Screening)
• Asthma as primary diagnosis
• Lung cancer
• Cystic fibrosis, pulmonary fibrosis, active tuberculosis, or sarcoidosis
• Clinically significant cardiac arrhythmias
• Uncontrolled hypertension
• Unstable angina
• Current malignancy or a previous history of cancer in remission for < 5yrs (localized basal cell or squamous cell carcinoma of the skin that has been resected is not excluded)
• Uncontrolled diabetes mellitus
• Uncontrolled hyperthyroidism or hypothyroidism
• Immunologic compromise
• Cushing's or Addison's disease
• An abnormal 12-lead electrocardiogram (ECG) at Visit 1 (Screening) deemed to be clinically significant by the investigator.
• A chest X-ray or computed tomography (CT) scan performed in the 6 months preceding Visit 1 that revealed evidence of clinically significant abnormalities not believed to be due to the presence of COPD. If the subject does not have a record of a chest X-ray, one must be obtained and reviewed prior to randomization.
• Female patients with a positive urine pregnancy test at Visit 1.
• Any infirmity, physical disability, or geographic location that would limit compliance for scheduled visits.
• Any adverse reaction, immediate or delayed, hypersensitivity to any Beta-agonist, sympathomimetic drug, or corticosteroid including any components of the study drug formulations.
• Limited ability to provide a valid informed consent due to psychiatric disease, intellectual deficiency, poor motivation, current substance abuse (including illicit drugs and alcohol), or neurological disorders that might interfere with completion of study procedures or hearing problems that may impede effective communication.
• Study site staff (i.e. participating investigator, sub-investigator, study coordinator, employee of the participating investigator) or family members of site staffs.