A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetic (PK), and Pharmacodynamic (PD) Profiles of 3 Doses of Fluticasone Furoate (FF)/GW642444 Inhalation Powder at the End of a 28-day Treatment Period in Subjects With Chronic Obstructive Pulmonary Disease (COPD) Compared to Placebo

Inclusion criteria

• Outpatient/Inpatient; Male or female subjects
• Subjects must give their signed and dated written informed consent to participate.
• A female is eligible to enter and participate in the study if she is of: Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being amenorrhoeic, > 45 years, in the absence of hormone replacement therapy. However in questionable cases, a blood sample with FSH >40MIU/ml and estradiol < 40pg/ml (<140 pmol/L) is confirmatory.

OR

Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the following acceptable contraceptive methods used consistently and correctly (i.e. in accordance with the approved product label and the instructions of the physician for the duration of the study - screening to follow-up contact):

• Complete abstinence from intercourse from screening until the follow-up contact; or
• Male partner is sterile (vasectomy with documentation of azoospermia) prior to female subject entry into the study, and this male partner is the sole partner for that subject; or
• Implants of levonorgestral inserted for at least 1 month prior to the study medication administration but not beyond the third successive year following insertion; or
• Injectable progestogen administered for at least 1 month prior to study medication administration; or
• Oral contraceptive (combined or progestogen only) administered for at least one monthly cycle prior to study medication administration; or
• Double barrier method: condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository); or
• An intrauterine device (IUD), inserted by a qualified physician, with published data showing that the highest expected failure rate is less than 1% per year; or
• Estrogenic vaginal ring; or
• Percutaneous contraceptive patches.
• Age: ≥40 years of age at Screening (Visit 1).
• COPD diagnosis: Subjects with a clinical history of COPD in accordance with the following definition by the American Thoracic Society/European Respiratory Society [Celli, 2004]: COPD is a preventable and treatable disease characterized 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.
• Tobacco use: subjects with a current or prior history of ≥10 pack-years of cigarette smoking at Screening (Visit 1). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Screening (Visit 1).

Note: Pipe and/or cigar use cannot be used to calculate pack year history. Number of pack years = (number of cigarettes per day/20)) x number of years smoked

• Severity of Disease:
• Subject with a measured post-albuterol/salbutamol FEV1/FVC ratio of ≤0.70 at Screening (Visit 1). [Pelligrino, 2005]
• Subjects with a measured post-albuterol/salbutamol FEV1 ≤ 70% of predicted normal values calculated using NHANES III reference equations [Hankinson, 1999] at Screening (Visit 1). Post-bronchodilator spirometry will be performed approximately 10-15 minutes after the subject has self-administered 4 inhalations (i.e. total 400mcg.) of albuterol/salbutamol via an MDI with a valved-holding chamber. The FEV1/FVC ratio and FEV1 percent predicted values will be calculated by the centralized spirometry equipment.
• Dyspnea: Achieved a score of ≥2 on the Modified Medical Research Council Dyspnea Scale (mMRC, 0-4 scale) at Screening (Visit 1).

Exclusion criteria

• Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.
• Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD)
• α1-antitrypsin deficiency: Subjects with α-1 antitrypsin deficiency as the underlying cause of COPD
• Other respiratory disorders: Subjects with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases
• Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening
• Chest X-ray (or CT scan): Subjects with a chest X-ray (or CT scan) thats reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray must be taken at Screening if a chest X-ray or CT scan is not available within 6 months prior to Screening (Visit 1)
• Hospitalization: Subjects who are hospitilized due to poorly controlled COPD with 12 weeks of Screening (Visit 1)
• Poorly controlled COPD: Subjects with poorly controlled COPD defined as the occurrence of any of the following in the 6 weeks prior to Screening (Visit 1):
• acute worsening of COPD that is managed by the subject with corticosteroids or antibiotics, or that requires treatment prescribed by a physician
• Lower respiratory tract infection: Subjects with lower respiratory tract infection that require the use of antibiotics within 6 weeks prior to Screening (Visit 1)
• Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular (i.e., pacemaker), neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or haematological abnormalities that are uncontrolled. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.
• Peptic Ulcer disease: Subjects with clinically significant peptic ulcer disease that is uncontrolled.
• Hypertension: Subjects with clinically significant hypertension that is uncontrolled
• Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded if the subject has been considered cured within 5 years since diagnosis.
• Drug/food allergy: Subjects with a history of hypersensitivity to any of the study medications (e.g. beta-agonists, corticosteroid) or components of the inhalation powder (e.g. lactose, magnesium stearate). In addition, patients with a history of severe milk protein allergy that, in the opinion of the study physician, contraindicates the subject's participation will also be excluded.
• Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years
• Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol/salbutamol or their ipratropium for the 4-hour period required prior to spirometry testing at each study visit.
• Additional medication: Use of certain medications such as bronchodilators and corticosteroids for the protocol-specific times prior to Visit 1 (the Investigator will discuss the specific medications)
• Oxygen therapy: Subjects receiving treatment with long-term oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day. Oxygen prn use (i.e. ≤12 hours per day) is not exclusionary.
• Sleep apnea: Subjects with clinically significant sleep apnea who require use of continuous positive airway pressure (CPAP) device or non-invasive positive pressure ventilation (NIPPV) device.
• Pulmonary rehabilitation: Subjects who have participated in the acute phase of a
• Pulmonary Rehabilitation Program within 4 weeks prior to Screening or who will enter the acute phase of a Pulmonary Rehabilitation Program during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Program are not excluded.
• Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits.
• Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study
• Prior use of study medication/other investigational drugs: Subjects who have previously been randomized in the Phase IIa (HZC111348 or B2C111045) study or Phase III (i.e. HZC112206, HZC112207, HZC102970, HZC102871) studies. Subjects who have received an investigational drug within 30 days of entry into this study (Screening), or within 5 drug half-lives of the investigational drug, whichever is longer
• Affiliation with investigator site: Study investigators, sub-investigators, study coordinators, employees of a participating investigator or immediate family members of the aforementioned are excluded from participating in this study.