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
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: Fluticasone Furoate (FF)/GW642444 Inhalation Powder; placebo
Intervention description: Inhaled Corticosteroid (ICS)/ Long Acting Beta Agonist(LABA) for COPD; placebo
Intervention MeSH terms: Fluticasone; Xhance
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 54.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: COPD; Safety; FEV1; Efficacy

Summary:

      The Purpose of this study is to evaluate the 24-hour spirometry effect Forced Expiratory
      Volume in One second (FEV1) 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 with placebo. Other objectives are to assess additional efficacy,
      plus the safety, pharmcodynamics and tolerability of concurrent treatment with Fluticasone
      Furoate (FF) plus GW642444 when administered at three dose levels for 28 days in subjects
      with COPD and to assess the steady-state pharmacokinetic profile of Fluticasone Furoatee (FF)
      and GW642444 at the end of each treatment period.
    

Eligibility criteria:

        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.