A Study To Assess Efficacy And Safety Of Different Doses Of GW642444 In Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Inclusion criteria

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

• Informed Consent: Subjects who give their signed written informed consent to participate.
• Gender: Male or females who are 40 - 80 years of age at Visit 1. 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
• 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 2 weeks after 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 levonorgestrel 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 and administered for 1 month following study completion; 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
• COPD Diagnosis: Subjects with an established 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 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.
• Tobacco Use: Must have current or prior history of at least 10 pack-years of cigarette smoking. [number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years]. Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.
• Severity of Disease:
• Subjects with a measured post-salbutamol FEV1/FVC ratio of ≤0.70 at Visit 1 (Screening).
• Subjects with a measured post-salbutamol FEV1 ≥35 and ≤70% of predicted normal values calculated using NHANES III reference equations at Visit 1 (Screening).

Exclusion criteria

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

• Pregnancy: Women who are pregnant or lactating.
• Asthma: Subjects with a primary diagnosis of asthma. (Subjects with a prior history of asthma are eligible if COPD is currently their primary diagnosis)
• a1-antitrypsin deficiency: Subjects with a1-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 disease or other active pulmonary disease.
• Lung Resection: Subjects with lung volume reduction surgery within the previous 12 months.
• Chest X-ray: Chest X-ray (or CT scan) reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest x-ray must be taken if a chest x-ray or CT scan is not available within the 6 months preceding the Screening Visit. For sites in Germany, if a chest x-ray (or CT scan) is not available in the 6 months preceding the Screening (Visit 1), the subject will not be eligible for the study.
• Hospitalization: Subjects who are hospitalized due to poorly controlled COPD within 12 weeks of the screening visit.
• Poorly controlled COPD: Subjects with poorly controlled COPD, defined as the occurrence of any of the following in the 6 weeks prior to Visit 1:
• acute worsening of COPD that is managed by subject with corticosteroids or antibiotics, or
• acute worsening of COPD that requires treatment prescribed by a physician
• Other Diseases/Abnormalities: Subjects with clinically significant cardiovascular neurological, psychiatric, renal, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled.
• Lower Respiratory Tract Infection: Subjects with lower respiratory tract infections which required the use of antibiotics within 6 weeks prior to visit 1.
• 12-Lead ECG: An abnormal and clinically significant 12-lead electrocardiogram (ECG) that results in an active medical problem. 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:
• Clinically significant conduction abnormalities (e.g., left bundle branch block, Wolff-Parkinson-White syndrome)
• Clinically significant arrhythmias (e.g., atrial fibrillation, ventricular tachycardia)

The investigator will determine the clinical significance of any ECG abnormality and determine if a subject is precluded from entering the study. However, the following predetermined ECG abnormalities are considered clinically significant and will result in exclusion of a subject:

• A mean QTc(B) value at screening >450msec, or uncorrected QT>600msec or an ECG that is not suitable for QT measurements (e.g. poorly defined termination of the T wave)
• Ventricular rate < 45 beats per minute.
• PR interval > 240msec.
• Evidence of second or third degree atrioventricular (AV) block
• Pathological Q waves
• Non-specific intraventricular conduction delay
• ST-T wave abnormalities (excluding non-specific ST-T wave abnormalities)
• Right or left complete bundle branch block
• Hypertension: Subjects with clinically significant hypertension that is uncontrolled.
• Hepatitis: Subjects with a positive Hepatitis B surface antigen or positive hepatitis C antibody pre-study or at Screening.
• 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 would not be excluded if the subject was considered cured in less than 5 years since diagnosis.
• Drug allergy: Subjects with a history of hypersensitivity to any beta-agonist or any component of the MDI and/or nebule or sensitivity to any of the constituents of the dry powder product (magnesium stearate or lactose). In addition patients with a history of severe milk protein allergy would also be excluded.
• Drug 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 salbutamol for the 6 hour period required prior to spirometry testing at each study visit would be ineligible for the study.
• Additional Medications: The following medications are not permitted during this study and must not have been taken for the indicated times prior to Visit 1 (See Prohibited Medications): Medication (Required period of time prior to screening visit):

• Ipratropium or ipratropium/salbutamol combination product (6 hours)
• Inhaled short acting beta-agonists (study salbutamol will be provided)(6 hours)
• Oral beta2-agonists (48 hours)
• LABAs (salmeterol and formoterol)(48 hours)
• Corticosteroids/Long acting beta-agonist combination products (48 hours for the LABA component)
• Theophylline preparations (48 hours)
• Cromolyn and nedocromil inhalers(24 hours)
• Zafirlukast, montelukast, zileuton(48 hours)
• Tiotropium (1 Week)
• Depot corticosteroids (12 Weeks)
• Intra-articular corticosteroids (24 hours)
• Inhaled corticosteroids>1000mcg/day of fluticasone propionate or equivalent (4 Weeks)
• Any other investigational medication (30 days or within 5 drug half-lives of the investigational drug (whichever is longer))
• P-glycoprotein inhibitors (e.g., ritonavir, ketoconazole) or Cytochrome P 3A4 inhibitors (e.g., cimetidine) (4 weeks (grapefruit is allowed up to the screening visit))
• Other Medications: Subjects receiving treatment with tricyclic antidepressants, MAOs, beta-adrenergic antagonists, anticonvulsants (barbiturates, hydantoins, and carbamazepine) or phenothiazines would be ineligible for the study.
• Oxygen: Subjects receiving long-term-oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day. Oxygen prn use is not exclusionary.
• Sleep apnea: Subjects with clinically significant sleep apnea that is uncontrolled.
• Pulmonary Rehabilitation: Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Program within 4 weeks prior to Visit 1 (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 unable to comply with study procedures.
• 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 participation in this study.
• Questionable validity of Consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation, substance abuse, (including drug and alcohol), or other conditions, which will limit the validity of informed consent to participate in the study.
• Prior use of Study Medication: Subjects who have received the investigational drug GW642444 in previous studies.