A Study To Assess Single Dosage Strength Of GW685698/GW642444 Chronic Obstructive Pulmonary Disease (COPD)

Study HZC111348, a Repeat-dose Study of GW685698/GW642444 Inhalation Powder Versus Placebo in the Treatment of Chronic Obstructive Pulmonary Disease (COPD)

The purpose of this study is to assess the safety and efficacy of a single dosage strength of GW685698/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:

1. Informed consent: Subjects must give their signed written informed consent to participate.

2. Gender: Male subjects or female subjects of non-child bearing potential (e.g. post-menopausal or surgical sterile) 40 - 80 years of age at screening (Visit 1).

   • Post-menopausal females are defined as being amenorrhoeic for greater than 2 years with an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms. However if indicated this can be confirmed by estradiol and FSH levels consistent with menopause (according to laboratory ranges) at screening (Visit 1).
   • Surgically sterile females are defined as those with a documented (medical report verification) hysterectomy and/or bilateral oophorectomy or Tubal Ligation.
   • Furthermore, male subjects in this study must use double-barrier (condom/spermicide) birth control methods or abstain from sexual intercourse with female partners who are pregnant, lactating, or able to bear children in addition to any birth control methods the female partner is using, from the first dose of the study medication until 90 days after the last dose of the study medication.

3. 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.

4. Tobacco use: subjects with a current or previous history of ≥ 10 pack-years of cigarette smoking at screening (Visit 1). Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.

   • Number of pack years = (number of cigarette per day/20)) x number of years smoked

5. Severity of Disease: subjects who conform to the current severity classification for Stage II/III disease in terms of post-bronchodilator spirometry at Screening Visit 1:

   • Subject with a measured post-salbutamol FEV1/FVC ratio of ≤0.70
   • Subjects with a measured post-salbutamol FEV1 ≥ 40 % and ≤ 80 % of predicted normal values calculated using NHANES III reference equations.

Exclusion Criteria:

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

1. Pregnancy: Women who are pregnant or lactating

2. Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if COPD is the current diagnosis)

3. α1- antitrypsin deficiency: Subjects with α-1 antitrypsin deficiency as the underlying cause of COPD

4. Other respiratory disorders: Subjects with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases

5. Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening

6. Chest X-ray (or CT scan): Subjects with a chest X-ray (or CT scan) that 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

7. Poorly controlled COPD: Subjects with poorly controlled COPD, defined as the occurrence of any of the following in the 6 weeks prior to Screening:

   • 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 Subjects who are hospitalized due to poorly controlled COPD within 12 weeks of the Screening Visit

8. Lower respiratory tract infection: Subjects with lower respiratory tract infection that required the use of antibiotics within 6 weeks prior to Visit 1

9. 12-lead ECG (Electrocardiogram): An abnormal and clinically significant 12-lead ECG that results in an active medical problem. For this study, an abnormal ECG is defined as a 12-lead tracing that is interpreted as, 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 independent cardiologist, contracted by GSK, will determine the clinical significance of any ECG abnormalities 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:

   • Ventricular rate < 45 bpm
   • PR interval > 240 msec
   • Evidence of Second-Degree (Mobitz type II) 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
   • A mean QTc(B) value at Screening > 450 msec, or uncorrected QT >600 msec or an ECG that is not suitable for QT measurements (e.g. poorly defined termination of the T wave)

10. Other Diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, 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.

11. Hepatitis: Subjects with a positive Hepatitis B surface antigen or positive Hepatitis C antibody pre-study or at Screening

12. Hypertension: Subjects with clinically significant hypertension that is uncontrolled

13. 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.

14. 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). Or a history of drug or other allergy such as a history of severe milk protein allergy that, in the opinion of the study physician, contraindicates the subject's participation

15. Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years

16. Medication prior to spirometry: Subjects who are medically unable to withhold their rescue medication for the 6-hour period required prior to spirometry testing at each study visit.

17. 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.

18. Pulmonary rehabilitation: Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Programme within 4 weeks prior to Screening or who will enter the acute phase of a Pulmonary Rehabilitation Programme during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Programme may be included.

19. Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures

20. 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

21. Prior use of study medication/other investigational drugs: Subjects who have received the GW642444 in previous 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

22. Sleep apnea: Subjects with clinically significant sleep apnea that is uncontrolled.

23. 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