A 3 Way Cross-over Study Evaluating the Effects of ADOAIR Twice Daily Plus Tiotropium Bromide Once Daily Compared With the Individual Treatments of Japanese Subjects

A Randomised, Double-blind, Double Dummy, 3 Way Cross-over Study Evaluating the Effects of ADOAIR 50/250mcg Twice Daily Plus Tiotropium Bromide 18mcg Once Daily Compared With the Individual Treatments (Tiotropium Bromide 18mcg Alone and ADOAIR 50/250mcg Alone) in the Treatment of Japanese Subjects With COPD

The purpose of this study is to evaluate the effects on lung function of a combination of ADOAIR 50/250mcg twice daily plus tiotropium bromide 18mcg once daily compared with the individual treatments (tiotropium bromide 18mcg once daily alone and ADOAIR 50/250mcg twice daily alone) in Japanese subjects with COPD. The study will utilize a three-way cross-over design with a 2-week wash-out period between each 4-week consecutive treatment period. The aim is to support the rationale for "triple combination" therapy by demonstrating that treatment with both ADOAIR and tiotropium can potentially produce improved, clinically relevant effects compared with either treatment alone.

This study will utilize a range of lung function measures in order to fully assess the benefits of triple therapy. The primary endpoint will be based on airways conductance measured using plethysmography (sGaw measured over 4hours post dose (AUC 0-4hr) on Day 28). Secondary endpoints will include lung function measures based on plethysmography and spirometry. The lung function measures will be supported by measurement of the use of relief salbutamol .

Inclusion Criteria:

• Male or female aged 40 - 80 years inclusive
• Has an established clinical history of COPD (defined as per the GOLD definition)
• A signed and dated written informed consent is obtained from the subject prior to study participation
• The subject has a post-bronchodilator FEV1 of >=30% to =<75% of predicted normal at Visit 1
• The subject has a post-bronchodilator FEV1/ FVC ratio <70% at Visit 1
• The subject achieves a score of 1 on the Modified Medical Research Council (mMRC) Dyspnoea Scale at Visit 1
• The subject is a current or ex-smoker with a smoking history of > 10 pack-years (10 pack years is defined as 20 cigarettes per day for 10 years, or 10 cigarettes (or equivalent if subject smoked cigars or a pipe) per day for 20 years). Ex-smokers are required to have stopped smoking for at least 6 months prior to visit 1. Ex-smokers who stopped smoking less than 6 months ago will be defined as current smokers.
• QTc <450 msec at Visit 1; or for patients with Bundle Branch Block QTc should be <480 msec.

(QTc(F) <450msec, or <480 in subjects with right bundle branch block, should be confirmed by the mean of three readings or one reading)

• ALT < 2xULN and bilirubin/ALP < 1.5xULN (>35% direct bilirubin)
• A female is eligible to enter this study if she is: i)of non-childbearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal), ii)of child-bearing potential, but has a negative urinary pregnancy test at screening and agrees to take contraceptive precautions (including abstinence) which are adequate to prevent pregnancy during the study or iii)not a nursing mother

Exclusion Criteria:

• Has had a COPD exacerbation within the 4 weeks prior to Visit 1
• Had any changes in COPD medication in the 4 weeks prior to Visit 1
• Has plan to change the dosage of Xanthines or to stop receiving it during the study
• Has a current medical diagnosis of asthma
• Has a medical diagnosis of narrow-angle glaucoma, prostatic hyperplasia or bladder neck obstruction that in the opinion of the investigator should prevent them from entering the study Note: As with other anticholinergic drugs, subjects with narrow-angle glaucoma, prostatic hyperplasia or bladder neck obstruction should only be entered into the study at the Investigator's discretion
• Has known respiratory disorders other than COPD (e.g. lung cancer, sarcoidosis, tuberculosis or lung fibrosis)
• Has undergone lung surgery e.g., lung transplant and/or lung volume reduction
• Is currently receiving pulmonary rehabilitation
• Had a chest X-ray indicating diagnosis other than COPD that might interfere with the study (chest X-ray to be taken at entry, if subject has not had one or CT image taken within 3 months of Visit 1)
• Requires regular (daily) or long term oxygen therapy (LTOT). (LTOT is defined as . 12 hours oxygen use per day)
• Requires regular treatment with oral, parenteral, or depot corticosteroids or has received 2 or more periods of oral corticosteroids for COPD exacerbation in the last 6 months
• Received oral, parenteral, or depot corticosteroids in the 4 weeks prior to Visit 1
• Received antibiotic therapy for either a lower respiratory tract infection or for COPD exacerbation within the 4 weeks prior to Visit 1
• Has been hospitalized for a COPD exacerbation in the last year
• Receiving non-selective β-blockers (except eye drops)
• Has serious, uncontrolled disease likely to interfere with the study (e.g. Left Ventricular failure, anaemia, renal or hepatic disease or serious psychological disorders)
• Received any other investigational drugs within 4 weeks (or 5 half lives) prior to Visit 1
• Has, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse
• Has a known or suspected hypersensitivity to β2-agonists, inhaled steroids, anticholinergic treatments or any components of the formulations (e.g. lactose or milk protein)
• Has previously been enrolled and randomized to this study
• Are not considered able to tolerate three 2-weeks wash-out periods according to the study schedule with all COPD medications removed apart from rescue use of SALBUTAMOL via MDI (inhaled PRN use).
• Is not eligible to participate this study in the opinion of the investigator/subinvestigator.