Evaluating the Control of COPD Symptoms in Patients Treated With Tiotropium Bromide 18mcg Once Daily Alone, ADOAIR 50/250mcg Twice Daily Alone or ADOAIR 50/250mcg Plus Tiotropium Bromide 18mcg

Evaluating the Control of COPD Symptoms in Patients Treated With Tiotropium Bromide 18mcg Once Daily Alone, ADOAIR 50/250mcg Twice Daily Alone or ADOAIR 50/250mcg Plus Tiotropium Bromide 18mcg

The purpose of this study is to assess the control of COPD using a symptom and exacerbation risk based treatment strategy based on GOLD 2011. This study is conducted in Japanese subjects with COPD and assess whether the GOLD 2011 strategy is effective in medical practice in Japan.

PROTOCOL SUMMARY Rationale Both ADOAIR and tiotropium bromide ( hereinafter tiotropium）are now well established, effective treatments for COPD and are frequently co-prescribed (hereinafter TRIPLE therapy). The addition of ADOAIR to tiotropium improves lung function and quality of life and may further reduce exacerbations. GOLD 2011 thus recommends TRIPLE therapy as the second choice of COPD treatment strategy. However, the criteria for switching from each individual treatment to TRIPLE therapy are not clearly shown so far.

This study will be conducted in Japanese subjects with COPD and will assess whether the GOLD 2011 strategy is effective in medical practice in Japan.

Objective(s) The objective of the study is to assess the control of COPD using a symptom and exacerbation risk based treatment strategy based on GOLD 2011.

Study Design Multicenter, randomized, double-dummy, 24-weeks, observational study Study Endpoints/Assessments Primary

• Proportion of patients who were able to remain on the randomized therapy Secondary
• Proportion of patients who switched to TRIPLE therapy
• Proportion of patients who controlled by TRIPLE therapy
• Proportion of patients controlled by randomized therapy plus TRIPLE therapy
• Time to switching to TRIPLE therapy
• Time to first exacerbation
• Proportion of diagnosed exacerbation confirmed by Daily Record Card
• Proportion of exacerbations detected by Daily Record Card not diagnosed
• CAT score change
• Change in FEV1
• Use of relief medication
• Proportion of patients who decreased treatment from TRIPLE therapy
• Proportion of patients who required additional treatment to TRIPLE therapy
• Proportion of patients who dropped out
• Patients' judgment of treatment efficacy
• Physician's judgment of treatment efficacy

Safety

• Adverse event reporting
• Exacerbations of COPD

Inclusion Criteria:

1. Male or female aged 40 - 80 years inclusive
2. Has an established clinical history of COPD (defined as per the GOLD definition)
3. The subject achieves a grade of ≥1 on mMRC at Visit 1
4. A signed and dated written informed consent is obtained from the subject prior to study participation
5. The subject has a post-bronchodilator FEV1 of ≥ 30% to ≤ 80% of predicted normal
6. The subject has a post-bronchodilator FEV1 / FVC ratio < 70%
7. The subject is a current or ex-smoker with a smoking history of > 10 pack-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.
8. QTc < 450 msec at Visit 1; or for patients with bundle branch block QTc should be < 480 msec.

(QTc(F) < 450 msec, or < 480 msec in subjects with right bundle branch block, should be confirmed by the mean of three readings or one reading) 9. ALT < 2 x ULN and bilirubin/ALP ≤ 1.5 x ULN (> 35% direct bilirubin) 10. 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), or 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 iii) not a nursing mother

Exclusion Criteria:

1. Has a predominant asthma (comorbid asthma is not an exclusion criteria)
2. 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
3. Has known respiratory disorders other than COPD (e.g. lung cancer, sarcoidosis, tuberculosis or lung fibrosis)
4. Has undergone lung surgery e.g., lung transplant and/or lung volume reduction
5. Had a chest X-ray indicating diagnosis other than COPD that might interfere with the study (chest X-ray to be taken at Visit 1, if subject has not had one and/or CT image taken within 3 months of Visit 1)
6. Requires regular (daily) or long term oxygen therapy (LTOT). (LTOT is defined as ≥ 12 hours oxygen use per day)
7. Has plan to start or to change the pulmonary rehabilitation program during the study period
8. Requires regular treatment with oral, parenteral, or depot corticosteroids
9. Has serious, uncontrolled disease likely to interfere with the study (e.g. Left Ventricular failure, anaemia, renal or hepatic disease or serious psychological disorders)
10. Received any other investigational drugs within 4 weeks (or 5 half lives) prior to Visit 1
11. Has, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse
12. Has a known or suspected hypersensitivity to β2-agonists, steroids, anticholinergic treatments or any components of the formulations
13. Has previously been enrolled to this study and investigational drugs has been administered
14. Is not eligible to participate this study in the opinion of the investigator/subinvestigator

The investigator must refer to the following document(s) for detailed information regarding warnings, precautions, contraindications, adverse events, and other significant data pertaining to the investigational product(s) being used in this study:

1. ADOAIR DISKUS package insert
2. Tiotropium/ HandiHaler package insert
3. Salbutamol package insert