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

Study Overview
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Brief Summary
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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 .

Official Title
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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

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: fluticasone propionate/salmeterol
* Drug: tiotropium bromide
* Drug: fluticasone propionate/salmeterol plus tiotropium bromide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: fluticasone propionate/salmeterol<br>250mcg fluticasone + 50 mcg salmeterol, twice daily 4 week treatment in each treatment sequence (crossover design) | Drug: fluticasone propionate/salmeterol<br>* 250mcg fluticasone + 50 mcg salmeterol, twice daily 4 week treatment in each treatment sequence (crossover design)<br>* Other names: ADOAIR is a registered trade mark of the GlaxoSmithKlline group of companies.;|
| Active Comparator: tiotropium bromide<br>18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design) | Drug: tiotropium bromide<br>* 18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design)<br>|
| Active Comparator: fluticasone propionate/salmeterol plus tiotropium bromide<br>250mcg fluticasone + 50 mcg salmeterol, twice daily plus 18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design) | Drug: fluticasone propionate/salmeterol plus tiotropium bromide<br>* 250mcg fluticasone + 50 mcg salmeterol, twice daily plus 18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design)<br>* Other names: ADOAIR is a registered trade mark of the GlaxoSmithKlline group of companies.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve Calculated From 0 to 4 Hours (AUC[0-4hr]) Specific Conductance (sGaw) After the Morning Dose of Study Medication at Day 28 of Each Treatment Period | sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sGaw. The AUC was determined by using the trapezoidal rule and then dividing by the relevant time interval. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, period and Baseline sGaw fitted as fixed effects and participants fitted as a random effect. Treatment ratios of all statistical comparisons were calculated by taking the anti-log of the difference between the Least Square (LS) means. | Day 28 of each treatment period (up to 35 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC (0-4hr) Specific Airway Resistance (sRaw) After the Morning Dose of Each Study Medication at Day 28 of Each Treatment Period | sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sRaw. The AUC was determined by using the trapezoidal rule and then dividing by the relevant time interval. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, period and Baseline sRaw fitted as fixed effects and participants fitted as a random effect. Treatment ratios of all statistical comparisons were calculated by taking the anti-log of the difference between the LS means. | Day 28 of each treatment period (up to 35 days) | 
| Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sGaws. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, time, period, a treatment by time interaction and Baseline sGaw fitted as fixed effects and participant fitted as a random effect. | Day 28 of each treatment period (up to 35 days) | 
| Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sRaw. A natural logarithmic transformation was applied and the data was analysed by a mixed model including treatment, time, period, a treatment by time interaction and Baseline sRaw fitted as fixed effects and participant fitted as a random effect. | Day 28 of each treatment period (up to 35 days) | 
| Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. IC is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Total lung capacity (TLC) is the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort; it is equal to the vital capacity (VC) plus the residual volume (RV). RV is defined as the volume of air remaining in the lungs. after a maximal exhalation. Thoracic gas volume at functional residual capacity (TGV) is defined as the volume of intrathoracic gas at the time the airway is occluded for the plethysmographic measurement at the end of a normal expiration. Trough values were the values taken pre-dose. | Day 28 of each treatment period (up to 35 days) | 
| Trough FEV1/FVC Ratio, at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. Trough values were the values taken pre-dose. | Day 28 of each treatment period (up to 35 days) | 
| Trough sRaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Trough values were the values taken pre-dose. | Day 28 of each treatment period (up to 35 days) | 
| Trough sGaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Trough values were the values taken pre-dose. | Day 28 of each treatment period (up to 35 days) | 
| Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. IC is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Total lung capacity (TLC) is the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort; it is equal to the vital capacity (VC) plus the RV. RV is defined as the volume of air remaining in the lungs after a maximal exhalation. Thoracic gas volume at functional residual capacity (TGV) is defined as the volume of intrathoracic gas at the time the airway is occluded for the plethysmographic measurement at the end of a normal expiration. | Day 28 of each treatment period (up to 35 days) | 
| Post-dose FEV1/FVC Ratio (Measured at Trough) at Day 28 of Each Treatment Period | FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. | Day 28 of each treatment period (up to 35 days) | 
| Use of Rescue Medication (Number of Occasions Per 24-hour Period) as Recorded in the Daily Record Card at Day 28 of Each Treatment Period | Participants were given daily record cards for daily completion during the run-in, washout and treatment periods. Each morning, participants recorded the number of occasions in the last 24 hours when they had used their rescue medication (salbutamol) for symptomatic relief of COPD symptoms. | Day 28 of each treatment period (up to 35 days) |