ADOAIR250 Anti-inflammatory Effects in Japanese Subjects With Chronic Obstructive Pulmonary Disease

Study Overview
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Brief Summary
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The study will be conducted in a respiratory specialist institute in Japan, with standardized techniques and data assurance checks to optimize data quality. The licensed dosage and administration of Adoair in Japan will be applied in this study. Each subject will receive treatment options in a randomized blinded fashion. Subjects will be randomized following a 4-week wash-out phase to take either Adoair 50/250mcg twice daily or placebo twice daily for 12 weeks.

Detailed Description
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This is a randomised, double-blind, placebo-controlled, two-arm, parallel-group, 12-week-treatment study in Japanese patients with COPD. At Visit 1, patients confirmed to be fulfilling all the inclusion criteria and not meeting any of the exclusion criteria will start the 4-week run-in period. During the entire study period, including the run-in period, the only drug allowed to use in addition to the study drug will be oxitropium (short-acting anticholinergic drug) as relief medication. At the end of the run-in period (Visit 2), subjects eligible for randomisation will be evenly randomised to one of the following two treatment groups and start the 12-week treatment period. ADOAIR®250 one inhalation twice daily from the DISKUS inhaler Placebo one inhalation twice daily from the DISKUS inhaler Study completers will be defined as subjects who have completed all examinations, assessments, and study procedures in the study period, including the run-in period and the follow-up period. At completion/discontinuation of the treatment period, subjects will be switched to appropriate COPD treatment at the discretion of the investigator (or subinvestigator).

Official Title
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A 12-week Randomised, Double-blind, Parallel-group Study to Evaluate the Anti-inflammatory Effects of ADOAIR® 50/250mcg Twice Daily Compared With Placebo Twice Daily in Japanese Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: ADOAIR250
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Japanese (male or female) outpatients aged 40-80 years inclusive at Visit 1 (Female patients may be enrolled only if they are not of child-bearing potential, or are of child-bearing potential who agree to properly use protocol-specified contraceptive measures. ) Have a diagnosis of COPD (defined as per the COPD guideline) Have a FEV1/FVC ratio < 0.70 at 15-60 minutes following use of SALTANOL® INHALER Have a FEV1 of >= 40% to < 80% of the predicted normal value at 15-60 minutes following use of SALTANOL® INHALER Current or ex-smokers with a smoking history of at least 10 pack-years Able to use the DISKUS inhaler and the short-acting inhaled anticholinergic drug Capable of providing written voluntary consent to participate in the study Exclusion Criteria: Diagnosed by the investigator (or subinvestigator) as having bronchial asthma Have any respiratory disorder other than COPD (e.g., lung cancer, sarcoidosis, tuberculosis [including old tuberculosis], pulmonary fibrosis) Have a chest X-ray (or CT scan) indicating a diagnosis other than COPD that might interfere with assessments in the study (This must be assessed using last imaging study performed within 6 months prior to Visit 1; or, a chest X-ray must be obtained at Visit 1.) Have chronic respiratory failure Have undergone lung volume reduction and/or lung transplant Have had a COPD exacerbation or respiratory infection requiring systemic corticosteroid or microbial therapy or hospitalisation, within 6 weeks prior to Visit 1 Have used inhaled corticosteroids and systemic corticosteroids within 4 weeks prior to Visit 1 Have used long-acting β2 agonists (inhaled or patch) within 2 weeks prior to Visit 1 Are unable to stop their short-acting β2 agonist therapy at Visit 1 (During the study participation, oxitropium bromide (TERSIGAN) will be used as relief medication.) Receiving long-term oxygen therapy with oxygen use for more than 12 hours per day Have a concurrent serious or uncontrolled disease that might interfere with assessments in the study (including psychiatric disease, unstable liver disease, and heart disease) Have a QTc > 450 msec (or > 480 msec in patients with bundle branch block) at Visit 1 (based on average QTc from three consecutive cardiac cycles on ECG) Have participated in another study and received any other study drug within 4 weeks prior to Visit 1 Diagnosed by the investigator (or subinvestigator) as having drug or alcohol dependence Have known or suspected hypersensitivity to bronchodilators, inhaled corticosteroid, or lactose Have known α1 antitrypsin deficiency Previously enrolled in this study Judged by the investigator (or subinvestigator) to be inappropriate to participate in this study

Ages Eligible for Study
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Minimum Age: 40 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ADOAIR250<br>ADOAIR 250mcg inhalations, twice daily, from week0 - 12 | Drug: ADOAIR250<br>* 250 mcg inhalation, twice daily, from week0 -12.<br>|
| Placebo Comparator: Placebo<br>Placebo inhalation, twice daily, from week0 -12 | Drug: Placebo<br>* Placebo inhalation, twice daily, from week0 -12.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Neutrophil Count in Induced Sputum at Week 12 | Induced sputum samples were collected at Baseline and at Week 12. The neutrophil count in induced sputum was measured with the use of a cytological specimen of inflammatory cells in the induced sputum. Change from Baseline in neutrophil count was calculated as the Week 12 value minus the Baseline value (percentage of neutrophil of total cells in induced sputum at Week 12 minus the Baseline value). | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in All Inflammatory Cell Count in Induced Sputum at Week 12 | Induced sputum samples were collected at Baseline and at Week 12. All inflammatory cells in induced sputum were counted with the use of a cytological specimen of cells in the induced sputum. Change from Baseline in all inflammatory cell count was calculated as the Week 12 value minus the Baseline value. | Baseline and Week 12 | 
| Change From Baseline in Interferon (INF)-Gamma-positive Cells and Perforin-positive Cells in Sputum at Week 12 | INF-gamma-positive cells and perforin-positive cells were not detected in samples collected in this study due to the conditions of the samples and/or antibodies. No re-assays were performed, no result/no data was entered into the case report forms, and no statistical analysis or data summarization was performed. | Baseline and Week 12 | 
| Change From Baseline in Interleukin (IL)-8 Levels in Sputum Supernatant at Week 12 | Induced sputum samples were collected at Baseline and at Week 12. The levels of IL-8 in the supernatant of an induced sputum sample were measured at the same time using the multiplex assay system. Change from Baseline in IL-8 levels was calculated as the Week 12 value minus the Baseline value. | Baseline and Week 12 | 
| Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) Levels in Sputum Supernatant at Week 12 | Data cannot be reported because hsCRP was under the lower limit of detection in all samples. | Baseline and Week 12 | 
| Change From Baseline in Myeloperoxidase (MPO) and Pulmonary Surfactant Protein (SP)-D Levels in Sputum Supernatant at Week 12 | Induced sputum samples were collected at Baseline and at Week 12. The levels of MPO and SP-D in the supernatant of an induced sputum sample were measured at the same time using the multiplex assay system. Change from Baseline in MPO and SP-D levels was calculated as the Week 12 value minus the Baseline value. | Baseline and Week 12 | 
| Change From Baseline in IL-6 and IL-8 Levels in Serum at Week 12 | Serum samples were collected at Baseline and at Week 12. The levels of IL-6 and IL-8 in serum samples were measured at the same time using the multiplex assay system. Change from Baseline in IL-6 and IL-8 levels was calculated as the Week 12 value minus the Baseline value. | Baseline and Week 12 | 
| Change From Baseline in hsCRP, SP-D, and Clara Cell Protein 16 (CC 16) Levels in Serum at Week 12 | Serum samples were collected at Baseline and at Week 12. The levels of hsCRP, SP-D, and CC16 in serum samples were measured at the same time using the multiplex assay system. Change from Baseline in hsCRP, SP-D, and CC16 was calculated as the Week 12 value minus the Baseline value. | Baseline and Week 12 | 
| Change From Baseline in Fibrinogen Levels in Serum at Week 12 | Per Protocol Amendment 4, the measurement of fibrinogen levels in serum was removed from the analysis plan because fibrinogen levels were found to be too low and too difficult to measure. | Baseline and Week 12 | 
| Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC) at Week 12 | FEV1 and FVC are measures of lung function. FEV1 is defined as the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. Respiratory function tests were performed for the measurement of FEV1 and FVC at Baseline and at Week 12. The values were measured at 15 to 60 minutes following the use of a pressurized metered-dose inhaler. Three technically acceptable values were obtained, and the highest value was recorded. Change from Baseline in FEV1 and FVC was calculated as the Week 12 value minus the Baseline value. | Baseline and Week 12 | 
| Change From Baseline in the COPD Assessment Test (CAT) Question 1 Score at Week 12 | Participants completed the CAT questionnaire before undergoing respiratory function tests at Baseline and at Week 12. The CAT questionnaire is an 8-item questionnaire (comprised of Question [Q] 1 to Q8) designed to assess the health status of participants with COPD. In Question 1, participants were asked to rate how much they cough on a scale of 0 to 5: 0, I never cough; 5, I cough all the time. Change from Baseline was calculated as the Week 12 score minus the Baseline score. | Baseline and Week 12 | 
| Change From Baseline in the COPD Assessment Test (CAT) Question 2 Score at Week 12 | Participants completed the CAT questionnaire before undergoing respiratory function tests at Baseline and at Week 12. The CAT questionnaire is an 8-item questionnaire (comprised of Question [Q] 1 to Q8) designed to assess the health status of participants with COPD. In Question 2, participants were asked to rate the amount of phlegm (mucus) in their chest on a scale of 0 to 5: 0, I have no phlegm (mucus) in my chest at all; 5, My chest is completely full of phlegm (mucus). Change from Baseline was calculated as the Week 12 score minus the Baseline score. | Baseline and Week 12 | 
| Change From Baseline in the COPD Assessment Test (CAT) Question 3 Score at Week 12 | Participants completed the CAT questionnaire before undergoing respiratory function tests at Baseline and at Week 12. The CAT questionnaire is an 8-item questionnaire (comprised of Question [Q] 1 to Q8) designed to assess the health status of participants with COPD. In Question 3, participants were asked to rate how tight their chest feels on a scale of 0 to 5: 0, My chest does not feel tight at all; 5, My chest feels very tight. Change from Baseline was calculated as the Week 12 score minus the Baseline score. | Baseline and Week 12 | 
| Change From Baseline in the COPD Assessment Test (CAT) Question 4 Score at Week 12 | Participants completed the CAT questionnaire before undergoing respiratory function tests at Baseline and at Week 12. The CAT questionnaire is an 8-item questionnaire (comprised of Question [Q] 1 to Q8) designed to assess the health status of participants with COPD. In Question 4, participants were asked to rate how breathless they feel when walking up a flight of stairs or a hill on a scale of 0 to 5: 0, When I walk up a hill or one flight of stairs I am not breathless; 5, When I walk up a hill or one flight of stairs I am very breathless. Change from Baseline was calculated as the Week 12 score minus the Baseline score. | Baseline and Week 12 | 
| Change From Baseline in the COPD Assessment Test (CAT) Question 5 Score at Week 12 | Participants completed the CAT questionnaire before undergoing respiratory function tests at Baseline and at Week 12. The CAT questionnaire is an 8-item questionnaire (comprised of Question [Q] 1 to Q8) designed to assess the health status of participants with COPD. In Question 5, participants were asked to rate how limited they are in doing activities at home on a scale of 0 to 5: 0, I am not limited doing any activities at home; 5, I am very limited doing activities at home. Change from Baseline was calculated as the Week 12 score minus the Baseline score. | Baseline and Week 12 | 
| Change From Baseline in the COPD Assessment Test (CAT) Question 6 Score at Week 12 | Participants completed the CAT questionnaire before undergoing respiratory function tests at Baseline and at Week 12. The CAT questionnaire is an 8-item questionnaire (comprised of Question [Q] 1 to Q8) designed to assess the health status of participants with COPD. In Question 6, participants were asked to rate how confident they are leaving home despite their lung condition on a scale of 0 to 5: 0, I am confident leaving my home despite my lung condition; 5, I am not at all confident leaving my home because of my lung condition. Change from Baseline was calculated as the Week 12 score minus the Baseline score. | Baseline and Week 12 | 
| Change From Baseline in the COPD Assessment Test (CAT) Question 7 Score at Week 12 | Participants completed the CAT questionnaire before undergoing respiratory function tests at Baseline and at Week 12. The CAT questionnaire is an 8-item questionnaire (comprised of Question [Q] 1 to Q8) designed to assess the health status of participants with COPD. In Question 7, participants were asked to rate how soundly they sleep on a scale of 0 to 5: 0, I sleep soundly; 5, I don't sleep soundly because of my lung condition. Change from Baseline was calculated as the Week 12 score minus the Baseline score. | Baseline and Week 12 | 
| Change From Baseline in the COPD Assessment Test (CAT) Question 8 Score at Week 12 | Participants completed the CAT questionnaire before undergoing respiratory function tests at Baseline and at Week 12. The CAT questionnaire is an 8-item questionnaire (comprised of Question [Q] 1 to Q8) designed to assess the health status of participants with COPD. In Question 8, participants were asked to rate how much energy they have on a scale of 0 to 5: 0, I have lots of energy; 5, I have no energy at all. Change from Baseline was calculated as the Week 12 score minus the Baseline score. | Baseline and Week 12 | 
| Change From Baseline in the COPD Assessment Test (CAT) Total Score at Week 12 | Participants completed the CAT questionnaire before undergoing respiratory function tests at Baseline and at Week 12. The CAT questionnaire is an 8-item questionnaire (comprised of Question [Q] 1 to Q8; each question scored from 0 to 5) designed to assess the health status of participants with COPD. The total score is calculated as the sum of the scores from Questions 1 to 8, for a range of possible scores of 0 to 40. A higher total score represents a lower quality of life, and vice versa. Change from Baseline was calculated as the Week 12 score minus the Baseline score. | Baseline and Week 12 | 
| Number of Participants Who Experienced the Indicated Number of COPD Exacerbations During the Treatment Period | The occurrence of a COPD exacerbation was assessed on each day of evaluation during the treatment period per the defined severity classifications. COPD exacerbations were classified based on severity as a mild exacerbation (exacerbation of COPD symptoms were manageable by the participant, not requiring systemic corticosteroid or antimicrobial therapy), a moderate exacerbation (exacerbation of COPD symptoms required systemic corticosteroid or antimicrobial therapy), or a severe exacerbation (exacerbation of COPD symptoms required hospitalization). The number of participants who experienced 0, 1, 2, and >=3 exacerbation(s) was summarized. | From Baseline up to Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Japan, COPD, CAT, placebo, serum, Adoair250, anti-inflammatory, sputum