Study To Evaluate The Efficacy And Safety Of PH-797804 For 12 Weeks In Adults With Moderate To Severe Chronic Obstructive Pulmonary Disease (COPD) On A Background Of Tiotropium Bromide

Study Overview
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Brief Summary
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PH-797804 is an oral anti-inflammatory drug that may reduce the inflammation that is associated with Chronic Obstructive Pulmonary Disease (COPD). PH-797804 will be dosed to patients with Chronic Obstructive Pulmonary Disease (COPD) to evaluate its potential safety and efficacy profile in Chronic Obstructive Pulmonary Disease (COPD)

Official Title
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A Phase 2B, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Parallel Group Study To Evaluate The Efficacy And Safety Of Once-Daily Orally Administered PH-797804 For 12 Weeks In Adults With Moderate To Severe Chronic Obstructive Pulmonary Disease (COPD) On A Background Of Tiotropium Bromide

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: PH-797804
* Drug: PH-797804
* Drug: PH-797804
* Drug: PH-797804
* Drug: PH-797804
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects between, and including, the ages of 40 and 80 years. Subjects with a diagnosis, for at least 6 months, of moderate to severe COPD (GOLD) and who meet the criteria for Stage II-III disease: Subjects must have a post-bronchodilator FEV1/FVC ratio <0.7 and a post-bronchodilator FEV1 of 30 - 80% (inclusive) of the predicted value for age, height, race and sex using European Community for Coal and Steel ECCS standards or NHANES III standards. Subjects must have a smoking history of at least 10 pack-years* and meet one of the following criteria: They are current smokers, or they are ex-smokers who have abstained from smoking for at least 6 months. Subjects treated with tiotropium bromide (SPIRIVA HandiHaler) 18 microgram daily for at least 1 month prior to screening. Subjects must have had stable disease for at least 1 month prior to screening. During the screening and run-in phase subjects must be able to manage disease symptoms adequately with tiotropium bromide +/- salbutamol (albuterol) rescue medication (subjects should not use >10 actuations [100 microgram/actuations] daily for more than 2 consecutive days), without reliance on other therapies including oral or inhaled corticosteroids, other long-acting bronchodilators, nebulizer therapy, theophylline, roflumilast or regular oxygen. Exclusion Criteria: A COPD exacerbation requiring treatment with oral steroids or hospitalization for the treatment of COPD within 3 months of screening. History of a lower respiratory tract infection or significant disease instability during the month preceding screening or during the time between screening and randomization. History or presence of respiratory failure, cor pulmonale or right ventricular failure. Subjects with home oxygen therapy (either PRN or long-term oxygen therapy). Any clearly documented history of adult asthma or other chronic respiratory disorders (eg, bronchiectasis, pulmonary fibrosis, pneumoconiosis). Known previous diagnosis of Hepatitis B or C or HIV infection (specific screening is not required). History of cancer (other than cutaneous basal cell) in the previous 5 years. Active or past history of GI hemorrhage of any etiology, peptic ulceration, erosive esophagitis, gastric outlet obstruction or inflammatory bowel disease. Regular use of aspirin at a dose greater than 325 mg/day. History within the previous 6 months of: myocardial infarction, cardiac arrhythmia (eg, atrial fibrillation, paroxysmal atrial fibrillation, atrial flutter, supraventricular tachycardia, ventricular tachycardia), left ventricular failure, unstable angina, coronary angioplasty, coronary artery bypass grafting (CABG) or cerebrovascular accident (including transient ischemic attacks). A family history of long QT syndrome. Presenting with: Any condition possibly affecting oral drug absorption (eg, gastrectomy or clinically significant diabetic gastroenteropathy). Any clinically significant skin lesions as described in Common Terminology Criteria for Adverse Events for Dermatology (CTCAE) Version 3.0. Any clinically significant active systemic or cutaneous infection including herpetic lesions. Congestive heart failure requiring treatment New York Heart Association (NYHA) Class III-IV. ECG abnormalities at screening or randomization, including those listed below: Subjects with pre-randomization evidence of QTcF prolongation (defined as >450 ms) at screening or baseline (Week 0) are not eligible for randomization. This assessment is based on a confirmed mean of the triplicate ECG recordings and is made by the investigator at the time of ECG collection. Predominant heart rhythm other than normal sinus rhythm eg, atrial fibrillation, atrial flutter, supraventricular tachycardia. Atrioventricular (AV) block greater than first degree. Resting heart rate >100 or <40 bpm. Evidence of previous myocardial infarction in the absence of clinical history consistent with these findings. Evidence of acute ischemia.

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PH-787904 (arm1)<br> | Drug: PH-797804<br>* 0.25 mg oral tablet plus tiotropium bromide 18 microgram once daily for 12 weeks<br>|
| Experimental: PH-787904 (arm2)<br> | Drug: PH-797804<br>* 1 mg oral tablet plus tiotropium bromide 18 microgram once daily for 12 weeks<br>|
| Experimental: PH-787904 (arm3)<br> | Drug: PH-797804<br>* 3 mg oral tablet plus tiotropium bromide 18 microgram once daily for 12 weeks<br>|
| Experimental: PH-787904 (arm4)<br> | Drug: PH-797804<br>* 6 mg oral tablet plus tiotropium bromide 18 microgram once daily for 12 weeks<br>|
| Experimental: PH-787904 (arm5)<br> | Drug: PH-797804<br>* 10 mg oral tablet plus tiotropium bromide 18 microgram once daily for 12 weeks<br>|
| Experimental: Placebo<br> | Drug: Placebo<br>* Placebo oral tablet plus tiotropium bromide 18 microgram once daily for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in trough (pre-treatment and pre-bronchodilator) Forced Expiratory Volume1 at Week 12. |  | Baseline, week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in trough, pre-bronchodilator Forced Expiratory Volume1 at Weeks 2, 6, and 10 |  | Baseline, week 2, 6, and 10 | 
| Change from baseline in trough, pre-bronchodilator Forced Expiratory Volume6 at Weeks 2, 6, 10 and 12 |  | Baseline, week 2, 6, 10 and 12 | 
| Change from baseline in trough, pre-bronchodilator Forced Vital Capacity at Weeks 2, 6, 10 and 12 |  | Baseline, week 2, 6, 10 and 12 | 
| Change from baseline in trough, pre-bronchodilator Inspiratory Capacity at Weeks 2, 6, 10 and 12 |  | Baseline, week 2, 6, 10 and 12 | 
| Average change from baseline in trough, pre-bronchodilator Forced Expiratory Volume 1, Forced Expiratory Volume 6, Forced Vital Capacity and Inspiratory Capacity over 12 weeks treatment |  | Baseline, week 12 | 
| Change from baseline in post-study drug, pre-bronchodilator Forced Expiratory Volume1, Forced Expiratory Volume6, Forced Vital Capacity and Inspiratory Capacity at Weeks 0 and 12 |  | Baseline, week 0, 12 | 
| Change from baseline in post-study drug, post-bronchodilator Forced Expiratory Volume1, Forced Expiratory Volume6, Forced Vital Capacity and Inspiratory Capacity at Weeks 0 and 12 |  | Baseline, week 0, week 12 | 
| Change from baseline in Chronic Obstructive Pulmonary Disease symptoms (EXACT-PRO Daily Diary) over 12 weeks treatment. |  | Baseline, week 12 | 
| Change from baseline in Chronic Respiratory Questionnaire - Self Administered Standard (CRQ-SAS) at Weeks 2, 6, 10 and 12 |  | Baseline, week 2, 4, 6, 10 and 12 | 
| Patient Global Impression of Change at Week 12 |  | Baseline, week 12 | 
| Change from baseline (Baseline Dyspnea Index) in dyspnea (Transition Dyspnea Index) at Weeks 2, 6, 10 and 12 |  | Baseline, week 2, 4, 6, 10, and 12 | 
| Clinician Global Impression of Change at Week 12 |  | Baseline, week 12 | 
| Rescue bronchodilator use (per daily diary) over 12 weeks of therapy |  | Baseline, week 12 |