A 24 Week Efficacy Study of Inhaled Umeclidinium (UMEC) in Patients of Chronic Obstructive Pulmonary Disease (COPD) Using a Novel Dry Powder Inhaler (NDPI)

A 24 Week Randomised, Double Blind and Placebo Controlled Study to Evaluate the Efficacy and Safety of 62.5 mcg Umeclidinium Inhalation Powder Delivered Once Daily Via a Novel Dry Powder Inhaler in Subjects With Chronic Obstructive Pulmonary Disease

Studies to date provides substantial evidence for the effectiveness for UMEC 62.5 microgram (mcg) as a long term maintenance therapy for the treatment of COPD; this study further evaluates the efficacy and safety of UMEC 62.5 mcg administered once-daily (OD) for 24 weeks via a NDPI compared with placebo in Asian subjects with COPD. Over approximate 27 weeks of entire study duration, 10 study clinic visits will be conducted on an outpatient basis. Pre-screening visit will be conducted for the informed consent form, review demography, COPD history and COPD concomitant medications. Subjects meeting the eligibility criteria at screening will complete a 7 to 14 day Run-in period and will be provided with albuterol/salbutamol as rescue medication on an "as-needed" basis. Further, subjects will be randomized to the UMEC 62.5 mcg or matching placebo in a 1:2 ratio for 24 week treatment period. A follow up for adverse event assessment will be scheduled approximately 7 days after the treatment period or the Early Withdrawal Visit.

Inclusion Criteria:

• Type of subject: outpatient, Asian ancestry.
• Informed Consent: A signed and dated written informed consent prior to study participation.
• Age: 40 years of age or older at Screening (Visit 1).
• Gender: Male or female subjects are eligible to participate in the study. A female is eligible to enter and participate in the study if she is of: Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g. age appropriate, >45 years, in the absence of hormone replacement therapy. However, in questionable cases, post-menopause status may be confirmed by analysis of a blood sample with follicle-stimulating hormone (FSH) >40 million international units per milliliter (MIU/ml) and estradiol <40 picogram (pg) /ml (<140 picomole per liter (pmol/L) as confirmatory. OR Child bearing potential, provided the subject has a negative pregnancy test at screening, and agrees to one of the following acceptable contraceptive methods used consistently and correctly (i.e. in accordance with the approved product label, and the instructions of the physician for the duration of the study - Screening to Follow-Up contact): Abstinence\ Oral contraceptive either combined or progestogen alone\ Injectable progestogen\ Implants of levonorgestrel\ Estrogenic vaginal ring\ Percutaneous contraceptive patches\ Intrauterine device (IUD) or intrauterine system (IUS)\ Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study and this male is the sole partner for that subject\ Double barrier method condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository).
• COPD History: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society as follows: COPD is a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences.
• Tobacco Use and Smoking History: Current or former cigarette smokers with a history of cigarette smoking of >= 10 pack-years [Number of pack years = (number of cigarettes per day /20) x number of years smoked (e.g. 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years both equal 10 pack years)]. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Note: Pipe and/or cigar use cannot be used to calculate pack-year history. COPD patients who only use a pipe and/or cigar are not eligible.
• Severity of Disease: A pre and post-salbutamol/albuterol FEV1/FVC ratio of <0.70 and a pre and post-salbutamol/albuterol FEV1 of <=70% of predicted normal values calculated using National Health and Nutrition Examination Survey III reference equations at Visit 1.
• Dyspnea: A score of >=2 on the Modified Medical Research Council Dyspnoea Scale (mMRC) at Screening (Visit 1)

Exclusion Criteria:

• Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.
• Asthma: A current diagnosis of asthma.
• Other Respiratory Disorders: Known alpha-1 antitrypsin deficiency, active lung infections (such as tuberculosis) and lung cancer are absolute exclusionary conditions. A subject, who in the opinion of the investigator has any other significant respiratory conditions in addition to COPD should be excluded. Examples may include clinically significant bronchiectasis, pulmonary hypertension, sarcoidosis or interstitial lung disease.
• Other Diseases/Abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or haematological abnormalities that are uncontrolled and/or a previous history of cancer in remission for <5 years prior to Visit 1 (localized carcinoma of the skin that has been resected for cure is not exclusionary). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.
• Chest X-Ray: A chest X-ray or computed tomography (CT) scan that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray must be taken at Visit 1 if a chest X-ray or CT scan is not available within 6 months prior to Visit 1.
• Contraindications: A history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate or a medical condition such as of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the study physician contraindicates study participation or use of an inhaled anticholinergic.
• Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1.
• Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1).
• 12-Lead electrocardiogram (ECG): An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1, including the presence of a paced rhythm on a 12-lead ECG which causes the underlying rhythm and ECG to be obscured. Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. Specific ECG findings that precluded subject eligibility are as listed. An ECG finding that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following: Sinus tachycardia ≥120 bpm*Note: sinus tachycardia ≥120bpm should be confirmed by two additional readings at least 5 minutes apart. Sinus bradycardia <45bpm*Note: Sinus bradycardia <45bpm should be confirmed by two additional readings at least 5 minutes apart.Multifocal atrial tachycardia.Supraventricular tachycardia (>100bpm).Atrial fibrillation with rapid ventricular response (rate >120bpm). Atrial flutter with rapid ventricular response (rate >120bpm). Ventricular tachycardias (non sustained, sustained, polymorphic, or monomorphic). Ventricular flutter. Ventricular fibrillation. Torsades de Pointes. Evidence of Mobitz type II second degree or third degree atrioventricular (AV) block. AV dissociation. Trifascicular Block. For subjects with QRS duration <120 ms: QTc(F) ≥450msec or an ECG that is unsuitable for QT measurements (e.g., poor defined termination of the T wave). For subjects with QRS duration>120: QTc(F) ≥480msec or an ECG that is unsuitable for QT measurements (e.g., poor defined termination of the T wave). Myocardial infarction (acute or recent) * Note: Evidence of an old (resolved) myocardial infarction is not exclusionary. The study investigator will determine the medical significance of any ECG abnormalities not listed above.
• Screening Labs: Significantly abnormal findings from clinical chemistry and haematology tests at Visit 1.
• Medications Prior to Spirometry: Unable to withhold albuterol/salbutamol for the 4 hour period required prior to spirometry testing at each study visit.
• Medications Prior to Screening: Use of the following medications according to the following defined time intervals prior to Visit 1 is presented as Medication with Time Interval Prior to Visit 1: Depot corticosteroids (12 weeks); Systemic, oral, parenteral (intra-articular) corticosteroids (4 weeks); Antibiotics (for lower respiratory tract infection) (4 weeks); inhaled corticosteroid/ long-acting beta agonist (ICS/LABA) combination products if ICS/LABA therapy is discontinued completely (30 days); Use of ICS at a dose >1000mcg/day of fluticasone propionate or equivalent (30 days); Initiation or discontinuation of ICS use (30 days); Phosphodiesterase 4 (PDE4) inhibitors (roflumilast) (14 days); Long-acting anticholinergics (e.g.,tiotropium and aclidinium, glycopyronium) (7 days); Theophyllines (12 hours stable dose of theophylline alone is allowed during the study but must be withheld 12 hours prior to each study visit); Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton) (48 hours); Oral beta2-agonists (Long- acting 48 hours, Short -acting 12 hours); Olodaterol and Indacaterol (inhaled long-acting beta2-agonist) (14 days); Salmeterol, formoterol, (inhaled long-acting beta2-agonist) (48 hours); LABA/ ICS combination products only if discontinuing LABA therapy and switching to ICS monotherapy (48 hours for LABA component); Inhaled sodium cromoglycate or nedocromil sodium (24 hours); Inhaled short acting beta2-agonists (4 hours); Inhaled short-acting anticholinergics (e.g. ipratropium bromide) (4 hours, stable dose of ipratropium alone is allowed during the study, provided that the subject is on a stable dose regimen from Screening [Visit 1 and remains so throughout the study] but must be withheld 4 hours prior to each study visit); Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products (4 hours); Any other investigational drug (30 days or 5 half lives, whichever is longer). Note: Further details related to allowable dosage of above listed medications will be explained by the Investigator)