A Comparison Study Between the Fixed Dose Triple Combination of Fluticasone Furoate/ Umeclidinium/ Vilanterol Trifenatate (FF/UMEC/VI) With Budesonide/Formoterol in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

A Phase III, 24 Week, Randomized, Double Blind, Double Dummy, Parallel Group Study (With an Extension to 52 Weeks in a Subset of Subjects) Comparing the Efficacy, Safety and Tolerability of the Fixed Dose Triple Combination FF/UMEC/VI Administered Once Daily in the Morning Via a Dry Powder Inhaler With Budesonide/Formoterol 400mcg/12mcg Administered Twice-Daily Via a Reservoir Inhaler in Subjects With Chronic Obstructive Pulmonary Disease

This is a phase IIIa, randomised, double-blind, double-dummy, parallel group multicenter study evaluating once daily FF/UMEC/VI (100 microgram [mcg]/62.5 mcg/25 mcg) inhalation powder versus twice daily budesonide/formoterol (400 mcg/12 mcg). The primary purpose of this study is to demonstrate improvements in lung function and health status for subjects treated with FF/UMEC/VI compared with budesonide/formoterol for 24 weeks. Once-daily 'closed' triple therapy of a Inhaled Corticosteroid/ Long-acting Muscarinic Receptor Antagonists/ Long Acting Beta-Agonist (ICS/LAMA/LABA) combination FF/UMEC/VI (100 mcg/62.5 mcg/25 mcg) in a single device is being developed with the aim of providing a new treatment option for the management of advanced (GOLD Group D) COPD which will reduce the exacerbation frequency, allow for a reduced burden of polypharmacy, convenience, and increase the potential for improvement in lung function, Health Related Quality of Life (HRQoL) and symptom control over established dual/monotherapies.

Subjects meeting all inclusion/exclusion criteria and who have successfully completed all protocol procedures at the Screening Visit will enter the two-week run-in period. Following the run-in period, eligible subjects will be randomised (1:1) to one of the following double-blind treatment groups: FF/UMEC/VI 100 mcg/62.5 mcg/25 mcg via the ELLIPTA™ dry powder inhaler (DPI) once daily in the morning and placebo via reservoir inhaler twice daily OR Budesonide/formoterol 400 mcg/12 mcg via reservoir inhaler twice daily and placebo via the ELLIPTA DPI once daily in the morning.

The target enrollment is 1800 randomised subjects at approximately 200 study centers globally. The total duration of subject participation will be approximately 27 weeks, consisting of a 2-week run-in period, 24-week treatment period and a 1-week follow-up period. Subjects will run-in on their existing COPD medications for 2 weeks and in addition will be provided with short acting albuterol/salbutamol to be used on an as-needed basis (rescue medication) throughout the study. Subjects will discontinue all existing COPD medications during the randomised treatment period but may continue their study supplied rescue albuterol/salbutamol. A sub-set of approximately 400 subjects will remain on blinded study treatment for up to a total of 52 weeks to provide additional long term safety data.

ELLIPTA and NUBULES are a trade marks of the GlaxoSmithKline Group of Companies. Other company or product names mentioned herein may be the property of their respective owners

Inclusion Criteria:

• Informed Consent: A signed and dated written informed consent prior to study participation.
• Type of subject: Outpatient.
• Age: Subjects 40 years of age or older at Screening (Visit 1).
• Gender: Male or female subjects. 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. OR Child bearing potential, 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 safety 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. For this definition, "documented" refers to the outcome of the investigator's/designee's medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records.; Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)
• COPD Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society.
• Smoking History: Current or former cigarette smokers with a history of cigarette smoking of >10 pack-years at Screening (Visit 1) [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)]. Previous 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.
• Severity of COPD symptoms: A score of >=10 on the COPD Assessment Test (CAT) at Screening (Visit 1).
• Severity of Disease: Subjects must demonstrate at Screening: <a post-bronchodilator FEV1 <50% predicted normal OR a post-bronchodilator FEV1 <80% predicted normal and a documented history of >=2 moderate exacerbations or one severe (hospitalized) exacerbation in the previous 12 months. Subjects must also have a measured post albuterol/salbutamol FEV1/FVC ratio of <0.70 at screening. Note: Percent predicted will be calculated using the European Respiratory Society Global Lung Function Initiative reference equations. Note: A documented history of a COPD exacerbation (e.g., medical record verification) is a medical record of worsening COPD symptoms that required systemic/oral corticosteroids and/or antibiotics (for a moderate exacerbation) or hospitalization (for a severe exacerbation). Prior use of antibiotics alone does not qualify as an exacerbation history unless the use was associated with treatment of worsening symptoms of COPD, such as increased dyspnoea, sputum volume, or sputum purulence (colour). Subject verbal reports are not acceptable.
• Existing COPD maintenance treatment: Subject must be receiving daily maintenance treatment for their COPD for at least 3 months prior to Screening. Note: Subjects receiving only as required (PRN) COPD medications are not eligible.
• Liver function tests: alanine aminotransferase (ALT) <2x upper limit of normal (ULN); alkaline phosphatase <=1.5xULN; bilirubin <=1.5xULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

Exclusion Criteria:

• Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.
• Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD). Alpha1-antitrypsin deficiency: Subjects with alpha1-antitrypsin deficiency as the underlying cause of COPD.
• Other respiratory disorders: Subjects with active tuberculosis, lung cancer, significant bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases.
• Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening.
• Risk Factors for Pneumonia: immune suppression (e.g. Human immunodeficiency virus [HIV], Lupus) or other risk factors for pneumonia (e.g. neurological disorders affecting control of the upper airway, such as Parkinson's Disease, Myasthenia Gravis). Subjects at potentially high risk (e.g. very low Body mass index [BMI], severely malnourished, or very low FEV1) will only be included at the discretion of the investigator.
• Pneumonia and/or moderate or severe COPD exacerbation that has not resolved at least 14 days prior to Screening and at least 30 days following the last dose of oral/systemic corticosteroids (if applicable). In addition, any subject that experiences pneumonia and/or moderate or severe COPD exacerbation during the run-in period will be excluded.
• Respiratory tract infection that has not resolved at least 7 days prior to Screening.
• Abnormal Chest X-ray (CXR): Chest X-ray (posteroanterior and lateral) reveals evidence of pneumonia or a clinically significant abnormality not believed to be due to the presence of COPD, or another condition that would hinder the ability to detect an infiltrate on CXR (e.g. significant cardiomegaly, pleural effusion or scarring). All subjects will have a CXR at Screening Visit 1) (or historical radiograph or Computed Tomography [CT] scan obtained within 3 months prior to screening) that will be over-read by a central vendor. Note: Subjects who have experienced pneumonia and/or moderate or severe COPD exacerbation within 3 months of screening must provide a post pneumonia/exacerbation CXR to be over-read by the central vendor or have a CXR conducted at Screening. For sites in Germany: If a chest x-ray (or CT scan) within 3 months prior to Screening (Visit 1) is not available, approval to conduct a diagnostic CXR will need to be obtained from the Federal Office for Radiation Protection (BfS).
• Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, sensory, endocrine (including uncontrolled diabetes or thyroid disease) or haematological abnormalities that are uncontrolled. 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. For subjects taking part in the physical activity monitor subset: Orthopaedic, neurological or other complaints that significantly impair normal biomechanical movement patterns and limit the ability to walk/cycle, as judged by the Investigator.
• Unstable liver disease as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice, cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Note: Chronic stable hepatitis B and C are acceptable if the subject otherwise meets entry criteria.
• Unstable or life threatening cardiac disease: subjects with any of the following at Screening (Visit 1) would be excluded: Myocardial infarction or unstable angina in the last 6 months; Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months; New York Heart Association (NYHA) Class IV Heart failure
• Abnormal and clinically significant 12-Lead Electrocardiogram (ECG) finding: Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. The Principal Investigator (PI) will determine the clinical significance of each abnormal ECG finding in relation to the subject's medical history and exclude subjects who would be at undue risk by participating in the trial. An abnormal and clinically significant 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: Atrial fibrillation (AF) with rapid ventricular rate >120 Beats Per Minute (BPM); sustained or non-sustained ventricular tachycardia (VT); Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted); QT interval corrected for heart rate by Fridericia's formula (QTcF) >=500 milliseconds (msec) in subjects with QRS <120 msec and QTcF >=530 msec in subjects with QRS >=120 msec.
• Contraindications: A history of allergy or hypersensitivity to any corticosteroid, anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the Investigator, contraindicates study participation.
• Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded based on the 5 year waiting period if the subject has been considered cured by treatment.
• Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy >3litres/minute (L/min) (Oxygen use <=3L/min flow is not exclusionary.)
• Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol/salbutamol for the 4-hour period required prior to spirometry testing at each study visit.
• Pulmonary rehabilitation: Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Program within 4 weeks prior to Screening or subjects who plan to enter the acute phase of a Pulmonary Rehabilitation Program during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Program are not excluded.
• Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years.
• Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits.
• Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study.
• Affiliation with investigator site: study investigators, sub-investigators, study coordinators, employees of a participating investigator or study site, or immediate family members of the aforementioned that is involved with this study.
• Inability to read: In the opinion of the investigator, any subject who is unable to read and/or would not be able to complete study related materials.
• Medication prior to screening: No use of the following medications within the following time intervals prior to Screening or during the study. Long term antibiotic therapy: Subjects receiving antibiotics for long term therapy are not eligible for the study (Antibiotics are allowed for the short term treatment of an exacerbation or for short term treatment of other acute infections); Systemic, Oral, parenteral corticosteroids: 30 days (Except during the study oral/systemic corticosteroids may be used to treat COPD exacerbations/pneumonia). Intra-articular injections are allowed. Any other investigational drug: 30 days or 5 half lives whichever is longer.