A Comparative Study Between Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) Single Inhaler Triple Therapy Versus Tiotropium Monotherapy in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

A Phase IV, 12 Week, Randomised, Double-blind, Double-dummy Study to Compare Single Inhaler Triple Therapy, Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI), With Tiotropium Monotherapy Based on Lung Function and Symptoms in Participants With Chronic Obstructive Pulmonary Disease

COPD is a progressive disease characterized by increasing obstruction to airflow and the progressive development of respiratory symptoms including chronic cough, increased sputum production, dyspnea and wheezing. Once-daily triple therapy of an Inhaled Corticosteroid/ Long-acting Muscarinic Receptor Antagonists/ Long Acting Beta-Agonist (ICS/LAMA/LABA) that is combination of FF/UMEC/VI in a single device is being developed with the aim of providing a new treatment option for the management of advanced COPD. The primary purpose of this study is to evaluate lung function and health related quality of life (HRQoL) after 84 days of treatment with a single inhaler triple therapy combination of FF/ UMEC/VI once daily via the ELLIPTA® dry powder inhaler (DPI) compared with tiotropium once daily via HANDIHALER®, in subjects with COPD. Subjects will be randomized 1:1 to receive FF/UMEC/VI or tiotropium in the morning for 84 days. Subjects will also receive albuterol/salbutamol as a rescue therapy throughout the study. Approximately 848 subjects with advanced COPD will be enrolled in the study. The total study duration will be approximately 17 weeks including, 4-week run-in period, 12-week treatment period and a 1-week follow-up period. ELLIPTA is a registered trademark of GlaxoSmithKline (GSK) group of companies. HANDIHALER and RESPIMAT are registered trademarks of Boeringher Ingelheim.

Inclusion Criteria:

• Subjects capable of giving signed informed consent.
• Outpatients will be included in the study.
• Subjects 40 years of age or older at Screening (Visit 1).
• Male or female subjects will be included; a female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance during the treatment period and until the safety follow-up contact after the last dose of study treatment.
• An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society.
• 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 [example given {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.
• A score of >=10 on the COPD Assessment Test (CAT) at Screening (Visit 1).
• Subjects must demonstrate at Screening: A post-bronchodilator FEV1 <50 percent predicted normal or a post-bronchodilator FEV1 <80 percent 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/forced vital capacity (FVC) ratio of <0.70 at screening.
• Subjects must have been receiving daily maintenance treatment with tiotropium alone (via the HANDIHALER or RESPIMAT®) for their COPD for at least 3 months prior to Screening.

Exclusion Criteria:

• Women who are pregnant or lactating or are planning on becoming pregnant during the study.
• Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD).
• Subjects with alpha1-antitrypsin deficiency as the underlying cause of COPD.
• Subjects with active tuberculosis, lung cancer, and clinically significant: bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung disease or other active pulmonary diseases.
• Subjects who have undergone lung volume reduction surgery within the 12 months prior to Screening.
• Immune suppression (e.g. advanced human immunodeficiency virus [HIV] with high viral load and low cluster of differentiation 4 [CD4] count, lupus on immunosuppressant's) that in the opinion of the investigator would increase risk of pneumonia 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 for pneumonia (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).
• Respiratory tract infection that has not resolved at least 7 days prior to Screening.
• 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 chest x-ray (e.g. significant cardiomegaly, pleural effusion or scarring). All subjects will have a chest x-ray at Screening Visit 1 (or historical radiograph or computerized tomography [CT] scan obtained within 3 months prior to 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 chest x-ray will need to be obtained from the Federal Office for Radiation Protection (BfS).
• 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 hematological 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.
• Alanine Transaminase (ALT) >2x Upper Limit of Normal (ULN); and bilirubin >1.5x ULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent). Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment). Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen [HBsAg] or positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment) are acceptable if subject otherwise meets entry criteria.
• Subjects with any of the following at Screening (Visit 1): 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 at Visit 1. The Investigator 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 ECG tracing that is interpreted at, but not limited to, any of the following: atrial fibrillation (AF) with rapid ventricular rate >120 beats per minute (BPM); sustained and 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 (QTc) >=500 millisecond (msec) in subjects with QRS <120 msec and QTc >=530 msec in subjects with QRS >=120 msec.
• 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.
• Subjects with carcinoma that has not been in complete remission for at least 3 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 3 year waiting period if the subject has been considered cured by treatment.
• Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy >3 Liters per minute (L/minute) (Oxygen use <=3 L/minute flow is not exclusionary.)
• Subjects who are medically unable to withhold their albuterol/salbutamol for the 4-hour period required prior to spirometry testing at each study visit.
• Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Programme within 4 weeks prior to screening or subjects who plan to enter the acute phase of a Pulmonary Rehabilitation Programme during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Programme are not excluded.
• Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years.
• 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.
• 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.
• 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.
• In the opinion of the Investigator, any subject who is unable to read and/or would not be able to complete study related materials.
• Subjects taking following drug therapies will be excluded; subjects taking inhaled short-acting anticholinergics alone or along with short-acting beta agonist combination within 6 hours prior to screening; subjects taking inhaled short-acting beta2 agonists within >=4 hours prior to screening; subjects taking ICS, ICS/inhaled LABA combinations (e.g., FF/salmeterol, mometasone furoate/formoterol fumarate, budesonide/formoterol fumarate; FF/VI), Phosphodiesterase 4 (PDE4) inhibitors (roflumilast), LABA (e.g., indacaterol, olodaterol), LAMA (e.g., LAMA/LABA combinations UMEC, aclidinium, glycopyrronium), LAMA/LABA combinations, theophyllines, sodium cromoglycate and nedocromil sodium, anti-leukotrienes as maintenance treatment within 3 months prior to Visit 1 will be excluded. Maintenance treatment is defined as use for >=14 consecutive days (at any time in the 3 months prior to Visit 1). Subjects taking long term antibiotic therapy. (Antibiotics are allowed for the short term treatment (<=14 days) of an exacerbation or for short term treatment (<=14 days) of other acute infections during the study); subjects taking systemic, oral, parenteral corticosteroids 30 days prior to screening; (During the study oral/systemic corticosteroids may be used for <=14 days to treat COPD exacerbations/pneumonia) will be excluded. Intra-articular injections are allowed; subjects taking any other investigational drug within 30 days or 5 half-lives whichever is longer prior to screening will be excluded.