A Randomized Study, Comparing Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC /VI) Single Inhaler Triple Therapy, Versus Multiple Inhaler Therapy (Budesonide/Formoterol Plus Tiotropium) in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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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 [100/62.5/25 microgram (mcg)] once daily via ELLIPTA® compared with a multiple inhaler combination therapy of Symbicort Metered Dose Inhaler (MDI) (budesonide/formoterol 320/9 mcg) twice daily plus Spiriva HandiHaler (tiotropium 18 mcg) once daily. The study will inform healthcare providers that subjects can be effectively and safely switched to FF/UMEC /VI single inhaler therapy from a multiple inhaler triple therapy regimen of Symbicort MDI and Spiriva Handihaler. Eligible subjects will enter a 4-week run-in period during which they will be administered budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once daily plus placebo via ELLIPTA. Following the run-in period, subjects will be randomized to receive one of the following study treatments for 84 days: 1) FF/UMEC /VI 100/62.5/25 mcg via ELLIPTA once daily in the morning plus two inhalations of placebo to match budesonide/formoterol via MDI, twice daily plus placebo to match tiotropium via HandiHaler once daily in the morning or 2) Budesonide/formoterol 320/9 mcg via MDI, twice daily plus tiotropium 18 mcg via HandiHaler once daily in the morning plus placebo via ELLIPTA once daily in the morning. Subjects will then enter a one week follow-up period. The total duration for a subject in the study will be approximately 17 weeks. ELLIPTA is a registered trademark of the GlaxoSmithKline group of companies.

Official Title
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A Phase IV, 12-week, Randomised, Double-blind, Triple Dummy Study to Compare Single Inhaler Triple Therapy, Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) With Multiple Inhaler Therapy (Budesonide/Formoterol Plus Tiotropium) Based on Lung Function and Symptoms in Participants With Chronic Obstructive Pulmonary Disease

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: budesonide/formoterol
* Drug: albuterol/salbutamol
* Drug: FF/UMEC/VI
* Drug: Placebo to match budesonide/formoterol
* Drug: tiotropium
* Drug: Placebo to match FF/UMEC/VI
* Drug: placebo to match tiotropium
* Device: ELLIPTA
* Device: MDI
* Device: HandiHaler


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be capable of giving signed informed consent prior to study start. Only outpatient subjects will be included Subjects (male or female) must be 40 years of age or older at Screening (Visit 1). 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 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 (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. Subjects with a score of >=10 on the COPD Assessment Test (CAT) at Screening (Visit 1) Subjects must demonstrate 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/forced vital capacity (FVC) ratio of <0.70 at screening Subjects must have been receiving daily maintenance treatment 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 alpha 1-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 immunosuppressants) 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). 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 or 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. Unstable liver disease: alanine transaminase (ALT) >2 times Upper Limit of Normal (ULN); and bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 %). 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). 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 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: i) Atrial Fibrillation (AF) with rapid ventricular rate >120 beats per minute (BPM); ii) Sustained and non-sustained Ventricular tachycardia (VT); iii). Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted); iv) 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. 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/min) at screening (Oxygen use <=3 L/min 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 Program during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Program 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, 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 Use of various medication prior to screening.

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
Interventional Model Description: This is a parallel group study. Eligible subjects will be randomized in a ratio of 1:1 to receive either FF/UMEC /VI single inhaler triple therapy or multiple inhaler triple combination therapy (budesonide/formoterol plus tiotropium) during the treatment period.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FF/UMEC/VI 100/62.5/25 mcg<br>Subjects will receive budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once daily plus placebo via ELLIPTA during the 4-week run-in period. Subjects will be administered FF/UMEC/VI 100/62.5/25 mcg via ELLIPTA once daily in the morning plus placebo to match budesonide/formoterol via MDI, two inhalations twice daily plus placebo to match tiotropium via HandiHaler once daily in the morning for 84 days in the treatment period. | Drug: budesonide/formoterol<br>* Subjects will be administered two inhalations of budesonide/formoterol via MDI twice daily<br>Drug: albuterol/salbutamol<br>* Subjects will be provided short-acting albuterol/salbutamol as-rescue medication to be used on an as-needed basis throughout the study.<br>Drug: FF/UMEC/VI<br>* Subjects will receive FF/UMEC/VI 100/62.5/25 mcg via ELLIPTA once daily in the morning<br>Drug: Placebo to match budesonide/formoterol<br>* Subjects will be administered two inhalations of matching placebo twice daily via MDI<br>Drug: tiotropium<br>* Subjects will receive tiotropium (18 mcg) once daily in the morning via HandiHaler device<br>Drug: placebo to match tiotropium<br>* Subjects will receive tiotropium matching placebo via Handihaler once daily in the morning<br>Device: ELLIPTA<br>* Subjects will receive FF/UMEC/VI 100/62.5/25 mcg and matching placebo via ELLIPTA in the treatment period. Budesonide/formoterol plus tiotropium once daily plus placebo will be administered via ELLIPTA during the run-in period.<br>Device: MDI<br>* Subjects will receive budesonide/formoterol and placebo to match budesonide/formoterol via MDI in the treatment period.<br>Device: HandiHaler<br>* Subjects will be administered tiotropium (18 mcg) or placebo to match tiotropium via HandiHaler during the treatment period.<br>|
| Active Comparator: Budesonide/formoterol plus tiotropium<br>Subjects will receive budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once daily plus placebo via ELLIPTA during the 4-week run-in period. Subjects will be administered budesonide/formoterol 160/4.5 mcg via MDI, two inhalations twice daily plus tiotropium 18 mcg via HandiHaler once daily in the morning plus placebo via ELLIPTA once daily in the morning for 84 days in the treatment period. | Drug: budesonide/formoterol<br>* Subjects will be administered two inhalations of budesonide/formoterol via MDI twice daily<br>Drug: albuterol/salbutamol<br>* Subjects will be provided short-acting albuterol/salbutamol as-rescue medication to be used on an as-needed basis throughout the study.<br>Drug: tiotropium<br>* Subjects will receive tiotropium (18 mcg) once daily in the morning via HandiHaler device<br>Drug: Placebo to match FF/UMEC/VI<br>* Matching placebo to FF/UMEC/VI will be administered via ELLIPTA once daily in the morning.<br>Device: ELLIPTA<br>* Subjects will receive FF/UMEC/VI 100/62.5/25 mcg and matching placebo via ELLIPTA in the treatment period. Budesonide/formoterol plus tiotropium once daily plus placebo will be administered via ELLIPTA during the run-in period.<br>Device: MDI<br>* Subjects will receive budesonide/formoterol and placebo to match budesonide/formoterol via MDI in the treatment period.<br>Device: HandiHaler<br>* Subjects will be administered tiotropium (18 mcg) or placebo to match tiotropium via HandiHaler during the treatment period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weighted Mean Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Over 0-24 Hours at Week 12 for Modified Per Protocol (mPP) Population | FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. Serial FEV1 assessments were performed at multiple time points (-30 and -5 minutes pre-dose, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 15 hours, 21 hours, 23 hours and 24 hours post-dose) over 24-hour period at Week 12. Weighted mean change from Baseline at week 12 was calculated by subtracting weighted mean FEV1 at week 12 from Baseline FEV1, where Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. The weighted mean was derived by calculating the area under the FEV1 time curve (AUC) over the actual time of assessment relative to the time of dosing (over 24-hour period) using the trapezoidal rule, and then dividing the value by the time interval (24-hour) over which the AUC was calculated. | Baseline and Week 12 | 
| Weighted Mean Change From Baseline in FEV1 Over 0-24 Hours at Week 12 for ITT Population | FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. Serial FEV1 assessments were performed at multiple time points (-30 and -5 minutes pre-dose, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 15 hours, 21 hours, 23 hours and 24 hours post-dose) over 24-hour period at Week 12. Weighted mean change from Baseline at week 12 was calculated by subtracting weighted mean FEV1 at week 12 from Baseline FEV1, where Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. The weighted mean was derived by calculating the area under the FEV1 time curve (AUC) over the actual time of assessment relative to the time of dosing (over 24-hour period) using the trapezoidal rule, and then dividing the value by the time interval (24-hour) over which the AUC was calculated. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Trough FEV1 on Day 2, Day 28, Day 84 and Day 85 | FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. For Day 2 and Day 85, trough FEV1 was defined as the mean of the 23-hour and 24-hour serial spirometry FEV1 measurements. For Day 28 and Day 84, trough FEV1 was defined as the average of the pre-dose FEV1 measurements recorded before the morning dose of randomized study treatment. Change from Baseline in trough FEV1 was calculated by subtracting post-dose trough FEV1 value from Baseline FEV1, where Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. The treatment effect to be estimated for trough FEV1 was hypothetical effect if all participants stayed on their randomized study treatment. Only on treatment data was included in analysis. | Baseline, Days 2, 28, 84 and 85 | 
| Weighted Mean Change From Baseline in FEV1 Over 0-24 Hours on Day 1 | FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. Serial FEV1 assessments were performed at multiple time points (-30 and -5 minutes pre-dose, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 15 hours, 21 hours, 23 hours and 24 hours post-dose) over 24-hour period on Day 1. Weighted mean change from Baseline on Day 1 was calculated by subtracting weighted mean FEV1 on Day 1 from Baseline FEV1, where Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. The weighted mean was derived by calculating the area under the FEV1 time curve (AUC) over the actual time of assessment relative to the time of dosing (over 24-hour period) using the trapezoidal rule, and then dividing the value by the time interval (24-hour) over which the AUC was calculated. | Baseline and Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tiotropium, fluticasone furoate/umeclidinium/vilanterol, HRQoL, COPD, long-acting muscarinic receptor antagonists, Budesonide/formoterol