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)

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03478683
• Collaborator: (none)
• Enrollment: 729
• Locations: 57
• Arms: 2
• Actual Duration (Months): 8.6
• Patients Per Site: 12.8
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

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 the 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.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	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	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 729 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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.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 (Participant, Investigator)
• Masking Description: This is a phase 4 double blind study, which will use a triple dummy design for dosing.
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Jun 25, 2018
• Actual Primary Completion Date: Mar 14, 2019
• Actual Study Completion Date: Mar 14, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FF/UMEC/VI 100/62.5/25 mcg 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; Subjects will be administered two inhalations of budesonide/formoterol via MDI twice daily; Drug: albuterol/salbutamol; Subjects will be provided short-acting albuterol/salbutamol as-rescue medication to be used on an as-needed basis throughout the study.; Drug: FF/UMEC/VI; Subjects will receive FF/UMEC/VI 100/62.5/25 mcg via ELLIPTA once daily in the morning; Drug: Placebo to match budesonide/formoterol; Subjects will be administered two inhalations of matching placebo twice daily via MDI; Drug: tiotropium; Subjects will receive tiotropium (18 mcg) once daily in the morning via HandiHaler device; Drug: placebo to match tiotropium; Subjects will receive tiotropium matching placebo via Handihaler once daily in the morning; Device: ELLIPTA; 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.; Device: MDI; Subjects will receive budesonide/formoterol and placebo to match budesonide/formoterol via MDI in the treatment period.; Device: HandiHaler; Subjects will be administered tiotropium (18 mcg) or placebo to match tiotropium via HandiHaler during the treatment period.
Active Comparator: Budesonide/formoterol plus tiotropium 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; Subjects will be administered two inhalations of budesonide/formoterol via MDI twice daily; Drug: albuterol/salbutamol; Subjects will be provided short-acting albuterol/salbutamol as-rescue medication to be used on an as-needed basis throughout the study.; Drug: tiotropium; Subjects will receive tiotropium (18 mcg) once daily in the morning via HandiHaler device; Drug: Placebo to match FF/UMEC/VI; Matching placebo to FF/UMEC/VI will be administered via ELLIPTA once daily in the morning.; Device: ELLIPTA; 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.; Device: MDI; Subjects will receive budesonide/formoterol and placebo to match budesonide/formoterol via MDI in the treatment period.; Device: HandiHaler; Subjects will be administered tiotropium (18 mcg) or placebo to match tiotropium via HandiHaler during the treatment period.

Outcome Measures

Primary Outcome Measures

1. 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 [Baseline and Week 12]

   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.

2. Weighted Mean Change From Baseline in FEV1 Over 0-24 Hours at Week 12 for ITT Population [Baseline and Week 12]

   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.

Secondary Outcome Measures

1. Change From Baseline in Trough FEV1 on Day 2, Day 28, Day 84 and Day 85 [Baseline, Days 2, 28, 84 and 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.

2. Weighted Mean Change From Baseline in FEV1 Over 0-24 Hours on Day 1 [Baseline and 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Gold River	California	United States	95670
2	GSK Investigational Site	Clearwater	Florida	United States	33756
3	GSK Investigational Site	Clearwater	Florida	United States	33765
4	GSK Investigational Site	DeBary	Florida	United States	32713
5	GSK Investigational Site	Edgewater	Florida	United States	32132
6	GSK Investigational Site	Miami	Florida	United States	33135
7	GSK Investigational Site	Miami	Florida	United States	33144
8	GSK Investigational Site	Miami	Florida	United States	33165
9	GSK Investigational Site	Miami	Florida	United States	33186
10	GSK Investigational Site	Ocala	Florida	United States	34470
11	GSK Investigational Site	Ocala	Florida	United States	34474
12	GSK Investigational Site	Port Charlotte	Florida	United States	33952
13	GSK Investigational Site	Port Orange	Florida	United States	32127
14	GSK Investigational Site	Peachtree Corners	Georgia	United States	30071
15	GSK Investigational Site	Flint	Michigan	United States	48503
16	GSK Investigational Site	Fridley	Minnesota	United States	55432
17	GSK Investigational Site	Woodbury	Minnesota	United States	55125
18	GSK Investigational Site	Albuquerque	New Mexico	United States	87108
19	GSK Investigational Site	Bronx	New York	United States	10455
20	GSK Investigational Site	Asheville	North Carolina	United States	28801
21	GSK Investigational Site	Raleigh	North Carolina	United States	27607
22	GSK Investigational Site	Shelby	North Carolina	United States	28150
23	GSK Investigational Site	Columbus	Ohio	United States	43213
24	GSK Investigational Site	Columbus	Ohio	United States	43215
25	GSK Investigational Site	Dayton	Ohio	United States	45417
26	GSK Investigational Site	Tulsa	Oklahoma	United States	74136
27	GSK Investigational Site	Portland	Oregon	United States	97202
28	GSK Investigational Site	Anderson	South Carolina	United States	29621
29	GSK Investigational Site	Columbia	South Carolina	United States	29204
30	GSK Investigational Site	Easley	South Carolina	United States	29640
31	GSK Investigational Site	Fort Mill	South Carolina	United States	29707
32	GSK Investigational Site	Greenville	South Carolina	United States	29615
33	GSK Investigational Site	Lancaster	South Carolina	United States	29720
34	GSK Investigational Site	Mount Pleasant	South Carolina	United States	29464
35	GSK Investigational Site	Rock Hill	South Carolina	United States	29732
36	GSK Investigational Site	Spartanburg	South Carolina	United States	29303
37	GSK Investigational Site	Baytown	Texas	United States	77521
38	GSK Investigational Site	Cypress	Texas	United States	77429
39	GSK Investigational Site	Houston	Texas	United States	77058
40	GSK Investigational Site	Tomball	Texas	United States	77375
41	GSK Investigational Site	Jindrichuv Hradec		Czechia	377 01
42	GSK Investigational Site	Kralupy nad Vltavou		Czechia	278 01
43	GSK Investigational Site	Lovosice		Czechia	410 02
44	GSK Investigational Site	Rokycany		Czechia	337 01
45	GSK Investigational Site	Teplice		Czechia	415 01
46	GSK Investigational Site	Ruedersdorf	Brandenburg	Germany	15562
47	GSK Investigational Site	Frankfurt	Hessen	Germany	60596
48	GSK Investigational Site	Hannover	Niedersachsen	Germany	30159
49	GSK Investigational Site	Hannover	Niedersachsen	Germany	30173
50	GSK Investigational Site	Grosshansdorf	Schleswig-Holstein	Germany	22927
51	GSK Investigational Site	Berlin		Germany	12157
52	GSK Investigational Site	Hamburg		Germany	20354
53	GSK Investigational Site	Breda		Netherlands	4818 CK
54	GSK Investigational Site	Heerlen		Netherlands	6419 PC
55	GSK Investigational Site	Hengelo		Netherlands	7555 DL
56	GSK Investigational Site	Hoorn		Netherlands	1624 NP
57	GSK Investigational Site	Zutphen		Netherlands	7207 AE

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Statistical Analysis Plan - Apr 16, 2019
• Study Protocol - Jul 17, 2018

More Information

Publications

• Ferguson GT, Brown N, Compton C, Corbridge TC, Dorais K, Fogarty C, Harvey C, Kaisermann MC, Lipson DA, Martin N, Sciurba F, Stiegler M, Zhu CQ, Bernstein D. Once-daily single-inhaler versus twice-daily multiple-inhaler triple therapy in patients with COPD: lung function and health status results from two replicate randomized controlled trials. Respir Res. 2020 May 29;21(1):131. doi: 10.1186/s12931-020-01360-w.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT03478683
• Other Study ID Numbers: 207608; 2017-001149-28
• First Posted: Mar 27, 2018
• Last Update Posted: Oct 28, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Keywords provided by GlaxoSmithKline: long-acting muscarinic receptor antagonists; tiotropium; HRQoL; Budesonide/formoterol; chronic obstructive pulmonary disease; COPD
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Budesonide; Albuterol; Formoterol Fumarate; Tiotropium Bromide; Budesonide, Formoterol Fumarate Drug Combination

Study Results

Participant Flow

Recruitment Details	This was a randomized, multicenter, parallel group study where participants with chronic obstructive pulmonary disease (COPD) were randomized to receive either fluticasone furoate/umeclidinium/vilanterol or budesonide/formoterol plus tiotropium in a 1:1 ratio. The study was conducted across 65 centers in 4 countries.
Pre-assignment Detail	A total of 1036 participants were screened in the study, of which 215 failed during screening. Of the 821 participants who entered the run-in period, 92 were run-in failures. A total of 729 participants were randomized in the study, of which one participant was randomized in error. A total of 728 participants received randomized treatment.

Arm/Group Title	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg	Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
Arm/Group Description	Participants received fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 microgram (mcg) via the ELLIPTA (once daily in the morning) plus placebo to match budesonide/formoterol (BUD/FOR) via metered dose inhaler (MDI) (two inhalations twice daily) plus placebo to match tiotropium (TIO) via HandiHaler (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.	Participants received two inhalations of budesonide/formoterol 160/4.5 mcg via MDI in the morning and two inhalations in the evening (total dose of 320/9 mcg twice daily) plus tiotropium 18 mcg via HandiHaler (once daily in the morning) plus placebo to match fluticasone furoate/umeclidinium/vilanterol via the ELLIPTA (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.
Period Title: Overall Study
STARTED	363	365
COMPLETED	350	347
NOT COMPLETED	13	18

Baseline Characteristics

Arm/Group Title	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg	Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg	Total
Arm/Group Description	Participants received fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 microgram (mcg) via the ELLIPTA (once daily in the morning) plus placebo to match budesonide/formoterol (BUD/FOR) via metered dose inhaler (MDI) (two inhalations twice daily) plus placebo to match tiotropium (TIO) via HandiHaler (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.	Participants received two inhalations of budesonide/formoterol 160/4.5 mcg via MDI in the morning and two inhalations in the evening (total dose of 320/9 mcg twice daily) plus tiotropium 18 mcg via HandiHaler (once daily in the morning) plus placebo to match fluticasone furoate/umeclidinium/vilanterol via the ELLIPTA (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.	Total of all reporting groups
Overall Participants	363	365	728
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	65.4 (7.90)	64.9 (8.06)	65.2 (7.98)
Sex: Female, Male (Count of Participants)
Female	180 49.6%	164 44.9%	344 47.3%
Male	183 50.4%	201 55.1%	384 52.7%
Race/Ethnicity, Customized (Count of Participants)
African American/African Heritage	34 9.4%	33 9%	67 9.2%
American Indian Or Alaska Native	0 0%	1 0.3%	1 0.1%
Asian - Central/South Asian Heritage	1 0.3%	0 0%	1 0.1%
Asian - South East Asian Heritage	0 0%	1 0.3%	1 0.1%
White - Arabic/North African Heritage	0 0%	2 0.5%	2 0.3%
White - White/Caucasian/European	327 90.1%	328 89.9%	655 90%
Multiple	1 0.3%	0 0%	1 0.1%

Outcome Measures

1. Primary Outcome

Title	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
Description	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.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

mPP Population comprised of all participants in the ITT population who do not have a protocol deviation of not meeting eligibility criteria or not meeting randomization criteria. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg	Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
Arm/Group Description	Participants received fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 microgram (mcg) via the ELLIPTA (once daily in the morning) plus placebo to match budesonide/formoterol (BUD/FOR) via metered dose inhaler (MDI) (two inhalations twice daily) plus placebo to match tiotropium (TIO) via HandiHaler (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.	Participants received two inhalations of budesonide/formoterol 160/4.5 mcg via MDI in the morning and two inhalations in the evening (total dose of 320/9 mcg twice daily) plus tiotropium 18 mcg via HandiHaler (once daily in the morning) plus placebo to match fluticasone furoate/umeclidinium/vilanterol via the ELLIPTA (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.
Measure Participants	282	272
Least Squares Mean (Standard Error) [Liters]	0.045 (0.0101)	0.030 (0.0101)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg, Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was to be demonstrated, if the lower bound of the two-sided 95 percentage (%) confidence interval around the (FF/UMEC/VI versus BUD/FOR+TIO) treatment difference was above -50 milliliter.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.015
	Confidence Interval	(2-Sided) 95%; -0.013 to 0.043
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0143
	Estimation Comments	The primary treatment effect estimated (hypothetical effect) excluded data following intercurrent events: discontinuation of treatment, taking wrong treatment, taking prohibited medication, unblinding, noncompliance, COPD exacerbation or pneumonia.

2. Secondary Outcome

Title	Change From Baseline in Trough FEV1 on Day 2, Day 28, Day 84 and Day 85
Description	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.
Time Frame	Baseline, Days 2, 28, 84 and 85

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg	Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
Arm/Group Description	Participants received fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 microgram (mcg) via the ELLIPTA (once daily in the morning) plus placebo to match budesonide/formoterol (BUD/FOR) via metered dose inhaler (MDI) (two inhalations twice daily) plus placebo to match tiotropium (TIO) via HandiHaler (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.	Participants received two inhalations of budesonide/formoterol 160/4.5 mcg via MDI in the morning and two inhalations in the evening (total dose of 320/9 mcg twice daily) plus tiotropium 18 mcg via HandiHaler (once daily in the morning) plus placebo to match fluticasone furoate/umeclidinium/vilanterol via the ELLIPTA (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.
Measure Participants	358	359
Day 2, n=358,359	0.008 (0.0098)	0.018 (0.0098)
Day 28, n=355,353	0.046 (0.0088)	-0.015 (0.0088)
Day 84, n=344,340	0.040 (0.0094)	-0.018 (0.0094)
Day 85, n=341,337	0.026 (0.0099)	-0.012 (0.0099)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg, Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.481
	Comments	Only if superiority is achieved on the primary study endpoint, then inferences can be made on change from Baseline in trough FEV1 on Day 2 using p-values.
	Method	Mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.010
	Confidence Interval	(2-Sided) 95%; -0.037 to 0.018
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0139
	Estimation Comments	Day 2

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg, Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Only if superiority is achieved on the primary study endpoint, then inferences can be made on change from Baseline in trough FEV1 on Day 28 using p-values.
	Method	Mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.061
	Confidence Interval	(2-Sided) 95%; 0.037 to 0.086
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0124
	Estimation Comments	Day 28

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg, Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Only if superiority is achieved on the primary study endpoint, then inferences can be made on change from Baseline in trough FEV1 on Day 84 using p-values.
	Method	Mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.058
	Confidence Interval	(2-Sided) 95%; 0.032 to 0.084
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0133
	Estimation Comments	Day 84

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg, Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	Only if superiority is achieved on the primary study endpoint, then inferences can be made on change from Baseline in trough FEV1 on Day 85 using p-values.
	Method	Mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.038
	Confidence Interval	(2-Sided) 95%; 0.010 to 0.066
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0140
	Estimation Comments	Day 85

3. Secondary Outcome

Title	Weighted Mean Change From Baseline in FEV1 Over 0-24 Hours on Day 1
Description	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.
Time Frame	Baseline and Day 1

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg	Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
Arm/Group Description	Participants received fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 microgram (mcg) via the ELLIPTA (once daily in the morning) plus placebo to match budesonide/formoterol (BUD/FOR) via metered dose inhaler (MDI) (two inhalations twice daily) plus placebo to match tiotropium (TIO) via HandiHaler (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.	Participants received two inhalations of budesonide/formoterol 160/4.5 mcg via MDI in the morning and two inhalations in the evening (total dose of 320/9 mcg twice daily) plus tiotropium 18 mcg via HandiHaler (once daily in the morning) plus placebo to match fluticasone furoate/umeclidinium/vilanterol via the ELLIPTA (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.
Measure Participants	354	355
Least Squares Mean (Standard Error) [Liters]	0.054 (0.0078)	0.063 (0.0077)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg, Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.415
	Comments	Only if superiority is achieved on the primary study endpoint, then inferences can be made on weighted mean change from Baseline in FEV1 over 0-24 hours on Day 1 using p-values.
	Method	Mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.009
	Confidence Interval	(2-Sided) 95%; -0.030 to 0.013
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0110
	Estimation Comments	The treatment effect to be estimated was hypothetical effect if all participants stayed on their randomized study treatment. Only on treatment data was included in analysis.

4. Primary Outcome

Title	Weighted Mean Change From Baseline in FEV1 Over 0-24 Hours at Week 12 for ITT Population
Description	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.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

ITT Population comprised of all randomized participants, excluding those who were randomized in error. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg	Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
Arm/Group Description	Participants received fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 microgram (mcg) via the ELLIPTA (once daily in the morning) plus placebo to match budesonide/formoterol (BUD/FOR) via metered dose inhaler (MDI) (two inhalations twice daily) plus placebo to match tiotropium (TIO) via HandiHaler (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.	Participants received two inhalations of budesonide/formoterol 160/4.5 mcg via MDI in the morning and two inhalations in the evening (total dose of 320/9 mcg twice daily) plus tiotropium 18 mcg via HandiHaler (once daily in the morning) plus placebo to match fluticasone furoate/umeclidinium/vilanterol via the ELLIPTA (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.
Measure Participants	336	332
Least Squares Mean (Standard Error) [Liters]	0.046 (0.0097)	0.032 (0.0098)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg, Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.335
	Comments	The analysis was performed using mixed model repeated measures analysis, which included covariates of Baseline FEV1, geographical region, treatment, visit, visit by treatment and visit by Baseline interaction.
	Method	Mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.013
	Confidence Interval	(2-Sided) 95%; -0.014 to 0.040
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0138
	Estimation Comments	The treatment effect to be estimated was hypothetical effect if all participants stayed on their randomized study treatment. Only on treatment data was included in analysis.

Adverse Events

Time Frame	Serious adverse events (SAEs) and non-SAEs were reported from start of study treatment and up to Week 13
Adverse Event Reporting Description	Non-SAEs and SAEs were reported for ITT Population. Adverse events were presented treatment-wise.
Arm/Group Title	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg		Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
Arm/Group Description	Participants received fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 microgram (mcg) via the ELLIPTA (once daily in the morning) plus placebo to match budesonide/formoterol (BUD/FOR) via metered dose inhaler (MDI) (two inhalations twice daily) plus placebo to match tiotropium (TIO) via HandiHaler (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.		Participants received two inhalations of budesonide/formoterol 160/4.5 mcg via MDI in the morning and two inhalations in the evening (total dose of 320/9 mcg twice daily) plus tiotropium 18 mcg via HandiHaler (once daily in the morning) plus placebo to match fluticasone furoate/umeclidinium/vilanterol via the ELLIPTA (once daily in the morning) for 84 days. Participants received albuterol/salbutamol as rescue medication during conduct of the study, if required.
All Cause Mortality
	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg		Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/363 (0%)		0/365 (0%)
Serious Adverse Events
	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg		Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/363 (8%)		16/365 (4.4%)
Cardiac disorders
Acute coronary syndrome	0/363 (0%)		1/365 (0.3%)
Acute myocardial infarction	0/363 (0%)		2/365 (0.5%)
Cardiac failure acute	0/363 (0%)		1/365 (0.3%)
Cardiac failure congestive	1/363 (0.3%)		0/365 (0%)
Coronary artery disease	1/363 (0.3%)		0/365 (0%)
Myocardial infarction	1/363 (0.3%)		0/365 (0%)
General disorders
Chest pain	0/363 (0%)		1/365 (0.3%)
Hepatobiliary disorders
Cholelithiasis	1/363 (0.3%)		0/365 (0%)
Infections and infestations
Cellulitis	2/363 (0.6%)		0/365 (0%)
Influenza	1/363 (0.3%)		0/365 (0%)
Pneumonia	4/363 (1.1%)		2/365 (0.5%)
Pneumonia bacterial	0/363 (0%)		1/365 (0.3%)
Psoas abscess	0/363 (0%)		1/365 (0.3%)
Sepsis	2/363 (0.6%)		1/365 (0.3%)
Injury, poisoning and procedural complications
Femur fracture	1/363 (0.3%)		1/365 (0.3%)
Lumbar vertebral fracture	1/363 (0.3%)		0/365 (0%)
Rib fracture	0/363 (0%)		1/365 (0.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/363 (0%)		1/365 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer	1/363 (0.3%)		0/365 (0%)
Nervous system disorders
Cerebrovascular accident	2/363 (0.6%)		0/365 (0%)
Seizure	0/363 (0%)		1/365 (0.3%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	2/363 (0.6%)		0/365 (0%)
Chronic obstructive pulmonary disease	15/363 (4.1%)		3/365 (0.8%)
Dyspnoea	1/363 (0.3%)		0/365 (0%)
Pneumothorax	0/363 (0%)		1/365 (0.3%)
Pulmonary oedema	0/363 (0%)		1/365 (0.3%)
Respiratory failure	2/363 (0.6%)		0/365 (0%)
Skin and subcutaneous tissue disorders
Angioedema	1/363 (0.3%)		0/365 (0%)
Vascular disorders
Superior vena cava syndrome	0/363 (0%)		1/365 (0.3%)
Other (Not Including Serious) Adverse Events
	Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg		Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/363 (5%)		12/365 (3.3%)
Infections and infestations
Nasopharyngitis	18/363 (5%)		12/365 (3.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.