Comparative Study of Umeclidinium/Vilanterol (UMEC/VI) in a Fixed Dose Combination With Indacaterol Plus Tiotropium

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02257385
• Collaborator: (none)
• Enrollment: 967
• Locations: 85
• Arms: 2
• Actual Duration (Months): 6.6
• Patients Per Site: 11.4
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

This is a Phase IIIb multicentre, randomised, blinded, triple dummy, parallel group study to evaluate the efficacy and safety of UMEC/VI inhalation powder (62.5/25 microgram [mcg] Once daily [QD]) when administered via ELLIPTA® Dry Powder Inhaler (DPI) compared to indacaterol plus tiotropium (150 mcg/18 mcg respectively QD) administered via individual inhalers over a treatment period of 12 weeks in participants with moderate to very severe Chronic Obstructive Pulmonary Disease (COPD). The purpose of this study is to demonstrate that UMEC/VI (delivered via ELLIPTA DPI), when used in symptomatic moderate to very severe COPD participants, is non-inferior to the combination of indacaterol (delivered via BREEZHALER® inhaler) plus tiotropium (delivered via HANDIHALER® inhaler) on measures of trough forced expiratory volume in one second (FEV1) after 12 weeks of treatment. Participants who met the eligibility criteria at screening (Visit 1) will complete a 5 to 7 day run in period prior to randomisation at Visit 2. Clinic visits will follow at day 2, week 2, week 4, week 8 and week 12 of treatment, plus week 12 + 1 day (Visits 3 to 8). The total duration of study participation will be approximately 14 weeks. ELLIPTA is a registered trademark of the GSK group of companies. HANDIHALER is a registered trademark of Boehringer Ingelheim Pharma GmbH & Co. KG. BREEZHALER is a registered trademark of Novartis AG.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: UMEC/VI; Drug: UMEC/VI matching placebo; Drug: Tiotropium; Drug: Tiotropium matching placebo; Drug: Indacaterol; Drug: Indacaterol matching placebo; Drug: Albuterol/salbutamol Metered Dose Inhaler (MDI)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 967 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Study DB2116961, A Multicentre, Randomised, Blinded, Parallel Group Study to Compare UMEC/VI (Umeclidinium/Vilanterol) in a Fixed Dose Combination With Indacaterol Plus Tiotropium in Symptomatic Subjects With Moderate to Very Severe COPD
• Actual Study Start Date: Oct 15, 2014
• Actual Primary Completion Date: May 4, 2015
• Actual Study Completion Date: May 4, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: UMEC/VI arm Participants will be instructed to self-administer one dose each morning of UMEC/VI Inhalation Powder 62.5/25 mcg once daily via ELLIPTA DPI, placebo once daily via HANDIHALER inhaler and placebo once daily via BREEZHALER inhaler	Drug: UMEC/VI; ELLIPTA DPI will be supplied with 30 doses (2 strips with 30 blisters per strip) where first strip contains Umeclidinium bromide (unit dose strengths 62.5 mcg per blister) blended with lactose monohydrate and magnesium stearate 0.6% weight/weight (w/w) of total drug product and second strip contains Vilanterol (unit dose strengths 25 mcg per blister) blended with lactose monohydrate and magnesium stearate 1.0% w/w of total drug product; Drug: UMEC/VI matching placebo; ELLIPTA DPI will be supplied with 30 doses (2 strips with 30 blisters per strip) where first strip contains lactose monohydrate and magnesium stearate 0.6% w/w of total drug product and second strip contains lactose monohydrate and magnesium stearate 1.0% w/w of total drug product; Drug: Albuterol/salbutamol Metered Dose Inhaler (MDI); Albuterol/salbutamol MDI or nebules for as needed use will be issued throughout the study. Albuterol/salbutamol will be sourced from local commercial stock. If not available locally, GSK will source centrally
Placebo Comparator: Tiotropium + Indacaterol arm Participants will be instructed to self-administer one dose each morning of Tiotropium bromide 18 mcg once daily via HANDIHALER inhaler, Indacaterol 150 mcg once daily via BREEZHALER inhaler and placebo once daily via ELLIPTA DPI	Drug: Tiotropium; Tiotropium (as bromide monohydrate) inhalation capsules 18 mcg per dose will be supplied along with HANDIHALER inhalers manufactured by Boehringer Ingelheim; Drug: Tiotropium matching placebo; Tiotropium matching placebo capsules manufactured by GSK, will contain lactose and will be supplied along with HANDIHALER inhalers; Drug: Indacaterol; Indacaterol inhalation capsules 150 mcg per dose will be supplied by GSK along with BREEZHALER inhalers manufactured by Novartis; Drug: Indacaterol matching placebo; Indacaterol matching placebo capsules manufactured by GSK, will contain lactose and will be supplied along with BREEZHALER inhalers manufactured by Novartis; Drug: Albuterol/salbutamol Metered Dose Inhaler (MDI); Albuterol/salbutamol MDI or nebules for as needed use will be issued throughout the study. Albuterol/salbutamol will be sourced from local commercial stock. If not available locally, GSK will source centrally

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Treatment Day 85 (Visit 8) [Baseline (BL) and Day 85]

   FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in 1 second. BL was the mean of the 2 assessments made 30 and 5 minutes (min) pre-dose (PD) on Day 1. Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84 and 85. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained at 23 and 24 hours (hr) after dosing on Day 84 (at Week 12 + 1 day). Analysis was performed using mixed model repeated measures (RM) with covariates of trt, BL FEV1 (mean of values measured at 30 and 5 min PD on Day 1), center group, day, day by BL interaction and day by trt interaction, where day was nominal.

Secondary Outcome Measures

1. Change From Baseline in Weighted Mean (WM) FEV1 Over 0-6 Hour Post-dose at Day 84 [Baseline and Day 84]

   BL FEV1 was the mean of the 2 assessments made 30 and 5 min PD on Day 1. WM FEV1 derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The WM was calculated at Days 1 and 84 using the 0-6 hr post-dose FEV1 measurements collected on that day, which included PD FEV1 (taken 30 and 5 min prior to dosing on Day 1 and the 30 and 5 min reading prior to dosing on Day 84) and post-dose FEV1 measurements at 1, 3 and 6 hr post-dose.WM change from BL was the WM at at the visit minus the BL value. Analysis was performed using a RM model with covariates of trt, BL FEV1 (mean of values measured at 30 and 5 min PD on Day 1) center group, day, day by BL and day by trt interaction, where day was nominal. Only par with data available at the specified TP were analyzed but all par w/o missing covariate information and with >=1 post-BL measurement were included in the analysis.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Type of subject: Outpatient

• Informed Consent: A signed and dated written informed consent prior to study participation.

• Participants 40 years of age or older at Visit 1.

• Gender: Male or female participants. 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 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) that meets the Standard Operating Procedure (SOP) effectiveness criteria as stated in the product label, 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)

• 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. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.

• Severity of Disease: A pre and post-albuterol/salbutamol Forced Expiratory Volume in One Second/ Forced Vital Capacity (FEV1/ FVC) ratio of <0.70 and a pre and post-albuterol/salbutamol FEV1 of <=70% predicted normal value at Visit 1, calculated using Quanjer reference equations.

• Dyspnoea: A score of >= 2 on the Modified Medical Research Council Dyspnoea Scale (mMRC) at Visit 1.

• QT interval corrected (QTc) Criteria: QTc <450 milliseconds (msec) or QTc <480 msec for patients with bundle branch block The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or another method, machine or manual overread. For subject eligibility and withdrawal, QTcF will be used. For purposes of data analysis, QTcF will be used as primary. The QTc should be based on single or averaged QTc values of triplicate Electrocardiogram (ECGs) obtained over a brief recording period.

• French participants: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

• Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.

• Asthma: A current diagnosis of asthma.

• Other Respiratory Disorders: Known alpha-1 antitrypsin deficiency, active lung infections (such as tuberculosis), and lung cancer are absolute exclusionary conditions. A subject who, in the opinion of the investigator, has any other significant respiratory conditions in addition to COPD should be excluded. Examples may include clinically significant bronchiectasis, pulmonary hypertension, sarcoidosis, or interstitial lung disease. Allergy rhinitis is not exclusionary.

• Other Diseases/Abnormalities: Participants with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled and/or a previous history of cancer in remission for <5 years prior to Visit 1 (localized carcinoma of the skin that has been resected for cure is not exclusionary). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.

• Contraindications: A history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the study physician, contraindicates study participation or use of an inhaled anticholinergic or beta 2 agonist.

• Hospitalisation: Hospitalisation for COPD or pneumonia within 12 weeks prior to Visit

• Lung Resection: Participants with lung volume reduction surgery within the 12 months prior to Screening (Visit 1).

• 12-Lead ECG: An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1. Specific ECG findings that preclude subject eligibility will be listed in protocol The study investigator will determine the medical significance of any ECG abnormalities not listed.

• Screening labs: Significantly abnormal finding from clinical chemistry or haematology tests at Visit 1 as determined by the study investigator.

• Medication Prior to Spirometry: Unable to withhold albuterol/salbutamol for the 4 hour period required prior to spirometry testing at each study visit.

• Medications prior to Screening: Use of the following medications according to the following defined time intervals prior to Visit 1: Depot corticosteroids (12 weeks); Oral or parenteral corticosteroids (6 weeks); Antibiotics (for lower respiratory tract infection) (6 weeks); Cytochrome P450 3A4 strong inhibitors ( 6 weeks); Long Acting Beta-Agonist (LABA)/ inhaled corticosteroids (ICS) combination products (e.g. fluticasone/salmeterol, mometasone, furoate/formoterol fumarate, budesonide/formoterol, fumarate), If LABA/ICS therapy is discontinued completely (30 days); If discontinuing LABA therapy and switching to ICS monotherapy (48 hours for salmeterol or formoterol, 14 days for Olodaterol, Indacaterol or, Vilanterol); Use of ICS at a dose >1000 mcg/day of fluticasone propionate or equivalent (30 days); Initiation or discontinuation of ICS use (30 days); Inhaled long acting beta2-agonists (LABA): Salmeterol, Formoterol (48 hours), Olodaterol, Indacaterol and Vilanterol (14 days); Long acting muscarinic antagonists (LAMA) (Tiotropium, Aclidinium, Glycopyrronium, Umeclidinium) (7 days); LABA/LAMA combination products (Whichever mono component has the longest washout); Roflumilast (14 days); Oral beta-agonists- Long-acting (48 hours), Short-acting(12 hours); Theophyllines (48 hours); Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton) (48 hours); Inhaled sodium cromoglycate or nedocromil sodium (24 hours); Inhaled short acting beta2-agonists (4 hours); Inhaled short-acting anticholinergic (short acting muscarinic antagonist [SAMA]) products eg ipratropium (4 hours); Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products (SAMA/Short Acting beta2-agonists [SABA]) (4 hours); Any other investigational medication (30 days or within 5 drug half-lives)

• Oxygen: Use of Long Term Oxygen Therapy (LTOT).This is defined as oxygen therapy prescribed for greater than 12 hours per day. As needed oxygen use (i.e. <=12 hours per day) is not exclusionary.

• Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g., albuterol/salbutamol) via nebulized therapy.

• Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 12 weeks prior to Visit 1. Participants who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.

• Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1.

• Affiliation with Investigator Site: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in 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 a questionnaire.

• Participants who are pre-screen or screen failures cannot be re-screened.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Mar del Plata	Buenos Aires	Argentina	7600
2	GSK Investigational Site	San Miguel de Tucuman	Tucumán	Argentina	4000
3	GSK Investigational Site	Buenos Aires		Argentina	C1424BSF
4	GSK Investigational Site	Buenos Aires		Argentina	C1425BEN
5	GSK Investigational Site	Ciudad Autónoma de Buenos Aires		Argentina	C1426ABP
6	GSK Investigational Site	Mendoza		Argentina	5500
7	GSK Investigational Site	Mendoza		Argentina	M5500CCG
8	GSK Investigational Site	San Miguel de Tucumán		Argentina	4000
9	GSK Investigational Site	Puente Alto - Santiago	Región Metro De Santiago	Chile	8207257
10	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	7500692
11	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	7510186
12	GSK Investigational Site	Santiago		Chile	7500698
13	GSK Investigational Site	Haapsalu		Estonia	90502
14	GSK Investigational Site	Tallinn		Estonia	10117
15	GSK Investigational Site	Tallinn		Estonia	10138
16	GSK Investigational Site	Gières		France	38610
17	GSK Investigational Site	Nantes cedex 2		France	44277
18	GSK Investigational Site	Perpignan		France	66000
19	GSK Investigational Site	Reims Cedex		France	51092
20	GSK Investigational Site	Strasbourg cedex		France	67091
21	GSK Investigational Site	Tarbes Cedex 09		France	65013
22	GSK Investigational Site	Ruedersdorf	Brandenburg	Germany	15562
23	GSK Investigational Site	Frankfurt am Main	Hessen	Germany	60596
24	GSK Investigational Site	Frankfurt	Hessen	Germany	60389
25	GSK Investigational Site	Frankfurt	Hessen	Germany	60596
26	GSK Investigational Site	Schwerin	Mecklenburg-Vorpommern	Germany	19055
27	GSK Investigational Site	Magdeburg	Sachsen-Anhalt	Germany	39112
28	GSK Investigational Site	Berlin		Germany	10367
29	GSK Investigational Site	Berlin		Germany	10787
30	GSK Investigational Site	Berlin		Germany	12203
31	GSK Investigational Site	Hamburg		Germany	20253
32	GSK Investigational Site	Hamburg		Germany	20354
33	GSK Investigational Site	Hamburg		Germany	22299
34	GSK Investigational Site	Balassagyarmat		Hungary	2660
35	GSK Investigational Site	Budaörs		Hungary	2040
36	GSK Investigational Site	Debrecen		Hungary	4032
37	GSK Investigational Site	Gödöllő		Hungary	2100
38	GSK Investigational Site	Nyíregyháza		Hungary	4400
39	GSK Investigational Site	Pécs		Hungary	7635
40	GSK Investigational Site	Szeged		Hungary	6722
41	GSK Investigational Site	Szikszó		Hungary	3800
42	GSK Investigational Site	Piacenza	Emilia-Romagna	Italy	29121
43	GSK Investigational Site	Pordenone	Friuli-Venezia-Giulia	Italy	33170
44	GSK Investigational Site	Mantova	Lombardia	Italy	46100
45	GSK Investigational Site	Tradate (VA)	Lombardia	Italy	21049
46	GSK Investigational Site	Novara	Piemonte	Italy	28100
47	GSK Investigational Site	Lima 27	Lima	Peru	Lima 27
48	GSK Investigational Site	Lima		Peru	Lima 14
49	GSK Investigational Site	Lima		Peru	Lima 18
50	GSK Investigational Site	Lima		Peru	Lima 1
51	GSK Investigational Site	Lima		Peru	Lima 32
52	GSK Investigational Site	Elblag		Poland	82-300
53	GSK Investigational Site	Krakow		Poland	31-024
54	GSK Investigational Site	Ostrow Wielkopolski		Poland	63-400
55	GSK Investigational Site	Piekary Slaskie		Poland	41-940
56	GSK Investigational Site	Slupsk		Poland	76-200
57	GSK Investigational Site	Sopot		Poland	81-741
58	GSK Investigational Site	Bucharest		Romania	020125
59	GSK Investigational Site	Bucharest		Romania	050159
60	GSK Investigational Site	Cluj Napoca		Romania	400371
61	GSK Investigational Site	Constanta		Romania	900002
62	GSK Investigational Site	Ramnicu Valcea		Romania	240564
63	GSK Investigational Site	Timisoara		Romania	300310
64	GSK Investigational Site	Timisoara		Romania	300465
65	GSK Investigational Site	Arkhangelsk		Russian Federation	153000
66	GSK Investigational Site	Ekaterinburg		Russian Federation	620039
67	GSK Investigational Site	Ekaterinburg		Russian Federation	620149
68	GSK Investigational Site	Irkutsk		Russian Federation	664079
69	GSK Investigational Site	Kazan		Russian Federation	420015
70	GSK Investigational Site	Moscow		Russian Federation	115 478
71	GSK Investigational Site	Moscow		Russian Federation	125284
72	GSK Investigational Site	Omsk		Russian Federation	644112
73	GSK Investigational Site	Orenburg		Russian Federation	460040
74	GSK Investigational Site	Perm		Russian Federation	614068
75	GSK Investigational Site	Saint Petesburg		Russian Federation	195030
76	GSK Investigational Site	St. Petersburg		Russian Federation	194356
77	GSK Investigational Site	St. Petersburg		Russian Federation	198216
78	GSK Investigational Site	Stavropol		Russian Federation	355017
79	GSK Investigational Site	Tomsk		Russian Federation	634063
80	GSK Investigational Site	Ulyanovsk		Russian Federation	432063
81	GSK Investigational Site	Bojnice		Slovakia	972 01
82	GSK Investigational Site	Humenne		Slovakia	066 01
83	GSK Investigational Site	Poprad		Slovakia	058 01
84	GSK Investigational Site	Spisska Nova Ves		Slovakia	052 01
85	GSK Investigational Site	Vrable		Slovakia	952 01

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT02257385
• Other Study ID Numbers: 116961
• First Posted: Oct 6, 2014
• Last Update Posted: Mar 1, 2018
• Last Verified: Feb 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: indacaterol; efficacy; FEV1; ELLIPTA; non inferiority; vilanterol; COPD; safety; tiotropium; umeclidinium bromide; GSK573719
• Additional relevant MeSH terms: Pulmonary Disease, Chronic Obstructive; Albuterol; Tiotropium Bromide

Study Results

Participant Flow

Recruitment Details	Eligible participants (par) completed a 5-7 day run-in period, and were randomized to blinded study medication for 12 weeks. Supplemental albuterol/salbutamol was provided to all par, to be used on an as-needed basis during run-in and up to Day 85.
Pre-assignment Detail	A total of 1190 par were screened; 967 par randomized and 961 par comprised the Intent-to-Treat (ITT) Population (Pop), comprised of all par randomized to treatment (trt) who received at least 1 dose of randomized study medication in the trt period.

Arm/Group Title	Umeclidinium/Vilanterol 62.5/25 µg	Indacaterol 150 µg + Tiotropium Bromide 18 µg
Arm/Group Description	Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg), BREEZHALER containing placebo, and HANDIHALER containing placebo. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing placebo, BREEZHALER containing indacaterol 150 µg, and HANDIHALER containing tiotropium bromide 18 µg. The inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
Period Title: Overall Study
STARTED	482	479
COMPLETED	460	457
NOT COMPLETED	22	22

Baseline Characteristics

Arm/Group Title	Umeclidinium/Vilanterol 62.5/25 µg	Indacaterol 150 µg + Tiotropium Bromide 18 µg	Total
Arm/Group Description	Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg), BREEZHALER containing placebo, and HANDIHALER containing placebo. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing placebo, BREEZHALER containing indacaterol 150 µg, and HANDIHALER containing tiotropium bromide 18 µg. The inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Total of all reporting groups
Overall Participants	482	479	961
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.4 (7.75)	64.0 (8.44)	64.2 (8.10)
Sex: Female, Male (Count of Participants)
Female	127 26.3%	138 28.8%	265 27.6%
Male	355 73.7%	341 71.2%	696 72.4%
Race/Ethnicity, Customized (Number) [Number]
American Indian or Alaska Native	24 5%	27 5.6%	51 5.3%
Asian - Central/South Asian Heritage	1 0.2%	0 0%	1 0.1%
Asian - East Asian Heritage	0 0%	1 0.2%	1 0.1%
Asian - Japanese Heritage	4 0.8%	1 0.2%	5 0.5%
White - Arabic/North African Heritage	0 0%	1 0.2%	1 0.1%
White -White/Caucasian/European Heritage	453 94%	449 93.7%	902 93.9%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Treatment Day 85 (Visit 8)
Description	FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in 1 second. BL was the mean of the 2 assessments made 30 and 5 minutes (min) pre-dose (PD) on Day 1. Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84 and 85. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained at 23 and 24 hours (hr) after dosing on Day 84 (at Week 12 + 1 day). Analysis was performed using mixed model repeated measures (RM) with covariates of trt, BL FEV1 (mean of values measured at 30 and 5 min PD on Day 1), center group, day, day by BL interaction and day by trt interaction, where day was nominal.
Time Frame	Baseline (BL) and Day 85

Outcome Measure Data

Analysis Population Description

Per Protocol (PP) Pop: all ITT Pop par who were not full protocol deviators considered to impact efficacy. Only par with data available at the specified time points (TP) were analyzed but all par without (w/o) missing covariate information and with >= 1 post BL measurement were included in the analysis.

Arm/Group Title	Umeclidinium/Vilanterol 62.5/25 µg	Indacaterol 150 µg + Tiotropium Bromide 18 µg
Arm/Group Description	Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg), BREEZHALER containing placebo, and HANDIHALER containing placebo. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing placebo, BREEZHALER containing indacaterol 150 µg, and HANDIHALER containing tiotropium bromide 18 µg. The inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
Measure Participants	392	392
Least Squares Mean (Standard Error) [Liters]	0.172 (0.0107)	0.171 (0.0108)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Umeclidinium/Vilanterol 62.5/25 µg, Indacaterol 150 µg + Tiotropium Bromide 18 µg
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Alternate hypothesis:the difference between the trt means (umeclidinium/vilanterol minus indacaterol + tiotropium bromide) would be > -50 milliliters (mL). If the lower CI (2.5% 1-sided significance level) of the statistical test should fall above -50 mL, then umeclidinium/vilanterol may be deemed statistically non-inferior to indacaterol plus tiotropium. If the lower CI (2.5% 1-sided significance) of the statistical testing exceeded 0 then, statistical superiority would have been established.
Statistical Test of Hypothesis	p-Value	0.964
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.001
	Confidence Interval	(2-Sided) 95%; -0.029 to 0.030
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Weighted Mean (WM) FEV1 Over 0-6 Hour Post-dose at Day 84
Description	BL FEV1 was the mean of the 2 assessments made 30 and 5 min PD on Day 1. WM FEV1 derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The WM was calculated at Days 1 and 84 using the 0-6 hr post-dose FEV1 measurements collected on that day, which included PD FEV1 (taken 30 and 5 min prior to dosing on Day 1 and the 30 and 5 min reading prior to dosing on Day 84) and post-dose FEV1 measurements at 1, 3 and 6 hr post-dose.WM change from BL was the WM at at the visit minus the BL value. Analysis was performed using a RM model with covariates of trt, BL FEV1 (mean of values measured at 30 and 5 min PD on Day 1) center group, day, day by BL and day by trt interaction, where day was nominal. Only par with data available at the specified TP were analyzed but all par w/o missing covariate information and with >=1 post-BL measurement were included in the analysis.
Time Frame	Baseline and Day 84

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Umeclidinium/Vilanterol 62.5/25 µg	Indacaterol 150 µg + Tiotropium Bromide 18 µg
Arm/Group Description	Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg), BREEZHALER containing placebo, and HANDIHALER containing placebo. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing placebo, BREEZHALER containing indacaterol 150 µg, and HANDIHALER containing tiotropium bromide 18 µg. The inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
Measure Participants	455	452
Least Squares Mean (Standard Error) [Liters]	0.235 (0.0111)	0.258 (0.0111)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Umeclidinium/Vilanterol 62.5/25 µg, Indacaterol 150 µg + Tiotropium Bromide 18 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.145
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.023
	Confidence Interval	(2-Sided) 95%; -0.054 to 0.008
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected over a period of a maximum of 96 days starting from Day 1 of treatment until the follow-up contact.
Adverse Event Reporting Description	On-treatment SAEs and non-serious AEs were reported for members of the ITT Population, comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period.
Arm/Group Title	Umeclidinium/Vilanterol 62.5/25 µg		Indacaterol 150 µg + Tiotropium Bromide 18 µg
Arm/Group Description	Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg), BREEZHALER containing placebo, and HANDIHALER containing placebo. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.		Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing placebo, BREEZHALER containing indacaterol 150 µg, and HANDIHALER containing tiotropium bromide 18 µg. The inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
All Cause Mortality
	Umeclidinium/Vilanterol 62.5/25 µg		Indacaterol 150 µg + Tiotropium Bromide 18 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Umeclidinium/Vilanterol 62.5/25 µg		Indacaterol 150 µg + Tiotropium Bromide 18 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/482 (4.4%)		16/479 (3.3%)
Cardiac disorders
Acute myocardial infarction	0/482 (0%)		1/479 (0.2%)
Angina pectoris	1/482 (0.2%)		0/479 (0%)
Atrial fibrillation	1/482 (0.2%)		0/479 (0%)
Atrioventricular block	0/482 (0%)		1/479 (0.2%)
Cardiac arrest	1/482 (0.2%)		0/479 (0%)
Cardiac failure	0/482 (0%)		1/479 (0.2%)
Coronary artery disease	0/482 (0%)		1/479 (0.2%)
Myocardial infarction	0/482 (0%)		1/479 (0.2%)
Myocardial ischaemia	0/482 (0%)		1/479 (0.2%)
Ventricular fibrillation	1/482 (0.2%)		0/479 (0%)
Gastrointestinal disorders
Crohn's disease	1/482 (0.2%)		0/479 (0%)
General disorders
Chest pain	0/482 (0%)		1/479 (0.2%)
Hepatobiliary disorders
Cholelithiasis	1/482 (0.2%)		0/479 (0%)
Infections and infestations
Pneumonia	2/482 (0.4%)		2/479 (0.4%)
Gastroenteritis	1/482 (0.2%)		0/479 (0%)
Laryngitis	0/482 (0%)		1/479 (0.2%)
Injury, poisoning and procedural complications
Alcohol poisoning	0/482 (0%)		1/479 (0.2%)
Concussion	0/482 (0%)		1/479 (0.2%)
Lower limb fracture	0/482 (0%)		1/479 (0.2%)
Spinal compression fracture	1/482 (0.2%)		0/479 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	0/482 (0%)		1/479 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain neoplasm	0/482 (0%)		1/479 (0.2%)
Laryngeal cancer	1/482 (0.2%)		0/479 (0%)
Squamous cell carcinoma of lung	1/482 (0.2%)		0/479 (0%)
Squamous cell carcinoma of the oral cavity	1/482 (0.2%)		0/479 (0%)
Nervous system disorders
Cerebrovascular accident	0/482 (0%)		1/479 (0.2%)
Epilepsy	0/482 (0%)		1/479 (0.2%)
Syncope	0/482 (0%)		1/479 (0.2%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	6/482 (1.2%)		3/479 (0.6%)
Respiratory failure	2/482 (0.4%)		0/479 (0%)
Acute respiratory failure	1/482 (0.2%)		0/479 (0%)
Pulmonary oedema	0/482 (0%)		1/479 (0.2%)
Vascular disorders
Circulatory collapse	1/482 (0.2%)		0/479 (0%)
Peripheral artery thrombosis	0/482 (0%)		1/479 (0.2%)
Peripheral ischaemia	1/482 (0.2%)		0/479 (0%)
Other (Not Including Serious) Adverse Events
	Umeclidinium/Vilanterol 62.5/25 µg		Indacaterol 150 µg + Tiotropium Bromide 18 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	76/482 (15.8%)		65/479 (13.6%)
Infections and infestations
Nasopharyngitis	32/482 (6.6%)	34	27/479 (5.6%)	31
Nervous system disorders
Headache	36/482 (7.5%)	56	28/479 (5.8%)	60
Respiratory, thoracic and mediastinal disorders
Cough	16/482 (3.3%)	18	17/479 (3.5%)	18

Limitations/Caveats

[Not Specified]

More Information

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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.