A 12-week Study to Evaluate the Efficacy and Safety of Umeclidinium 62.5 Microgram (mcg) Compared With Glycopyrronium 44 mcg in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02236611
• Collaborator: (none)
• Enrollment: 1,036
• Locations: 96
• Arms: 2
• Actual Duration (Months): 8.2
• Patients Per Site: 10.8
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

This is a 12-week, multicentre, randomized, open-label, 2-arm, parallel-group study designed to compare the efficacy and safety of umeclidinium inhalation powder (62.5 mcg once daily [QD]) administered via a novel Dry Powder Inhaler (nDPI) with glycopyrronium (44 mcg QD) administered via a Breezhaler® inhaler in subjects with COPD over 12 weeks of treatment. At the end of the run-in period, eligible subjects will be randomized in a 1:1 ratio to receive umeclidinium 62.5 mcg administered via nDPI or glycopyrronium 44 mcg administered via BREEZHALER inhaler. There will be up to 8 clinic visits conducted on an outpatient basis at Pre-Screening (Visit 0), Screening (Visit 1), Randomization at Day 1 (Visit 2), and after Randomization at Day 2 (Visit 3), Day 28 (Visit 4), Day 56 (Visit 5), Day 84 (Visit 6) and Day 85 (Visit 7). The total duration of subject participation in the study will be approximately 15 weeks. The primary endpoint of the study is clinic visit trough FEV1 (forced expiratory volume in one second) on treatment Day 85. All subjects will have spirometry performed at clinic Visits 1 though 7. Trough spirometry will be obtained 23 and 24 hours after the previous day's dose of open-label study medication at Visits 3 to 7.

BREEZHALER is a registered trademark of Novartis AG.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: Umeclidinium; Drug: Glycopyrronium	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 1036 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Parallel-group, Open-label Study to Evaluate the Efficacy and Safety of Umeclidinium (UMEC) 62.5 mcg Compared With Glycopyrronium 44 mcg in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
• Actual Study Start Date: Sep 26, 2014
• Actual Primary Completion Date: Jun 2, 2015
• Actual Study Completion Date: Jun 2, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Umeclidinium 62.5 mcg Randomized subjects will receive umeclidinium inhalation powder 62.5 mcg, once daily over a period of 12 weeks via a nDPI. Subjects will be instructed to take one dose each morning.	Drug: Umeclidinium; Umeclidinium 62.5 mcg will be available as dry inhalation powder to be taken using a nDPI
Experimental: Glycopyrronium 44 mcg Randomized subjects will receive glycopyrronium 44 mcg, once daily over a period of 12 weeks via a BREEZHALER inhaler. Subjects will be instructed to take one dose each morning.	Drug: Glycopyrronium; Glycopyrronium bromide will be available as inhalation capsules, 44 mcg per capsule, taken using BREEZHALER inhalers

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Trough FEV1 on Day 85 [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 one second. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on Day 84 (Week 12). Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84 and 85. Baseline trough FEV1 is the mean of the two assessments made -30 and -5 minutes (min) pre-dose on Day 1. Change from baseline was calculated as the trough FEV1 value on Day 85 minus the BL value. Analysis performed using a repeated measures model with covariates of treatment, baseline FEV1, centre group, 24 hour subset flag, Day, Day by baseline and Day by treatment interactions. The least squares mean changes are presented here.

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

• Age: subjects 40 years of age or older at Visit 1.

• Gender: male and female subjects are eligible to participate in the study. 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, eg, 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 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.

• Diagnosis: an established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society (ERS)

• Smoking history: current or former cigarette smokers with a history of cigarette smoking of >= 10 pack-years [number of pack years = (number of cigarettes per day /

1. x number of years smoked (eg. 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years both equal 10 pack-years)]. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Pipe and/or cigar use cannot be used to calculate pack-year history

• 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 post-albuterol/salbutamol FEV1 of >=30% and =<70% of predicted normal values at Visit

1. Predicted values will be based upon the ERS Global Lung Function Initiative

• Dyspnea: A score of >=2 on the modified medical research council dyspnea scale (mMRC) at Visit 1

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.

• Other diseases/abnormalities: any subject who is considered unlikely to survive the duration of the study period or has any rapidly progressing disease or immediate life-threatening illness (e.g. cancer). In addition, any subject who has any condition (e.g. neurological condition) that is likely to affect respiratory function should not be included in the study.

• Severe hepatic impairment: patients with severe hepatic impairment (Child-Pugh class

1. should be excluded unless, in the opinion of the investigator, the benefit is likely to outweigh the risk.

• Severe renal impairment: patients with severe renal impairment (e.g., end-stage renal disease requiring dialysis) should be excluded, unless in the opinion of the investigator, the benefit is likely to outweigh the risk.

• Unstable or life threatening cardiac disease: long-acting muscarinic antagonists (LAMA) should be used with caution in subjects with severe cardiovascular disease. In the opinion of the investigator, use should only be considered if the benefit is likely to outweigh the risk in conditions such as: 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

• Contraindications: Any history of allergy or hypersensitivity to any anticholinergic/ muscarinic receptor antagonist, sympathomimetic, lactose/milk protein or magnesium stearate.

• Antimuscarinic effects: Subjects with medical conditions such as narrow-angle glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction should only be included if, in the opinion of the study physician, the benefit outweighs the risk.

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

• Lung resection: lung volume reduction surgery within the 12 months prior to Visit 1.

• 12-Lead electrocardiogram (ECG): Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. 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. Subjects with the following abnormalities are excluded from participation in the study: Atrial fibrillation with rapid ventricular rate >120 beats per minute; sustained or nonsustained ventricular tachycardia; second degree heart block Mobitz type II or third degree heart block (unless pacemaker or defibrillator had been inserted)

• 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, systemic, oral or parenteral corticosteroids 6 weeks, antibiotics (for lower respiratory tract infection) 6 weeks, inhaled long acting beta2 agonists/ inhaled corticosteroid (LABA/ICS) combination products if LABA/ICS therapy is discontinued completely 30 days; LABA/ICS combination products only If discontinuing ICS/ LABA therapy and switching to ICS monotherapy 48 hours for the salmeterol or formoterol component 14 days for the vilanterol component (note: the dose of ICS must be a dose of fluticasone propionate (FP) or equivalent but not to exceed 1000 mcg/day), use of ICS at a dose >1000 microgram (mcg)/day of FP or equivalent 30 days (note: use of ICS is permitted provided the dose does not exceed 1000 mcg of FP or equivalent; ICS use not to be initiated or discontinued within 30 days prior to Visit 1, except for subjects on LABA/ICS therapy who may discontinue the ICS/LABA product as indicated in the table above and switch to ICS monotherapy); initiation or discontinuation of ICS use 30 days (note: use of ICS is permitted provided the dose does not exceed 1000 mcg of FP or equivalent; ICS use not to be initiated or discontinued within 30 days prior to Visit 1, except for subjects on LABA/ICS therapy who may discontinue the ICS/LABA product as indicated in the table above and switch to ICS monotherapy); phosphodiesterase 4 (PDE4) Inhibitor (roflumilast) 14 days; LABA: salmeterol and formoterol 48 hours; olodaterol, indacaterol, and vilanterol 14 days; LAMA: tiotropium, aclidinium, glycopyrronium, umeclidinium 7 days; LAMA/LABA combination products if LAMA/LABA therapy is discontinued completely then apply whichever mono component has the longest washout; theophyllines 48 hours; Oral beta2-agonists: long-acting 48 hours, short-acting 12 hours; inhaled short acting beta2-agonists 4 hours (note: use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to spirometry testing); inhaled short-acting anticholinergics 4 hours; inhaled short-acting anticholinergic/short-acting beta2-agonist combination products 4 hours; any other investigational medication 30 days or within 5 drug half-lives (whichever is longer).

• Oxygen: use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a 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 4 weeks prior to Visit 1. Subjects 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Paraná	Buenos Aires	Argentina	E3100BHK
2	GSK Investigational Site	Concepcion del Uruguay	Entre Ríos	Argentina	3260
3	GSK Investigational Site	San Rafael	Mendoza	Argentina	5600
4	GSK Investigational Site	Rosario	Santa Fe	Argentina	S2000JKR
5	GSK Investigational Site	Mendoza		Argentina	5500
6	GSK Investigational Site	Mendoza		Argentina	M5500CCG
7	GSK Investigational Site	San Miguel de Tucuman		Argentina	T4000IFL
8	GSK Investigational Site	San Miguel de Tucumán		Argentina	4000
9	GSK Investigational Site	Concepción	Región Del Biobio	Chile	4070038
10	GSK Investigational Site	Talca	Región Del Maule	Chile	3465584
11	GSK Investigational Site	Puente Alto - Santiago	Región Metro De Santiago	Chile	8207257
12	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	7500710
13	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	7510186
14	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	8242238
15	GSK Investigational Site	Santiago		Chile	7500698
16	GSK Investigational Site	Santiago		Chile	8380453
17	GSK Investigational Site	Jindrichuv Hradec		Czechia	377 01
18	GSK Investigational Site	Kralupy nad Vltavou		Czechia	278 01
19	GSK Investigational Site	Lovosice		Czechia	410 02
20	GSK Investigational Site	Ostrava - Poruba		Czechia	70868
21	GSK Investigational Site	Rudna U Prahy		Czechia	252 19
22	GSK Investigational Site	Trebic		Czechia	674 01
23	GSK Investigational Site	Varnsdorf		Czechia	407 47
24	GSK Investigational Site	Bamberg	Bayern	Germany	96049
25	GSK Investigational Site	Muenchen	Bayern	Germany	80539
26	GSK Investigational Site	Frankfurt	Hessen	Germany	60596
27	GSK Investigational Site	Brinkum/Stuhr	Niedersachsen	Germany	28816
28	GSK Investigational Site	Hannover	Niedersachsen	Germany	30167
29	GSK Investigational Site	Hannover	Niedersachsen	Germany	30173
30	GSK Investigational Site	Dueren	Nordrhein-Westfalen	Germany	52349
31	GSK Investigational Site	Essen	Nordrhein-Westfalen	Germany	45359
32	GSK Investigational Site	Gelsenkirchen	Nordrhein-Westfalen	Germany	45879
33	GSK Investigational Site	Koblenz	Rheinland-Pfalz	Germany	56068
34	GSK Investigational Site	Leipzig	Sachsen	Germany	04103
35	GSK Investigational Site	Leipzig	Sachsen	Germany	04275
36	GSK Investigational Site	Leipzig	Sachsen	Germany	04357
37	GSK Investigational Site	Luebeck	Schleswig-Holstein	Germany	23552
38	GSK Investigational Site	Balassagyarmat		Hungary	2660
39	GSK Investigational Site	Budapest		Hungary	1085
40	GSK Investigational Site	Debrecen		Hungary	4032
41	GSK Investigational Site	Debrecen		Hungary	4043
42	GSK Investigational Site	Kapuvár		Hungary	9330
43	GSK Investigational Site	Nagykanizsa		Hungary	8800
44	GSK Investigational Site	Törökbálint		Hungary	2045
45	GSK Investigational Site	Hakadal		Norway	1487
46	GSK Investigational Site	Hamar		Norway	2317
47	GSK Investigational Site	Hønefoss		Norway	N-3515
48	GSK Investigational Site	Kolbjørnsvik		Norway	4816
49	GSK Investigational Site	Kongsvinger		Norway	N-2200
50	GSK Investigational Site	Løvenstad		Norway	2006
51	GSK Investigational Site	Ålesund		Norway	6017
52	GSK Investigational Site	Brasov		Romania	500283
53	GSK Investigational Site	Bucharest		Romania	020125
54	GSK Investigational Site	Cluj Napoca		Romania	400371
55	GSK Investigational Site	Cluj-Napoca		Romania	400371
56	GSK Investigational Site	Iasi		Romania	700115
57	GSK Investigational Site	Ramnicu Valcea		Romania	240564
58	GSK Investigational Site	Suceava		Romania	720284
59	GSK Investigational Site	Timisoara		Romania	300310
60	GSK Investigational Site	Barnaul		Russian Federation	656024
61	GSK Investigational Site	Barnaul		Russian Federation	656038
62	GSK Investigational Site	Chelyabinsk		Russian Federation	454076
63	GSK Investigational Site	Chelyabinsk		Russian Federation	454091
64	GSK Investigational Site	Chelyabinsk		Russian Federation	454106
65	GSK Investigational Site	Chita		Russian Federation	672000
66	GSK Investigational Site	Ekaterinburg		Russian Federation	620109
67	GSK Investigational Site	Irkutsk		Russian Federation	664005
68	GSK Investigational Site	Ivanovo		Russian Federation	153005
69	GSK Investigational Site	Kazan		Russian Federation	420012
70	GSK Investigational Site	Kemerovo		Russian Federation	650000
71	GSK Investigational Site	Moscow		Russian Federation	105 077
72	GSK Investigational Site	Moscow		Russian Federation	119620
73	GSK Investigational Site	Moscow		Russian Federation	125315
74	GSK Investigational Site	Nizhniy Novgorod		Russian Federation	603126
75	GSK Investigational Site	Novosibirsk		Russian Federation
76	GSK Investigational Site	Perm		Russian Federation	614097
77	GSK Investigational Site	Ryazan,		Russian Federation	390026
78	GSK Investigational Site	Saint Petesburg		Russian Federation	195030
79	GSK Investigational Site	Saint-Petersburg		Russian Federation	194044
80	GSK Investigational Site	Saint-Petersburg		Russian Federation	194354
81	GSK Investigational Site	Saint-Petersburg		Russian Federation	194356
82	GSK Investigational Site	Saint-Petersburg		Russian Federation	195271
83	GSK Investigational Site	St. Petersburg		Russian Federation	194356
84	GSK Investigational Site	St. Petersburg		Russian Federation	198216
85	GSK Investigational Site	Stavropol		Russian Federation	355017
86	GSK Investigational Site	Laredo	Cantabria	Spain	39770
87	GSK Investigational Site	Barcelona		Spain	08017
88	GSK Investigational Site	Barcelona		Spain	08023
89	GSK Investigational Site	Barcelona		Spain	08028
90	GSK Investigational Site	Fuenlabrada / Madrid		Spain	28943
91	GSK Investigational Site	La Roca Del Valles (Barcelona)		Spain	08430
92	GSK Investigational Site	Peralada( Girona)		Spain	17491
93	GSK Investigational Site	Göteborg		Sweden	SE-413 45
94	GSK Investigational Site	Göteborg		Sweden	SE-413 90
95	GSK Investigational Site	Stockholm		Sweden	SE-111 57
96	GSK Investigational Site	Stockholm		Sweden	SE-113 61

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: NCT02236611
• Other Study ID Numbers: 201315
• First Posted: Sep 10, 2014
• Last Update Posted: May 2, 2018
• Last Verified: Apr 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by GlaxoSmithKline: COPD; inhaler ease of use; glycopyrronium; umeclidinium; novel dry powder inhaler; long-acting muscarinic antagonist; inhaler errors
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Glycopyrrolate

Study Results

Participant Flow

Recruitment Details	A total of 1290 par. were screened; 1037 par. were randomized and 1034 were in the ITT population which comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period. Two par. were randomized in error and one par. was randomized, but did not take any study medication.
Pre-assignment Detail	Participants, with clinical history of chronic obstructive pulmonary disease, who meet the eligibility criteria at screening were enrolled in a 7 to 14 day run-in period. Participant meeting continuation criteria, during run-in period, were randomized (1:1) to receive umeclidinium or glycopyrronium.

Arm/Group Title	UMEC 62.5 mcg QD	GLYCO 44 mcg QD
Arm/Group Description	Participants received Umeclidinium (UMEC) inhalation powder 62.5 microgram (mcg) once-daily (QD) in morning via a novel dry powder inhaler (nDPI) for 12 weeks. Participants also received albuterol/salbutamol via metered-dose-inhaler (MDI) or nebules as needed throughout the study.	Participants received glycopyrronium bromide (GLYCO) inhalation capsules 44 mcg QD in morning via an alternative dry powder inhaler (DPI) for 12 weeks. Participants also received albuterol/salbutamol via MDI or nebules as needed throughout the study.
Period Title: Overall Study
STARTED	516	518
COMPLETED	490	484
NOT COMPLETED	26	34

Baseline Characteristics

Arm/Group Title	UMEC 62.5 mcg QD	GLYCO 44 mcg QD	Total
Arm/Group Description	Participants received Umeclidinium (UMEC) inhalation powder 62.5 microgram (mcg) once-daily (QD) in morning via a novel dry powder inhaler (nDPI) for 12 weeks. Participants also received albuterol/salbutamol via metered-dose-inhaler (MDI) or nebules as needed throughout the study.	Participants received glycopyrronium bromide (GLYCO) inhalation capsules 44 mcg QD in morning via an alternative dry powder inhaler (DPI) for 12 weeks. Participants also received albuterol/salbutamol via MDI or nebules as needed throughout the study.	Total of all reporting groups
Overall Participants	516	518	1034
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.1 (8.35)	64.0 (8.26)	64.1 (8.30)
Sex: Female, Male (Count of Participants)
Female	161 31.2%	168 32.4%	329 31.8%
Male	355 68.8%	350 67.6%	705 68.2%
Race/Ethnicity, Customized (Number) [Number]
Central/South Asian Heritage (HRTG)	3 0.6%	0 0%	3 0.3%
Japanese/East Asian Heritage/South East Asian HRTG	0 0%	1 0.2%	1 0.1%
White	513 99.4%	517 99.8%	1030 99.6%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Trough FEV1 on Day 85
Description	FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on Day 84 (Week 12). Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84 and 85. Baseline trough FEV1 is the mean of the two assessments made -30 and -5 minutes (min) pre-dose on Day 1. Change from baseline was calculated as the trough FEV1 value on Day 85 minus the BL value. Analysis performed using a repeated measures model with covariates of treatment, baseline FEV1, centre group, 24 hour subset flag, Day, Day by baseline and Day by treatment interactions. The least squares mean changes are presented here.
Time Frame	Baseline (BL) and Day 85

Outcome Measure Data

Analysis Population Description

Per Protocol(PP) Population(pop): Participants(par) in the Intent-To-Treat pop who did not have a full protocol deviation considered to impact efficacy. Par represent those with data available at time point presented; however, all par. in the PP pop. without missing covariate information and >=1 post BL measurement are included in analysis

Arm/Group Title	UMEC 62.5 mcg QD	GLYCO 44 mcg QD
Arm/Group Description	Participants received Umeclidinium (UMEC) inhalation powder 62.5 microgram (mcg) once-daily (QD) in morning via a novel dry powder inhaler (nDPI) for 12 weeks. Participants also received albuterol/salbutamol via metered-dose-inhaler (MDI) or nebules as needed throughout the study.	Participants received glycopyrronium bromide (GLYCO) inhalation capsules 44 mcg QD in morning via an alternative dry powder inhaler (DPI) for 12 weeks. Participants also received albuterol/salbutamol via MDI or nebules as needed throughout the study.
Measure Participants	431	425
Least Squares Mean (Standard Error) [Liter]	0.123 (0.0105)	0.099 (0.0105)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UMEC 62.5 mcg QD, GLYCO 44 mcg QD
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Alternate hypothesis: the difference between the trt means (umeclidinium minus glycopyrronium) 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 may be deemed statistically non-inferior to glycopyrronium. If the lower CI (2.5% 1-sided significance) of the statistical testing exceeded 0 then, umeclidinium may be deemed statistically superior to glycopyrronium.
Statistical Test of Hypothesis	p-Value	0.100
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.024
	Confidence Interval	(2-Sided) 95%; -0.005 to 0.054
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	On-treatment(trt) non-serious adverse events(AEs) and serious AEs are events occurring while par were on trt or events with an onset during follow-up period(up to 13 weeks).
Adverse Event Reporting Description	On-treatment SAEs and non-serious AEs were reported for the Intent-To Treat Population comprised all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period.
Arm/Group Title	UMEC 62.5 mcg QD		GLYCO 44 mcg QD
Arm/Group Description	Participants received Umeclidinium (UMEC) inhalation powder 62.5 microgram (mcg) once-daily (QD) in morning via a novel dry powder inhaler (nDPI) for 12 weeks. Participants also received albuterol/salbutamol via metered-dose-inhaler (MDI) or nebules as needed throughout the study.		Participants received glycopyrronium bromide (GLYCO) inhalation capsules 44 mcg QD in morning via an alternative dry powder inhaler (DPI) for 12 weeks. Participants also received albuterol/salbutamol via MDI or nebules as needed throughout the study.
All Cause Mortality
	UMEC 62.5 mcg QD		GLYCO 44 mcg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	UMEC 62.5 mcg QD		GLYCO 44 mcg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/516 (3.3%)		15/518 (2.9%)
Cardiac disorders
Atrial fibrillation	1/516 (0.2%)		1/518 (0.2%)
Acute coronary syndrome	0/516 (0%)		1/518 (0.2%)
Cardiac failure	0/516 (0%)		1/518 (0.2%)
Myocardial infarction	1/516 (0.2%)		0/518 (0%)
Gastrointestinal disorders
Abdominal pain	0/516 (0%)		1/518 (0.2%)
Mouth ulceration	1/516 (0.2%)		0/518 (0%)
Rectal haemorrhage	0/516 (0%)		1/518 (0.2%)
General disorders
Sudden cardiac death	1/516 (0.2%)		0/518 (0%)
Sudden death	1/516 (0.2%)		0/518 (0%)
Hepatobiliary disorders
Cholelithiasis	0/516 (0%)		1/518 (0.2%)
Infections and infestations
Pneumonia	2/516 (0.4%)		0/518 (0%)
Urinary tract infection	0/516 (0%)		1/518 (0.2%)
Injury, poisoning and procedural complications
Ankle fracture	1/516 (0.2%)		0/518 (0%)
Femoral neck fracture	0/516 (0%)		1/518 (0.2%)
Hip fracture	0/516 (0%)		1/518 (0.2%)
Metabolism and nutrition disorders
Hyponatraemia	0/516 (0%)		1/518 (0.2%)
Musculoskeletal and connective tissue disorders
Foot deformity	0/516 (0%)		1/518 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Laryngeal cancer	0/516 (0%)		1/518 (0.2%)
Neoplasm malignant	1/516 (0.2%)		0/518 (0%)
Nervous system disorders
Cerebrovascular accident	1/516 (0.2%)		0/518 (0%)
Ischaemic stroke	1/516 (0.2%)		0/518 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	7/516 (1.4%)		5/518 (1%)
Dyspnoea	0/516 (0%)		1/518 (0.2%)
Other (Not Including Serious) Adverse Events
	UMEC 62.5 mcg QD		GLYCO 44 mcg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	77/516 (14.9%)		80/518 (15.4%)
Infections and infestations
Nasopharyngitis	42/516 (8.1%)		39/518 (7.5%)
Nervous system disorders
Headache	42/516 (8.1%)		51/518 (9.8%)

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.