AERISTO: Efficacy and Safety of Glycopyrronium/Formoterol Fumarate Fixed-dose Combination Relative to Umeclidinium/Vilanterol Fixed-dose Combination Over 24 Weeks in Patients With Moderate to Very Severe Chronic Obstructive Pulmonary Disease

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03162055
• Collaborator: Parexel International Ltd (Other), Cognizant Technology Solution (Other), Center for Information & Study on Clinical Research Participation (CISCRP) (Other), eResearchTechnology (Other), QuintilesIMS Limited (Other), Corporate Translations Inc (Other)
• Enrollment: 1,119
• Locations: 107
• Arms: 2
• Actual Duration (Months): 11.3
• Patients Per Site: 10.5
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This is a phase IIIb randomised, double-blind, double-dummy, multicentre, parallel group, 24 week study to assess the efficacy and safety of Glycopyrronium/Formoterol Fumarate (GFF) fixed-dose combination 7.2/4.8 μg 2 inhalations twice daily compared to Umeclidinium/Vilanterol (UV) 62.5/25 μg fixed-dose combination 1 inhalation once daily in Patients with moderate to very severe COPD.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease COPD	Drug: Glycopyrronium/Formoterol Fumarate; Drug: umeclidinium/vilanterol	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1119 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomised, Double-Blind, Double-Dummy, Multicentre, Parallel Group Study to Assess the Efficacy and Safety of Glycopyrronium/Formoterol Fumarate Fixed-dose Combination Relative to Umeclidinium/Vilanterol Fixed-dose Combination Over 24 Weeks in Patients With Moderate to Very Severe Chronic Obstructive Pulmonary Disease (AERISTO)
• Actual Study Start Date: May 25, 2017
• Actual Primary Completion Date: May 4, 2018
• Actual Study Completion Date: May 4, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental glycopyrronium/formoterol fumarate 7.2/4.8 μg per actuation, twice daily	Drug: Glycopyrronium/Formoterol Fumarate; Metered dose inhaler (MDI), contains glycopyrronium/formoterol fumarate fixed-dose combination 7.2/4.8 μg per actuation
Active Comparator: Active comparator umeclidinium/vilanterol 62.5/ 25μg per inhalation, once daily	Drug: umeclidinium/vilanterol; Dry powder inhaler (DPI), Each metered dose contains umeclidinium/vilanterol 62.5/ 25μg fixed-dose combination per inhalation

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline in Morning Pre-dose Trough Forced Expiratory Volume in 1 Second (FEV1) Over 24 Weeks [From Baseline (Day 1) up to 24 weeks]

   To assess the effects of GFF relative to UV on lung function as measured by change from baseline in morning pre-dose trough FEV1 is defined as the average of the -60 and -30 minute pre-dose values at each visit minus baseline using spirometry. Baseline is defined as the mean of the non-missing -60 and -30 minute values obtained prior to dosing at randomization (Day 1). BR a/s = bronchodilator responsiveness to albuterol/salbutamol.

2. Mean Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over 24 Weeks in PP Analysis Set Population [From Baseline (Day 1) up to 24 weeks]

   To assess the effects of GFF relative to UV on lung function in PP analysis set population as measured by peak change from baseline in FEV1 is defined as the maximum of the FEV1 assessments within the 2 hours post-dosing time windows at each visit minus baseline using spirometry. Baseline is defined as the mean of the non-missing -60 and -30 minute values obtained prior to dosing at randomization (Day 1).

3. Mean Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over 24 Weeks in FAS Population [From Baseline (Day 1) up to 24 weeks]

   To assess the effects of GFF relative to UV on lung function in FAS population as measured by peak change from baseline in FEV1 is defined as the maximum of the FEV1 assessments within the 2 hours post-dosing time windows at each visit minus baseline using spirometry. Baseline is defined as the mean of the non-missing -60 and -30 minute values obtained prior to dosing at randomization (Day 1).

Secondary Outcome Measures

1. Percentage of Participants With Increase of FEV1 of >=100 mL From Baseline at 5 Minutes Post-dosing on Day 1 [5 minutes post-dose on Day 1]

   The percentage of participants with an increase in FEV1 of >=100 mL from baseline at 5 minutes post-dosing on Day 1 was determined to assess the early onset of action. Baseline is defined as the average of available evaluable -60 and -30 minute pre-dose assessments conducted at randomization (Day 1). Only data assigned to the 5 minute window was used to determine response. Participants with missing data were considered non-responders for the analysis.

2. Mean Peak Change From Baseline in Inspiratory Capacity (IC) Within 2 Hours Post-dosing Over 24 Weeks [From Baseline (Day 1) up to 24 weeks]

   Peak change from baseline in IC is defined as the maximum of the IC assessments within the 2 hours post-dosing time windows at each visit minus baseline. Baseline is defined as the average of available evaluable -60 and -30 minute pre-dose assessments conducted at randomization (Day 1).

3. Mean Transition Dyspnea Index (TDI) Focal Score Over 24 Weeks [From Baseline (Day -7 or 1) up to 24 weeks]

   The baseline dyspnea index (BDI) and TDI consist of 3 individual components: functional impairment, magnitude of task, and magnitude of effort. For the BDI, each of these 3 components were rated in 5 grades from 0 (very severe) to 4 (no impairment), and were summed to form a baseline total score from 0 to 12. For the TDI, changes in dyspnea were rated for each component by 7 grades from -3 (major deterioration) to +3 (major improvement), and were added to form a TDI focal score from -9 to +9. Baseline is defined as the latest BDI assessment within 7 days before or at randomization (Day 1).

4. Mean Change From Baseline in Early Morning Symptoms of COPD Instrument (EMSCI) Over 24 Weeks [From Baseline (Day -7) up to 24 weeks]

   Change from baseline in the 6-item EMSCI Symptom Severity Score was derived by averaging the responses from a participant on the 6 item-level symptom scores (scored on a 4-point scale from 1 to 4, whereas 1= mild and 4= very severe). The EMSCI collected data about the frequency and severity of early morning symptoms and the impact of COPD symptoms on early morning activity in participants with COPD. Participants completed a daily electronic patient-reported outcome (ePRO) questionnaire for their COPD symptoms. Baseline is defined as the average of the non-missing values from the ePRO data collected in the last 7 days before the randomization (Day 1). TI = Time interval.

Other Outcome Measures

1. Mean Change From Baseline in Night-Time Symptoms of COPD Instrument (NiSCI) Over 24 Weeks [From Baseline (Day -7) up to 24 weeks]

   Change from baseline in the 6-item NiSCI Symptom Severity Score was derived by averaging the responses from a participant on the 6 item-level symptom scores (scored on a 4-point scale from 1 to 4, whereas 1= mild and 4= very severe). The NiSCI collected data about the frequency and severity of night-time symptoms and the impact of COPD symptoms on night-time awakenings in participants with COPD. Participants completed a daily ePRO questionnaire for their COPD symptoms. Baseline is defined as the average of the non-missing values from the ePRO data collected in the last 7 days before the randomization (Day 1).

2. Mean Change From Baseline in Daily Rescue (Albuterol/Salbutamol MDI) Use Over 24 Weeks [From Baseline (Day -7) up to 24 weeks]

   The number of inhalations of rescue albuterol/salbutamol MDI was recorded in the participant ePRO in the morning and evening. Baseline is defined as the average of the non-missing values from the ePRO data collected in the last 7 days before the randomization (Day 1). a/s = albuterol/salbutamol.

3. Mean Change From Baseline in COPD Assessment Test (CAT) Score Over 24 Weeks [From Baseline (Day -7 or 1) up to 24 weeks]

   The CAT is used to quantify the impact of COPD symptoms on health status. The CAT has a scoring range of 0-40, and it is calculated as the sum of the responses given for each of the 8 items (scored on a 6-point scale from 0 to 5), with higher scores indicating a higher impact of COPD symptoms on health status. If the response to 1 of the 8 items is missing, the missing item was considered equal to the average of the 7 non-missing items for that participant. If more than 1 item is missing the score was considered missing. Baseline is defined as the latest assessment within 7 days before or at randomization (Day 1).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 95 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Age 40-95 years at screening

• Current or former smoker with a history of at least 10 pack-years of cigarette smoking

• Current clinical diagnosis of COPD, with COPD symptoms > 1 year prior to screening, as defined by GOLD criteria or other current guidelines

• COPD Severity defined by FEV1/FVC ratio <0.70 and FEV1 <80% of predicted normal value at screening and at randomisation

• COPD treatment with rescue medication only, or stable dose of maintenance monotherapy (LAMA, LABA or ICS), or stable dose of double maintenance therapy (LAMA/LABA or ICS/LABA), for one month prior to screening

• COPD Assessment Test (CAT) score ≥10 at randomisation

• Documentation of a chest x-ray (as per local practice) or computed tomography (CT) within 6 months prior to screening, with no clinically significant pulmonary abnormalities other than related to COPD

Exclusion criteria:

• Respiratory disease other than COPD, including:

• Current diagnosis of asthma

• Alpha-1 Antitrypsin Deficiency as the cause of COPD

• Other respiratory disorders and conditions as listed in the protocol

• Severe COPD exacerbation (resulting in hospitalisation) not resolved within 8 weeks prior to screening, or moderate exacerbation not resolved within 4 weeks, or during screening

• Pneumonia or lower respiratory tract infection that required antibiotics within 8 weeks prior to screening, or during screening.

• Significant diseases or conditions other than COPD which may put the patient at risk, or influence the results of the study or the patient's ability to participate, including cardiac disease, advanced renal disease, and cancer that has not been in complete remission for at least 5 years.

• Patients who have needed additions or alterations to their usual maintenance therapy for COPD due to worsening symptoms within 1 month prior to and during screening

• Treatment with depot corticosteroids within 6 weeks, or other systemic corticosteroids within 4 weeks, prior to screening. (Patients maintained on an equivalent of 5 mg prednisone per day for at least 3 months prior to screening are allowed.)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Tempe	Arizona	United States	85283
2	Research Site	Escondido	California	United States	92025
3	Research Site	Sacramento	California	United States	95821
4	Research Site	Hollywood	Florida	United States	33021
5	Research Site	Lawrenceville	Georgia	United States	30046
6	Research Site	Rincon	Georgia	United States	31326
7	Research Site	Farmington Hills	Michigan	United States	48336
8	Research Site	Bronx	New York	United States	10455
9	Research Site	Gastonia	North Carolina	United States	28054
10	Research Site	Dublin	Ohio	United States	43016
11	Research Site	Pittsburgh	Pennsylvania	United States	15243
12	Research Site	Greenville	South Carolina	United States	29615
13	Research Site	Spartanburg	South Carolina	United States	29303
14	Research Site	Sherman	Texas	United States	75092
15	Research Site	Tomball	Texas	United States	77375
16	Research Site	Dupnitsa		Bulgaria	2600
17	Research Site	Dupnitsa		Bulgaria	2602
18	Research Site	Haskovo		Bulgaria	6305
19	Research Site	Kozloduy		Bulgaria	3320
20	Research Site	Pazardzhik		Bulgaria	4400
21	Research Site	Petrich		Bulgaria	2850
22	Research Site	Pleven		Bulgaria	5800
23	Research Site	Plovdiv		Bulgaria	4002
24	Research Site	Razlog		Bulgaria	2760
25	Research Site	Ruse		Bulgaria	7002
26	Research Site	Sliven		Bulgaria	8800
27	Research Site	Smolyan		Bulgaria	4700
28	Research Site	Sofia		Bulgaria	1002
29	Research Site	Sofia		Bulgaria	1233
30	Research Site	Sofia		Bulgaria	1407
31	Research Site	Sofia		Bulgaria	1408
32	Research Site	Sofia		Bulgaria	1618
33	Research Site	Stara Zagora		Bulgaria	6000
34	Research Site	Varna		Bulgaria	9000
35	Research Site	Vidin		Bulgaria	3700
36	Research Site	Sherwood Park	Alberta	Canada	T8L 0N2
37	Research Site	Winnipeg	Manitoba	Canada	R2V 4W3
38	Research Site	Truro	Nova Scotia	Canada	B2N 1L2
39	Research Site	Burlington	Ontario	Canada	L7M 4Y1
40	Research Site	Burlington	Ontario	Canada	L7N 3V2
41	Research Site	Etobicoke	Ontario	Canada	M9W 4L6
42	Research Site	Windsor	Ontario	Canada	N8X 1T3
43	Research Site	Windsor	Ontario	Canada	N8X-5A6
44	Research Site	Gatineau	Quebec	Canada	J8Y 6S8
45	Research Site	Levis	Quebec	Canada	G6W 0M5
46	Research Site	St Charles Borromee	Quebec	Canada	J6E 2B4
47	Research Site	Quebec		Canada	G1G 3Y8
48	Research Site	Quebec		Canada	G1V 4G5
49	Research Site	Quebec		Canada	G3K 2P8
50	Research Site	Besancon Cedex		France	25030
51	Research Site	Brest Cedex		France	29609
52	Research Site	Lyon Cedex 04		France	69317
53	Research Site	Montpellier		France	34295
54	Research Site	Nantes Cedex 2		France	44277
55	Research Site	Pessac		France	33604
56	Research Site	Poitiers		France	86021
57	Research Site	Reims		France	51092
58	Research Site	Balassagyarmat		Hungary	2660
59	Research Site	Budapest		Hungary	1135
60	Research Site	Debrecen		Hungary	4032
61	Research Site	Debrecen		Hungary	H-4031
62	Research Site	Farkasgyepü		Hungary	8582
63	Research Site	Hajdúnánás		Hungary	4080
64	Research Site	Komló		Hungary	7300
65	Research Site	Komárom		Hungary	2900
66	Research Site	Miskolc		Hungary	3529
67	Research Site	Püspökladány		Hungary	4150
68	Research Site	Siófok		Hungary	8600
69	Research Site	Szeged		Hungary	H-6722
70	Research Site	Szombathely		Hungary	9700
71	Research Site	Vásárosnamény		Hungary	4800
72	Research Site	Barnaul		Russian Federation	656038
73	Research Site	Barnaul		Russian Federation	656045
74	Research Site	Chelyabinsk		Russian Federation	454021
75	Research Site	Ekaterinburg		Russian Federation	620028
76	Research Site	Izhevsk		Russian Federation	426035
77	Research Site	Moscow		Russian Federation	109544
78	Research Site	Novosibirsk		Russian Federation	630051
79	Research Site	Penza		Russian Federation	440026
80	Research Site	Penza		Russian Federation	440067
81	Research Site	Ryazan		Russian Federation	390005
82	Research Site	Saint Petersburg		Russian Federation	191015
83	Research Site	Saint Petersburg		Russian Federation	197342
84	Research Site	Saint Petersburg		Russian Federation	198260
85	Research Site	Saint-Petersburg		Russian Federation	191180
86	Research Site	Saint-Petersburg		Russian Federation	194291
87	Research Site	Saint-Petersburg		Russian Federation	196084
88	Research Site	Saratov		Russian Federation	410012
89	Research Site	Smolensk		Russian Federation	214006
90	Research Site	St. Petersburg		Russian Federation	197022
91	Research Site	Tomsk		Russian Federation	634050
92	Research Site	Ulyanovsk		Russian Federation	432009
93	Research Site	Chernivtsi		Ukraine	58000
94	Research Site	Chernivtsi		Ukraine	58001
95	Research Site	Ivano-Frankivsk		Ukraine	76012
96	Research Site	Kharkiv		Ukraine	61002
97	Research Site	Kharkiv		Ukraine	61035
98	Research Site	Kharkiv		Ukraine	61058
99	Research Site	Kyiv		Ukraine	03680
100	Research Site	Kyiv		Ukraine	04107
101	Research Site	Lutsk		Ukraine	43000
102	Research Site	Lviv		Ukraine	79066
103	Research Site	Odesa		Ukraine	65025
104	Research Site	Poltava		Ukraine	36040
105	Research Site	Vinnytsia		Ukraine	21001
106	Research Site	Vinnytsia		Ukraine	21029
107	Research Site	Zaporizhzhia		Ukraine	69096

Sponsors and Collaborators

• AstraZeneca
• Parexel International Ltd
• Cognizant Technology Solution
• Center for Information & Study on Clinical Research Participation (CISCRP)
• eResearchTechnology
• QuintilesIMS Limited
• Corporate Translations Inc

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 14, 2017
• Statistical Analysis Plan - Jun 8, 2018

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT03162055
• Other Study ID Numbers: D5970C00002
• First Posted: May 22, 2017
• Last Update Posted: May 22, 2019
• Last Verified: Apr 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by AstraZeneca: COPD
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Glycopyrrolate; Formoterol Fumarate

Study Results

Participant Flow

Recruitment Details	This study was conducted in 110 centers in 7 countries (Russia, Bulgaria, Ukraine, United States of America, Canada, Hungary and France) between 25 May 2017 and 04 May 2018. Participants with moderate to very severe chronic obstructive pulmonary disease (COPD) were recruited in this study.
Pre-assignment Detail	The study had a screening period, followed by a 24-week double-blind and double-dummy treatment period. A total of 1445 participants were screened. Of which, 1119 participants were enrolled and randomized to study treatment.

Arm/Group Title	Glycopyrronium/Formoterol Fumarate	Umeclidinium/Vilanterol
Arm/Group Description	Participants were randomized to receive 2 inhalations of glycopyrronium/formoterol fumarate (GFF) fixed-dose combination 7.2/4.8 micrograms (mcg) per actuation administered in the morning and evening by metered dose inhaler (MDI) for 24 weeks. Participants also received 1 inhalation of placebo matched to umeclidinium/vilanterol (UV) administered once daily in the morning by dry powder inhaler (DPI) for 24 weeks.	Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Period Title: Overall Study
STARTED	559	560
Received Treatment	557	560
Safety Analysis Set	552	552
Full Analysis Set (FAS)	552	552
Per Protocol (PP) Analysis Set	506	510
COMPLETED	497	517
NOT COMPLETED	62	43

Baseline Characteristics

Arm/Group Title	Glycopyrronium/Formoterol Fumarate	Umeclidinium/Vilanterol	Total
Arm/Group Description	Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.	Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.	Total of all reporting groups
Overall Participants	552	552	1104
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.3 (8.0)	63.8 (8.1)	64.1 (8.0)
Age, Customized (Count of Participants)
<65 years	273 49.5%	292 52.9%	565 51.2%
65 - 74 years	223 40.4%	214 38.8%	437 39.6%
75 - 84 years	53 9.6%	43 7.8%	96 8.7%
>=85 years	3 0.5%	3 0.5%	6 0.5%
Sex: Female, Male (Count of Participants)
Female	142 25.7%	160 29%	302 27.4%
Male	410 74.3%	392 71%	802 72.6%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	13 2.4%	10 1.8%	23 2.1%
White	538 97.5%	542 98.2%	1080 97.8%
More than one race	0 0%	0 0%	0 0%
Other	1 0.2%	0 0%	1 0.1%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in Morning Pre-dose Trough Forced Expiratory Volume in 1 Second (FEV1) Over 24 Weeks
Description	To assess the effects of GFF relative to UV on lung function as measured by change from baseline in morning pre-dose trough FEV1 is defined as the average of the -60 and -30 minute pre-dose values at each visit minus baseline using spirometry. Baseline is defined as the mean of the non-missing -60 and -30 minute values obtained prior to dosing at randomization (Day 1). BR a/s = bronchodilator responsiveness to albuterol/salbutamol.
Time Frame	From Baseline (Day 1) up to 24 weeks

Outcome Measure Data

Analysis Population Description

The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.

Arm/Group Title	Glycopyrronium/Formoterol Fumarate	Umeclidinium/Vilanterol
Arm/Group Description	Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.	Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Measure Participants	506	510
Least Squares Mean (Standard Error) [milliliter (mL)]	82.4 (11.2)	169.6 (11.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority p-value is calculated corresponding to the non-inferiority margin -50 mL.
Statistical Test of Hypothesis	p-Value	0.9974
	Comments
	Method	Repeated measures analysis
	Comments	Change from baseline = Treatment + baseline FEV1 + BR a/s MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-87.2
	Confidence Interval	(2-Sided) 97.5%; -117.0 to -57.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.3
	Estimation Comments	Estimate of the mean change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.

2. Primary Outcome

Title	Mean Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over 24 Weeks in PP Analysis Set Population
Description	To assess the effects of GFF relative to UV on lung function in PP analysis set population as measured by peak change from baseline in FEV1 is defined as the maximum of the FEV1 assessments within the 2 hours post-dosing time windows at each visit minus baseline using spirometry. Baseline is defined as the mean of the non-missing -60 and -30 minute values obtained prior to dosing at randomization (Day 1).
Time Frame	From Baseline (Day 1) up to 24 weeks

Outcome Measure Data

Analysis Population Description

The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.

Arm/Group Title	Glycopyrronium/Formoterol Fumarate	Umeclidinium/Vilanterol
Arm/Group Description	Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.	Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Measure Participants	506	510
Least Squares Mean (Standard Error) [mL]	293.5 (10.2)	296.9 (10.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority p-value is calculated corresponding to the non-inferiority margin -50 mL.
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Repeated measures analysis
	Comments	Change from baseline = Treatment + baseline FEV1 + BR a/s MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-3.4
	Confidence Interval	(2-Sided) 97.5%; -32.8 to 25.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.1
	Estimation Comments	Estimate of the mean peak change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.

3. Secondary Outcome

Title	Percentage of Participants With Increase of FEV1 of >=100 mL From Baseline at 5 Minutes Post-dosing on Day 1
Description	The percentage of participants with an increase in FEV1 of >=100 mL from baseline at 5 minutes post-dosing on Day 1 was determined to assess the early onset of action. Baseline is defined as the average of available evaluable -60 and -30 minute pre-dose assessments conducted at randomization (Day 1). Only data assigned to the 5 minute window was used to determine response. Participants with missing data were considered non-responders for the analysis.
Time Frame	5 minutes post-dose on Day 1

Outcome Measure Data

Analysis Population Description

The FAS analysis set included all randomized participants who received at least 1 inhalation of IP from the GFF or UV inhaler (active or placebo).

Arm/Group Title	Glycopyrronium/Formoterol Fumarate	Umeclidinium/Vilanterol
Arm/Group Description	Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.	Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Measure Participants	552	552
Number [Percentage of participants]	60.1 10.9%	40.8 7.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments	ln (1/(1-p))=Treatment+baseline FEV1+BR a/s MDI+stratification factor (prior treatment)+region.p=percentage of participants with increase of >=100 mL.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.30
	Confidence Interval	(2-Sided) 95%; 1.79 to 2.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate of the log odds of being a responder in the GFF treatment group compared to the UV treatment group using a logistic regression.

4. Secondary Outcome

Title	Mean Peak Change From Baseline in Inspiratory Capacity (IC) Within 2 Hours Post-dosing Over 24 Weeks
Description	Peak change from baseline in IC is defined as the maximum of the IC assessments within the 2 hours post-dosing time windows at each visit minus baseline. Baseline is defined as the average of available evaluable -60 and -30 minute pre-dose assessments conducted at randomization (Day 1).
Time Frame	From Baseline (Day 1) up to 24 weeks

Outcome Measure Data

Analysis Population Description

The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.

Arm/Group Title	Glycopyrronium/Formoterol Fumarate	Umeclidinium/Vilanterol
Arm/Group Description	Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.	Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Measure Participants	506	510
Least Squares Mean (Standard Error) [mL]	363.1 (15.5)	378.3 (15.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority p-value is calculated corresponding to the non-inferiority margin -50 mL.
Statistical Test of Hypothesis	p-Value	0.0371
	Comments
	Method	Repeated measures analysis
	Comments	Change from baseline = Treatment + baseline IC + BR a/s MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-15.2
	Confidence Interval	(2-Sided) 95%; -53.4 to 22.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.4
	Estimation Comments	Estimate of the mean peak change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.

5. Secondary Outcome

Title	Mean Transition Dyspnea Index (TDI) Focal Score Over 24 Weeks
Description	The baseline dyspnea index (BDI) and TDI consist of 3 individual components: functional impairment, magnitude of task, and magnitude of effort. For the BDI, each of these 3 components were rated in 5 grades from 0 (very severe) to 4 (no impairment), and were summed to form a baseline total score from 0 to 12. For the TDI, changes in dyspnea were rated for each component by 7 grades from -3 (major deterioration) to +3 (major improvement), and were added to form a TDI focal score from -9 to +9. Baseline is defined as the latest BDI assessment within 7 days before or at randomization (Day 1).
Time Frame	From Baseline (Day -7 or 1) up to 24 weeks

Outcome Measure Data

Analysis Population Description

The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.

Arm/Group Title	Glycopyrronium/Formoterol Fumarate	Umeclidinium/Vilanterol
Arm/Group Description	Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.	Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Measure Participants	506	510
Least Squares Mean (Standard Error) [Units on a scale]	1.23 (0.10)	1.60 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority p-value is calculated corresponding to the non-inferiority margin -1.0 unit.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Repeated measures analysis
	Comments	TDI focal score = Treatment + Baseline Dyspnea Index + BR a/s MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -0.59 to -0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments	Estimate of the mean TDI focal score over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.

6. Secondary Outcome

Title	Mean Change From Baseline in Early Morning Symptoms of COPD Instrument (EMSCI) Over 24 Weeks
Description	Change from baseline in the 6-item EMSCI Symptom Severity Score was derived by averaging the responses from a participant on the 6 item-level symptom scores (scored on a 4-point scale from 1 to 4, whereas 1= mild and 4= very severe). The EMSCI collected data about the frequency and severity of early morning symptoms and the impact of COPD symptoms on early morning activity in participants with COPD. Participants completed a daily electronic patient-reported outcome (ePRO) questionnaire for their COPD symptoms. Baseline is defined as the average of the non-missing values from the ePRO data collected in the last 7 days before the randomization (Day 1). TI = Time interval.
Time Frame	From Baseline (Day -7) up to 24 weeks

Outcome Measure Data

Analysis Population Description

The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.

Arm/Group Title	Glycopyrronium/Formoterol Fumarate	Umeclidinium/Vilanterol
Arm/Group Description	Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.	Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Measure Participants	506	510
Least Squares Mean (Standard Error) [Units on a scale]	-0.142 (0.018)	-0.176 (0.018)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority p-value is calculated corresponding to the non-inferiority margin 0.1 unit.
Statistical Test of Hypothesis	p-Value	0.0017
	Comments
	Method	Repeated measures analysis
	Comments	Change from baseline = Treatment + baseline EMSCI score + BR a/s MDI + stratification factor (prior treatment) + region + TI + treatment by TI.
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	0.034
	Confidence Interval	(2-Sided) 95%; -0.011 to 0.078
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.023
	Estimation Comments	Estimate of the mean change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.

7. Other Pre-specified Outcome

Title	Mean Change From Baseline in Night-Time Symptoms of COPD Instrument (NiSCI) Over 24 Weeks
Description	Change from baseline in the 6-item NiSCI Symptom Severity Score was derived by averaging the responses from a participant on the 6 item-level symptom scores (scored on a 4-point scale from 1 to 4, whereas 1= mild and 4= very severe). The NiSCI collected data about the frequency and severity of night-time symptoms and the impact of COPD symptoms on night-time awakenings in participants with COPD. Participants completed a daily ePRO questionnaire for their COPD symptoms. Baseline is defined as the average of the non-missing values from the ePRO data collected in the last 7 days before the randomization (Day 1).
Time Frame	From Baseline (Day -7) up to 24 weeks

Outcome Measure Data

Analysis Population Description

The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.

Arm/Group Title	Glycopyrronium/Formoterol Fumarate	Umeclidinium/Vilanterol
Arm/Group Description	Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.	Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Measure Participants	506	510
Least Squares Mean (Standard Error) [Units on a scale]	-0.165 (0.019)	-0.207 (0.019)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority p-value is calculated corresponding to the non-inferiority margin 0.1 unit.
Statistical Test of Hypothesis	p-Value	0.0088
	Comments
	Method	Repeated measures analysis
	Comments	Change from baseline = Treatment + baseline NiSCI score + BR a/s MDI + stratification factor (prior treatment) + region + TI + treatment by TI.
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	0.042
	Confidence Interval	(2-Sided) 95%; -0.005 to 0.090
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Estimate of the mean change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.

8. Other Pre-specified Outcome

Title	Mean Change From Baseline in Daily Rescue (Albuterol/Salbutamol MDI) Use Over 24 Weeks
Description	The number of inhalations of rescue albuterol/salbutamol MDI was recorded in the participant ePRO in the morning and evening. Baseline is defined as the average of the non-missing values from the ePRO data collected in the last 7 days before the randomization (Day 1). a/s = albuterol/salbutamol.
Time Frame	From Baseline (Day -7) up to 24 weeks

Outcome Measure Data

Analysis Population Description

The rescue medication user analysis set included all participants in the FAS with average baseline rescue albuterol/salbutamol MDI use of >=1 inhalation/day. Only participants with data available for analysis are presented.

Arm/Group Title	Glycopyrronium/Formoterol Fumarate	Umeclidinium/Vilanterol
Arm/Group Description	Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.	Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Measure Participants	456	454
Least Squares Mean (Standard Error) [puffs/day]	-1.70 (0.16)	-2.35 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9995
	Comments
	Method	Repeated measures analysis
	Comments	Change from baseline =Treatment + baseline rescue a/s MDI use + BR a/s MDI + stratification factor (prior treatment) + region + TI + treatment by TI.
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.26 to 1.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.20
	Estimation Comments	Estimate of the mean change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.

9. Other Pre-specified Outcome

Title	Mean Change From Baseline in COPD Assessment Test (CAT) Score Over 24 Weeks
Description	The CAT is used to quantify the impact of COPD symptoms on health status. The CAT has a scoring range of 0-40, and it is calculated as the sum of the responses given for each of the 8 items (scored on a 6-point scale from 0 to 5), with higher scores indicating a higher impact of COPD symptoms on health status. If the response to 1 of the 8 items is missing, the missing item was considered equal to the average of the 7 non-missing items for that participant. If more than 1 item is missing the score was considered missing. Baseline is defined as the latest assessment within 7 days before or at randomization (Day 1).
Time Frame	From Baseline (Day -7 or 1) up to 24 weeks

Outcome Measure Data

Analysis Population Description

The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.

Arm/Group Title	Glycopyrronium/Formoterol Fumarate	Umeclidinium/Vilanterol
Arm/Group Description	Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.	Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Measure Participants	506	510
Least Squares Mean (Standard Error) [Units on a scale]	-2.97 (0.21)	-3.56 (0.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority p-value is calculated corresponding to the non-inferiority margin 2.0 unit.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Repeated measures analysis
	Comments	Change from baseline = Treatment + baseline CAT score + BR a/s MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.07 to 1.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.27
	Estimation Comments	Estimate of the mean change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.

10. Primary Outcome

Title	Mean Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over 24 Weeks in FAS Population
Description	To assess the effects of GFF relative to UV on lung function in FAS population as measured by peak change from baseline in FEV1 is defined as the maximum of the FEV1 assessments within the 2 hours post-dosing time windows at each visit minus baseline using spirometry. Baseline is defined as the mean of the non-missing -60 and -30 minute values obtained prior to dosing at randomization (Day 1).
Time Frame	From Baseline (Day 1) up to 24 weeks

Outcome Measure Data

Analysis Population Description

The FAS included all randomized participants who received at least 1 inhalation of IP from the GFF or UV inhaler (active or placebo).

Arm/Group Title	Glycopyrronium/Formoterol Fumarate	Umeclidinium/Vilanterol
Arm/Group Description	Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.	Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
Measure Participants	552	552
Least Squares Mean (Standard Error) [mL]	299.1 (9.9)	300.8 (9.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Glycopyrronium/Formoterol Fumarate, Umeclidinium/Vilanterol
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5516
	Comments
	Method	Repeated measures analysis
	Comments	Change from baseline = Treatment + baseline FEV1 + BR a/s MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 97.5%; -30.3 to 27.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.8
	Estimation Comments	Estimate of the mean peak change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.

Adverse Events

Time Frame	From Baseline (Day 1) up to 14 days after last IP dose, approximately 26 weeks.
Adverse Event Reporting Description	The safety analysis set included all participants who received at least 1 inhalation of the randomized active IP that they were assigned.
Arm/Group Title	Glycopyrronium/Formoterol Fumarate		Umeclidinium/Vilanterol
Arm/Group Description	Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.		Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
All Cause Mortality
	Glycopyrronium/Formoterol Fumarate		Umeclidinium/Vilanterol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/552 (0.5%)		3/552 (0.5%)
Serious Adverse Events
	Glycopyrronium/Formoterol Fumarate		Umeclidinium/Vilanterol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/552 (5.8%)		40/552 (7.2%)
Blood and lymphatic system disorders
Iron deficiency anaemia	1/552 (0.2%)	1	0/552 (0%)	0
Cardiac disorders
Acute myocardial infarction	1/552 (0.2%)	1	1/552 (0.2%)	1
Angina unstable	1/552 (0.2%)	1	2/552 (0.4%)	2
Arteriosclerosis coronary artery	1/552 (0.2%)	1	0/552 (0%)	0
Cardiac failure	1/552 (0.2%)	1	1/552 (0.2%)	1
Cardiac failure acute	0/552 (0%)	0	2/552 (0.4%)	2
Myocardial infarction	0/552 (0%)	0	1/552 (0.2%)	1
Congenital, familial and genetic disorders
Hydrocele	0/552 (0%)	0	1/552 (0.2%)	1
Eye disorders
Cataract	1/552 (0.2%)	1	0/552 (0%)	0
Gastrointestinal disorders
Colitis	0/552 (0%)	0	1/552 (0.2%)	1
Intestinal obstruction	0/552 (0%)	0	1/552 (0.2%)	1
Mesenteric artery thrombosis	0/552 (0%)	0	1/552 (0.2%)	1
Umbilical hernia	0/552 (0%)	0	1/552 (0.2%)	1
General disorders
Death	1/552 (0.2%)	1	1/552 (0.2%)	1
Incarcerated hernia	0/552 (0%)	0	1/552 (0.2%)	1
Non-cardiac chest pain	1/552 (0.2%)	1	0/552 (0%)	0
Immune system disorders
Anaphylactic shock	0/552 (0%)	0	1/552 (0.2%)	1
Infections and infestations
Erysipelas	0/552 (0%)	0	1/552 (0.2%)	1
Gastroenteritis	1/552 (0.2%)	1	2/552 (0.4%)	2
Pneumonia	3/552 (0.5%)	3	3/552 (0.5%)	3
Pneumonia bacterial	1/552 (0.2%)	1	2/552 (0.4%)	2
Pneumonia staphylococcal	0/552 (0%)	0	1/552 (0.2%)	1
Pneumonia streptococcal	1/552 (0.2%)	1	0/552 (0%)	0
Pneumonia viral	0/552 (0%)	0	1/552 (0.2%)	1
Sepsis	0/552 (0%)	0	1/552 (0.2%)	1
Urosepsis	1/552 (0.2%)	1	0/552 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/552 (0%)	0	1/552 (0.2%)	1
Femur fracture	0/552 (0%)	0	1/552 (0.2%)	1
Multiple fractures	1/552 (0.2%)	1	0/552 (0%)	0
Pelvic fracture	0/552 (0%)	0	1/552 (0.2%)	1
Metabolism and nutrition disorders
Diabetic metabolic decompensation	0/552 (0%)	0	1/552 (0.2%)	1
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/552 (0%)	0	1/552 (0.2%)	1
Muscular weakness	0/552 (0%)	0	1/552 (0.2%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung adenocarcinoma	1/552 (0.2%)	1	0/552 (0%)	0
Ovarian fibroma	0/552 (0%)	0	1/552 (0.2%)	1
Small cell lung cancer	0/552 (0%)	0	1/552 (0.2%)	1
Squamous cell carcinoma of lung	1/552 (0.2%)	1	0/552 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	16/552 (2.9%)	17	10/552 (1.8%)	12
Pulmonary hypertension	0/552 (0%)	0	1/552 (0.2%)	1
Pulmonary mass	1/552 (0.2%)	1	0/552 (0%)	0
Respiratory failure	0/552 (0%)	0	2/552 (0.4%)	2
Skin and subcutaneous tissue disorders
Diabetic foot	0/552 (0%)	0	2/552 (0.4%)	2
Vascular disorders
Essential hypertension	0/552 (0%)	0	1/552 (0.2%)	1
Hypertensive crisis	1/552 (0.2%)	1	0/552 (0%)	0
Malignant hypertension	1/552 (0.2%)	1	0/552 (0%)	0
Post thrombotic syndrome	0/552 (0%)	0	1/552 (0.2%)	1
Thrombosis	0/552 (0%)	0	1/552 (0.2%)	1
Other (Not Including Serious) Adverse Events
	Glycopyrronium/Formoterol Fumarate		Umeclidinium/Vilanterol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	129/552 (23.4%)		153/552 (27.7%)
Ear and labyrinth disorders
Vertigo	5/552 (0.9%)	6	6/552 (1.1%)	6
Gastrointestinal disorders
Abdominal pain	4/552 (0.7%)	4	7/552 (1.3%)	8
Constipation	1/552 (0.2%)	1	7/552 (1.3%)	7
Diarrhoea	7/552 (1.3%)	8	13/552 (2.4%)	15
Dry mouth	2/552 (0.4%)	2	6/552 (1.1%)	6
Toothache	1/552 (0.2%)	1	6/552 (1.1%)	6
Infections and infestations
Nasopharyngitis	30/552 (5.4%)	32	36/552 (6.5%)	42
Sinusitis	4/552 (0.7%)	4	6/552 (1.1%)	8
Upper respiratory tract infection	10/552 (1.8%)	13	10/552 (1.8%)	13
Viral upper respiratory tract infection	17/552 (3.1%)	18	26/552 (4.7%)	27
Musculoskeletal and connective tissue disorders
Arthralgia	1/552 (0.2%)	1	6/552 (1.1%)	7
Back pain	12/552 (2.2%)	13	9/552 (1.6%)	9
Pain in extremity	1/552 (0.2%)	1	7/552 (1.3%)	7
Nervous system disorders
Headache	34/552 (6.2%)	52	41/552 (7.4%)	55
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	20/552 (3.6%)	22	20/552 (3.6%)	22
Vascular disorders
Hypertension	13/552 (2.4%)	16	7/552 (1.3%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.