Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects With Moderate to Very Severe COPD

• Sponsor: Pearl Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02343458
• Collaborator: (none)
• Enrollment: 1,756
• Locations: 167
• Arms: 4
• Actual Duration (Months): 29.1
• Patients Per Site: 10.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

A chronic dosing (24 weeks) study to assess the efficacy and safety GFF MDI; PT003), FF MDI; PT005, and GP MDI; PT001) in subjects with moderate to very severe COPD, compared with placebo.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: GFF MDI (PT003); Drug: FF MDI (PT005); Drug: GP MDI (PT001); Drug: Placebo MDI	Phase 3

Detailed Description

A randomized, double-blind, chronic dosing (24 weeks), placebo-controlled, parallel group, multi-center study to assess the efficacy and safety of glycopyrronium and formoterol fumarate inhalation aerosol (GFF; PT003), formoterol fumarate inhalation aerosol (FF; PT005), and glycopyrronium inhalation aerosol (GP; PT001) in subjects with moderate to very severe COPD, compared with placebo.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1756 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Chronic Dosing (24 Weeks), Placebo-Controlled, Parallel Group, Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects With Moderate to Very Severe COPD, Compared With Placebo
• Actual Study Start Date: Mar 30, 2015
• Actual Primary Completion Date: Aug 31, 2017
• Actual Study Completion Date: Aug 31, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GFF MDI (PT003) Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI; PT003); Glycopyrronium and Formoterol Fumarate Inhalation Aerosol administered as 2 inhalations twice-daily (BID)	Drug: GFF MDI (PT003); Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI; PT003); Glycopyrronium and Formoterol Fumarate Inhalation Aerosol administered as 2 inhalations twice-daily (BID); Other Names: Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI; PT003); Glycopyrronium and Formoterol Fumarate Inhalation Aerosol
Experimental: FF MDI (PT005) Formoterol Fumarate Metered Dose Inhaler (FF MDI; PT005); Formoterol Fumarate Inhalation Aerosol administered as 2 inhalations twice-daily (BID)	Drug: FF MDI (PT005); Formoterol Fumarate Metered Dose Inhaler (FF MDI; PT005); Formoterol Fumarate Inhalation Aerosol administered as 2 inhalations twice-daily (BID); Other Names: Formoterol Fumarate Metered Dose Inhaler (FF MDI; PT005); Formoterol Fumarate Inhalation Aerosol
Experimental: GP MDI (PT001) Glycopyrronium Metered Dose Inhaler (GP MDI; PT001); Glycopyrronium Inhalation Aerosol administered as 2 inhalations twice-daily (BID)	Drug: GP MDI (PT001); Glycopyrronium Metered Dose Inhaler (GP MDI; PT001); Glycopyrronium Inhalation Aerosol administered as 2 inhalations twice-daily (BID); Other Names: Glycopyrronium Metered Dose Inhaler (GP MDI; PT001); Glycopyrronium Inhalation Aerosol
Placebo Comparator: Placebo MDI Placebo (matching) for GFF MDI, FF MDI, and GP MDI administered as 2 inhalations twice-daily (BID)	Drug: Placebo MDI; Placebo (matching) for GFF MDI, FF MDI, and GP MDI administered as 2 inhalations twice-daily (BID); Other Names: Placebo (matching) for GFF MDI, FF MDI, and GP MDI

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 of Treatment (US/China Approach) [at week 24]

   For the US/China approach, the primary endpoint was the change from baseline in morning pre-dose trough FEV1 at Week 24 of treatment

2. Change From Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24, Japan Approach [over weeks 12-24]

   Change from baseline in morning pre-dose trough FEV1 over weeks 12-24, Japan approach

3. Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks. Primary Endpoint, EU/SK/TW Approach, Secondary Endpoint US/China Approach. [over 24 weeks]

   Change from baseline in morning pre-dose trough FEV1 over 24 weeks. Primary endpoint, EU/SK/TW approach, Secondary endpoint US/China approach.

Secondary Outcome Measures

1. TDI Focal Score Over 24 Weeks, US/China and EU/SK/TW Approach [over 24 Weeks]

   TDI focal score over 24 Weeks as a Model-Based Average (ITT Population) The TDI is an instrument which measures the changes in the participant's dyspnea from Baseline. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9

2. TDI Focal Score Over Weeks 12-24 Japan Approach [over Weeks 12-24]

   TDI focal score over 12-24 Weeks as a Model-Based Average (ITT Population) The TDI is an instrument which measures the changes in the participant's dyspnea from Baseline. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9

3. TDI Focal Score Over 24 Weeks - US/China and EU/SK/TW Approaches -Symptomatic Population [over 24 Weeks]

   TDI focal score over 24 Weeks as a Model-Based Average (ITT Population) The TDI is an instrument which measures the changes in the participant's dyspnea from Baseline. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9

4. TDI Focal Score Over Weeks 12-24 - Japan Approach - Symptomatic Population [over weeks 12-24]

   TDI focal score over 12-24 Weeks as a Model-Based Average (ITT Population) The TDI is an instrument which measures the changes in the participant's dyspnea from Baseline. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9

5. Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing at Week 24 US/China Approach [at week 24]

   Peak change from baseline in FEV1 within 2 hours post-dosing at Week 24 US/China approach

6. Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over Weeks 12-24 Japan Approach [over weeks 12-24]

   Peak change from baseline in FEV1 within 2 hours post-dosing over weeks 12-24 Japan approach

7. Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over 24 Weeks EU/SK/TW Approach [over 24 weeks]

   Peak change from baseline in FEV1 within 2 hours post-dosing over 24 weeks EU/SK/TW approach

8. Change From Baseline in SGRQ Total Score at Week 24, US/China Approach [at week 24]

   Change from baseline in the SGRQ total score. The SGRQ is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of GFF MDI, FF MDI and GP MDI on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life

9. Change From Baseline in SGRQ Total Score Over Weeks 12-24 , Japan & EU/SK/TW Approach [over weeks 12-24]

   Change from baseline in the SGRQ total score. The SGRQ is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of GFF MDI, FF MDI and GP MDI on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life

10. Change From Baseline in SGRQ Total Score at Week 24 in Symptomatic Population, US/China Approach [at week 24]

    Change from baseline in the SGRQ total score. The SGRQ is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of GFF MDI, FF MDI and GP MDI on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life

11. Change From Baseline in SGRQ Total Score Over Weeks 12-24, in Symptomatic Population, Japan & EU/SK/TW Approach [over weeks 12-24]

    Change from baseline in the SGRQ total score. The SGRQ is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of GFF MDI, FF MDI and GP MDI on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life

12. Change From Baseline in Average Daily Rescue Ventolin Use Over 24 Weeks in RVU Population, All Approaches [over 24 weeks]

    Change from baseline in average daily rescue Ventolin use over 24 weeks in RVU population, all approaches

13. FEV1 Measured at 5 Minutes Post-dose on Day 1 [Assessed at 5-minutes post dose on Day 1]

    Onset of Action as Assessed by FEV1 Day 1 at 5 Minutes Post-Dose. Reported is the FEV1 measured at 5 minutes post-dose on Day 1 as the first time point when the difference from Placebo was statistically significant

14. FEV1 Measured at 15 Minutes Post-dose on Day 1 [Assessed at 15-minute post dose on Day 1]

    Onset of Action as Assessed by FEV1 Day 1 at 15 Minutes Post-Dose. Reported is the FEV1 measured at 15 minutes post-dose on Day 1 as the first time point when the difference from Placebo was statistically significant

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Non-child bearing potential (ie, physiologically incapable of becoming pregnant, including any female who is 2 years post-menopausal); or Child bearing potential, has a negative serum pregnancy test at Visit 1, and agrees to acceptable contraceptive methods used consistently and correctly for the duration of the study.

• Subjects with an established clinical history of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS).

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

• Forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio of <0.70.

• FEV1 must be <80% predicted normal value calculated using the Third National Health and Nutrition Examination Survey (NHANES III) reference equations. (Or reference norms applicable to other regions).

Exclusion Criteria:

• Significant diseases other than COPD, ie, disease or condition which, in the opinion of the Investigator, may put the subject at risk because of participation in the study or may influence either the results of the study or the subject's ability to participate in the study.

• Women who are pregnant or lactating or women of childbearing potential who are not using an acceptable method of contraception.

• Subjects, who in the opinion of the Investigator, have a current diagnosis of asthma.

• Subjects who have been hospitalized due to poorly controlled COPD within 3 months prior to Visit 1 (Screening) or during the Screening Period (Visit 1 to Visit 4).

• Subjects who have poorly controlled COPD, defined as acute worsening of COPD that requires treatment with oral corticosteroids or antibiotics within 6 weeks prior to Visit 1 (Screening) or during the Screening Period (Visit 1 to Visit 4).

• Subjects with a diagnosis of angle closure glaucoma will be excluded, regardless of whether or not they have been treated. Subjects with a diagnosis of open angle glaucoma who have intraocular pressure controlled with medication(s) are eligible.

• Subjects who have a history of hypersensitivity to β2-agonists, glycopyrronium or other muscarinic anticholinergics, or any component of the MDI.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Andalusia	Alabama	United States	36420
2	Research Site	Birmingham	Alabama	United States	35209
3	Research Site	Foley	Alabama	United States	36535
4	Research Site	Jasper	Alabama	United States	35501
5	Research Site	Anaheim	California	United States	92801
6	Research Site	Boulder	Colorado	United States	80301
7	Research Site	Clearwater	Florida	United States	33756
8	Research Site	Clearwater	Florida	United States	33765
9	Research Site	Kissimmee	Florida	United States	34744
10	Research Site	Miami	Florida	United States	33175
11	Research Site	Miami	Florida	United States	33186
12	Research Site	Panama City	Florida	United States	32405
13	Research Site	Pensacola	Florida	United States	32503
14	Research Site	Tamarac	Florida	United States	33321
15	Research Site	Tampa	Florida	United States	33603
16	Research Site	Winter Park	Florida	United States	32789-4681
17	Research Site	Atlanta	Georgia	United States	30331
18	Research Site	Blue Ridge	Georgia	United States	30513
19	Research Site	North Dartmouth	Massachusetts	United States	02747
20	Research Site	Edina	Minnesota	United States	55435
21	Research Site	Fridley	Minnesota	United States	55432
22	Research Site	Minneapolis	Minnesota	United States	55407
23	Research Site	Woodbury	Minnesota	United States	55125
24	Research Site	Saint Charles	Missouri	United States	63301
25	Research Site	Saint Louis	Missouri	United States	63141
26	Research Site	Gastonia	North Carolina	United States	28054
27	Research Site	Winston-Salem	North Carolina	United States	27103
28	Research Site	Cincinnati	Ohio	United States	45242
29	Research Site	Columbus	Ohio	United States	43215
30	Research Site	Columbus	Ohio	United States	43231
31	Research Site	Dayton	Ohio	United States	45419
32	Research Site	Dayton	Ohio	United States	45459
33	Research Site	Dublin	Ohio	United States	43016
34	Research Site	Oklahoma City	Oklahoma	United States	73103
35	Research Site	Medford	Oregon	United States	97504
36	Research Site	Easley	South Carolina	United States	29640
37	Research Site	Gaffney	South Carolina	United States	29341
38	Research Site	Greenville	South Carolina	United States	29615
39	Research Site	Rock Hill	South Carolina	United States	29732
40	Research Site	Seneca	South Carolina	United States	29678
41	Research Site	Spartanburg	South Carolina	United States	29303
42	Research Site	Union	South Carolina	United States	29379
43	Research Site	Johnson City	Tennessee	United States	37601
44	Research Site	Abingdon	Virginia	United States	24210
45	Research Site	Beijing		China	100029
46	Research Site	Beijing		China	100050
47	Research Site	Beijing		China	100144
48	Research Site	Changchun		China	130021
49	Research Site	Changsha		China	410011
50	Research Site	Chengdu		China	610083
51	Research Site	Chengdu		China	CN-610041
52	Research Site	Guangzhou		China	510000
53	Research Site	Guangzhou		China	510120
54	Research Site	Guangzhou		China	510515
55	Research Site	Guiyang		China	510630
56	Research Site	Haikou		China	570311
57	Research Site	Hefei		China	230001
58	Research Site	Hohhot		China	010017
59	Research Site	Nanchang		China	330006
60	Research Site	Nanjing		China	210009
61	Research Site	Nanning		China	530021
62	Research Site	Shanghai		China	200040
63	Research Site	Shanghai		China	200120
64	Research Site	Shanghai		China	200433
65	Research Site	Shengyang		China	110004
66	Research Site	Shenyang		China	110016
67	Research Site	Shijiazhuang		China	050000
68	Research Site	Shijiazhuang		China	050051
69	Research Site	Soochow City		China	215006
70	Research Site	Taiyuan		China	030001
71	Research Site	Tianjin		China	300052
72	Research Site	Wuxi		China	214023
73	Research Site	Xiamen		China	361004
74	Research Site	Xining		China	810007
75	Research Site	Yiyang Shi		China	413000
76	Research Site	Jindrichuv Hradec		Czechia	37701
77	Research Site	Ostrava-Hrabuvka		Czechia	700 30
78	Research Site	Praha		Czechia	15000
79	Research Site	Teplice		Czechia	415 01
80	Research Site	Augsburg		Germany	86150
81	Research Site	Berlin		Germany	10629
82	Research Site	Berlin		Germany	10787
83	Research Site	Berlin		Germany	12157
84	Research Site	Grosshansdof		Germany	22927
85	Research Site	Hamburg		Germany	20354
86	Research Site	Leipzig		Germany	04103
87	Research Site	Leipzig		Germany	04357
88	Research Site	Lübeck		Germany	23552
89	Research Site	Wiesbaden		Germany	65187
90	Research Site	Budapest		Hungary	1135
91	Research Site	Gödöllő		Hungary	2100
92	Research Site	Nyíregyháza		Hungary	4400
93	Research Site	Pécs		Hungary	7635
94	Research Site	Siófok		Hungary	8600
95	Research Site	Szeged		Hungary	H-6722
96	Research Site	Ako-shi		Japan	678-0239
97	Research Site	Asahikawa-shi		Japan	070-8644
98	Research Site	Chuo-ku		Japan	103-0027
99	Research Site	Chuo-ku		Japan	103-0028
100	Research Site	Fukuoka-shi		Japan	811-1394
101	Research Site	Hamamatsu-shi		Japan	434-8511
102	Research Site	Himeji-shi		Japan	671-0102
103	Research Site	Himeji-shi		Japan	672-8064
104	Research Site	Hitachinaka-shi		Japan	312-0057
105	Research Site	Itabashi-ku		Japan	173-8610
106	Research Site	Kakogawa-shi		Japan	675-0023
107	Research Site	Kamogawa-shi		Japan	296-0041
108	Research Site	Kanazawa-shi		Japan	920-8201
109	Research Site	Kishiwada-shi		Japan	596-8501
110	Research Site	Kobe-shi		Japan	650-0047
111	Research Site	Koga-shi		Japan	811-3195
112	Research Site	Matsumoto-shi		Japan	390-0872
113	Research Site	Matsumoto-shi		Japan	390-8621
114	Research Site	Mito-shi		Japan	310-0015
115	Research Site	Nagaoka-shi		Japan	940-2085
116	Research Site	Nagoya-shi		Japan	457-0866
117	Research Site	Naka-gun		Japan	319-1113
118	Research Site	Ohota-ku		Japan	145-0063
119	Research Site	Oita-shi		Japan	870-0951
120	Research Site	Saiki-shi		Japan	876-0813
121	Research Site	Sendai-shi		Japan	981-8563
122	Research Site	Sendai-shi		Japan	983-0824
123	Research Site	Seto-shi		Japan	489-8642
124	Research Site	Shimotsuga-gun		Japan	321-0293
125	Research Site	Takamatsu-shi		Japan	760-8538
126	Research Site	Toon-shi		Japan	791-0281
127	Research Site	Yanagawa-shi		Japan	832-0059
128	Research Site	Yokohama-shi		Japan	232-0066
129	Research Site	Yokohama-shi		Japan	241-0811
130	Research Site	Busan		Korea, Republic of	602-715
131	Research Site	Daegu		Korea, Republic of	42415
132	Research Site	Seoul		Korea, Republic of	04551
133	Research Site	Seoul		Korea, Republic of	130-709
134	Research Site	Seoul		Korea, Republic of	130-872
135	Research Site	Seoul		Korea, Republic of	136-705
136	Research Site	Seoul		Korea, Republic of	152-703
137	Research Site	Wonju-si		Korea, Republic of	220-701
138	Research Site	Białystok		Poland	15-003
139	Research Site	Białystok		Poland	15-044
140	Research Site	Elbląg		Poland	82-300
141	Research Site	Inowrocław		Poland	88-100
142	Research Site	Lodz		Poland	90-153
143	Research Site	Piekary Śląskie		Poland	41-94O
144	Research Site	Rzeszów		Poland	35-205
145	Research Site	Skierniewice		Poland	96-100
146	Research Site	Szczecin		Poland	70-111
147	Research Site	Tarnów		Poland	33-100
148	Research Site	Torun		Poland	87-100
149	Research Site	Warszawa Targowek		Poland	03-291
150	Research Site	Łódź		Poland	90-203
151	Research Site	Gatchina		Russian Federation	188300
152	Research Site	Moscow		Russian Federation	105229
153	Research Site	Moscow		Russian Federation	127018
154	Research Site	Pytigorsk		Russian Federation	357538
155	Research Site	Saint Petersburg		Russian Federation	198260
156	Research Site	Saint-Petersburg		Russian Federation	195271
157	Research Site	Saint-Petersburg		Russian Federation	197022
158	Research Site	St. Petersburg		Russian Federation	197022
159	Research Site	Kaohsiung City		Taiwan	83301
160	Research Site	Taichung		Taiwan	40447
161	Research Site	Taichung		Taiwan	40705
162	Research Site	Taipei		Taiwan	10002
163	Research Site	Dundee		United Kingdom	DD1 9SY
164	Research Site	London		United Kingdom	EC1M 6BQ
165	Research Site	London		United Kingdom	W1G 8HU
166	Research Site	Northwood		United Kingdom	HA6 2RN
167	Research Site	Sidcup		United Kingdom	DA14 6LT

Sponsors and Collaborators

• Pearl Therapeutics, Inc.

Investigators

• Study Chair: Colin Reisner, MD, Pearl Therapeutics, Inc.

Study Documents (Full-Text)

• Study Protocol - Jan 20, 2017
• Statistical Analysis Plan - Mar 7, 2017

More Information

Additional Information:

• Updated cover page
• Updated Cover page
• Updated Cover page
• Updated cover page

Publications

None provided.

• Responsible Party: Pearl Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT02343458
• Other Study ID Numbers: PT003014
• First Posted: Jan 22, 2015
• Last Update Posted: Feb 20, 2019
• Last Verified: Jan 1, 2019

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

Study Results

Participant Flow

Recruitment Details	The study was conducted at 175 sites in the United States, United Kingdom, Taiwan (TW),South Korea (SK), Russia, Poland, Hungary, Germany, Czech Republic, China, and Japan from April 2015 to August 2017. The entire study period was scheduled to take approximately 30 weeks for each individual subject from the time of screening.
Pre-assignment Detail	Subjects were randomized in a 7:6:6:3 scheme (GFF MDI, FF MDI, GP MDI, and Placebo MDI). Randomization was stratified by reversibility to Ventolin HFA and COPD disease severity (moderate vs severe or very severe) to ensure a similar distribution of treatment arms across stratum.

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Period Title: Overall Study
STARTED	555	483	480	238
COMPLETED	494	417	417	200
NOT COMPLETED	61	66	63	38

Baseline Characteristics

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI	Total
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation	Total of all reporting groups
Overall Participants	551	480	474	235	1740
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.7 (7.4)	64.1 (7.6)	64.0 (8.1)	63.9 (7.5)	64.2 (7.7)
Sex: Female, Male (Count of Participants)
Female	143 26%	115 24%	128 27%	64 27.2%	450 25.9%
Male	408 74%	365 76%	346 73%	171 72.8%	1290 74.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.2%	0 0%	0 0%	0 0%	1 0.1%
Asian	223 40.5%	204 42.5%	181 38.2%	92 39.1%	700 40.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	12 2.2%	16 3.3%	18 3.8%	6 2.6%	52 3%
White	315 57.2%	260 54.2%	275 58%	137 58.3%	987 56.7%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 of Treatment (US/China Approach)
Description	For the US/China approach, the primary endpoint was the change from baseline in morning pre-dose trough FEV1 at Week 24 of treatment
Time Frame	at week 24

Outcome Measure Data

Analysis Population Description

ITT Population - defined as all subjects who were randomized to treatment and received at least 1 dose of the study treatment. Subjects were analyzed according to the treatment they were assigned to at randomization. Number of participants analyzed reflects the ITT population with available data

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	488	413	412	196
Least Squares Mean (95% Confidence Interval) [mL]	120	47	60	-45

2. Primary Outcome

Title	Change From Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24, Japan Approach
Description	Change from baseline in morning pre-dose trough FEV1 over weeks 12-24, Japan approach
Time Frame	over weeks 12-24

Outcome Measure Data

Analysis Population Description

ITT Population - defined as all subjects who were randomized to treatment and received at least 1 dose of the study treatment. Subjects were analyzed according to the treatment they were assigned to at randomization. Number of participants analyzed reflects the ITT population with available data

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	517	436	437	205
Least Squares Mean (95% Confidence Interval) [mL]	128	54	74	-25

3. Primary Outcome

Title	Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks. Primary Endpoint, EU/SK/TW Approach, Secondary Endpoint US/China Approach.
Description	Change from baseline in morning pre-dose trough FEV1 over 24 weeks. Primary endpoint, EU/SK/TW approach, Secondary endpoint US/China approach.
Time Frame	over 24 weeks

Outcome Measure Data

Analysis Population Description

ITT Population - defined as all subjects who were randomized to treatment and received at least 1 dose of the study treatment. Subjects were analyzed according to the treatment they were assigned to at randomization. Number of participants analyzed reflects the ITT population with available data

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	541	467	465	225
Least Squares Mean (95% Confidence Interval) [mL]	135	63	80	-20

4. Secondary Outcome

Title	TDI Focal Score Over 24 Weeks, US/China and EU/SK/TW Approach
Description	TDI focal score over 24 Weeks as a Model-Based Average (ITT Population) The TDI is an instrument which measures the changes in the participant's dyspnea from Baseline. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9
Time Frame	over 24 Weeks

Outcome Measure Data

Analysis Population Description

ITT Population - defined as all subjects who were randomized to treatment and received at least 1 dose of the study treatment. Subjects were analyzed according to the treatment they were assigned to at randomization. Number of participants analyzed reflects the ITT population with available data

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	532	458	457	217
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	1.6	1.5	1.3	0.8

5. Secondary Outcome

Title	TDI Focal Score Over Weeks 12-24 Japan Approach
Description	TDI focal score over 12-24 Weeks as a Model-Based Average (ITT Population) The TDI is an instrument which measures the changes in the participant's dyspnea from Baseline. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9
Time Frame	over Weeks 12-24

Outcome Measure Data

Analysis Population Description

ITT Population - defined as all subjects who were randomized to treatment and received at least 1 dose of the study treatment. Subjects were analyzed according to the treatment they were assigned to at randomization. Number of participants analyzed reflects the ITT population with available data

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	515	434	436	205
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	1.7	1.5	1.4	0.8

6. Secondary Outcome

Title	TDI Focal Score Over 24 Weeks - US/China and EU/SK/TW Approaches -Symptomatic Population
Description	TDI focal score over 24 Weeks as a Model-Based Average (ITT Population) The TDI is an instrument which measures the changes in the participant's dyspnea from Baseline. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9
Time Frame	over 24 Weeks

Outcome Measure Data

Analysis Population Description

Symptomatic Population was defined as all subjects in the ITT Population with CAT scores of ≥15 at Visit 2

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	244	217	228	108
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	1.5	1.3	1.1	0.7

7. Secondary Outcome

Title	TDI Focal Score Over Weeks 12-24 - Japan Approach - Symptomatic Population
Description	TDI focal score over 12-24 Weeks as a Model-Based Average (ITT Population) The TDI is an instrument which measures the changes in the participant's dyspnea from Baseline. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9
Time Frame	over weeks 12-24

Outcome Measure Data

Analysis Population Description

Symptomatic Population was defined as all subjects in the ITT Population with CAT scores of ≥15 at Visit 2

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	237	200	218	97
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	1.5	1.4	1.1	0.7

8. Secondary Outcome

Title	Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing at Week 24 US/China Approach
Description	Peak change from baseline in FEV1 within 2 hours post-dosing at Week 24 US/China approach
Time Frame	at week 24

Outcome Measure Data

Analysis Population Description

ITT Population - defined as all subjects who were randomized to treatment and received at least 1 dose of the study treatment. Subjects were analyzed according to the treatment they were assigned to at randomization. Number of participants analyzed reflects the ITT population with available data

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	490	413	412	196
Least Squares Mean (95% Confidence Interval) [mL]	358	247	214	55

9. Secondary Outcome

Title	Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over Weeks 12-24 Japan Approach
Description	Peak change from baseline in FEV1 within 2 hours post-dosing over weeks 12-24 Japan approach
Time Frame	over weeks 12-24

Outcome Measure Data

Analysis Population Description

ITT Population - defined as all subjects who were randomized to treatment and received at least 1 dose of the study treatment. Subjects were analyzed according to the treatment they were assigned to at randomization. Number of participants analyzed reflects the ITT population with available data

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	516	436	436	205
Least Squares Mean (95% Confidence Interval) [mL]	368	255	228	70

10. Secondary Outcome

Title	Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over 24 Weeks EU/SK/TW Approach
Description	Peak change from baseline in FEV1 within 2 hours post-dosing over 24 weeks EU/SK/TW approach
Time Frame	over 24 weeks

Outcome Measure Data

Analysis Population Description

ITT Population - defined as all subjects who were randomized to treatment and received at least 1 dose of the study treatment. Subjects were analyzed according to the treatment they were assigned to at randomization. Number of participants analyzed reflects the ITT population with available data

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	550	480	474	235
Least Squares Mean (95% Confidence Interval) [mL]	375	277	234	82

11. Secondary Outcome

Title	Change From Baseline in SGRQ Total Score at Week 24, US/China Approach
Description	Change from baseline in the SGRQ total score. The SGRQ is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of GFF MDI, FF MDI and GP MDI on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life
Time Frame	at week 24

Outcome Measure Data

Analysis Population Description

ITT Population - defined as all subjects who were randomized to treatment and received at least 1 dose of the study treatment. Subjects were analyzed according to the treatment they were assigned to at randomization. Number of participants analyzed reflects the ITT population with available data

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	489	415	412	196
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	-5.3	-5.6	-3.7	-0.9

12. Secondary Outcome

Title	Change From Baseline in SGRQ Total Score Over Weeks 12-24 , Japan & EU/SK/TW Approach
Description	Change from baseline in the SGRQ total score. The SGRQ is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of GFF MDI, FF MDI and GP MDI on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life
Time Frame	over weeks 12-24

Outcome Measure Data

Analysis Population Description

ITT Population - defined as all subjects who were randomized to treatment and received at least 1 dose of the study treatment. Subjects were analyzed according to the treatment they were assigned to at randomization. Number of participants analyzed reflects the ITT population with available data

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	516	436	436	205
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	-5.2	-5.0	-3.6	-1.7

13. Secondary Outcome

Title	Change From Baseline in SGRQ Total Score at Week 24 in Symptomatic Population, US/China Approach
Description	Change from baseline in the SGRQ total score. The SGRQ is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of GFF MDI, FF MDI and GP MDI on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life
Time Frame	at week 24

Outcome Measure Data

Analysis Population Description

Symptomatic Population was defined as all subjects in the ITT Population with CAT scores of ≥15 at Visit 2n

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	220	189	202	92
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	-6.9	-7.8	-3.8	-1.6

14. Secondary Outcome

Title	Change From Baseline in SGRQ Total Score Over Weeks 12-24, in Symptomatic Population, Japan & EU/SK/TW Approach
Description	Change from baseline in the SGRQ total score. The SGRQ is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of GFF MDI, FF MDI and GP MDI on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life
Time Frame	over weeks 12-24

Outcome Measure Data

Analysis Population Description

Symptomatic Population was defined as all subjects in the ITT Population with CAT scores of ≥15 at Visit 2

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	237	200	218	97
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	-6.9	-7.3	-3.9	-3.1

15. Secondary Outcome

Title	Change From Baseline in Average Daily Rescue Ventolin Use Over 24 Weeks in RVU Population, All Approaches
Description	Change from baseline in average daily rescue Ventolin use over 24 weeks in RVU population, all approaches
Time Frame	over 24 weeks

Outcome Measure Data

Analysis Population Description

RVU Population - defined as Rescue Ventolin User

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	256	232	225	109
Least Squares Mean (95% Confidence Interval) [Puffs/day]	-1.4	-1.0	-0.6	-0.4

16. Secondary Outcome

Title	FEV1 Measured at 5 Minutes Post-dose on Day 1
Description	Onset of Action as Assessed by FEV1 Day 1 at 5 Minutes Post-Dose. Reported is the FEV1 measured at 5 minutes post-dose on Day 1 as the first time point when the difference from Placebo was statistically significant
Time Frame	Assessed at 5-minutes post dose on Day 1

Outcome Measure Data

Analysis Population Description

ITT Population - defined as all subjects who were randomized to treatment and received at least 1 dose of the study treatment. Subjects were analyzed according to the treatment they were assigned to at randomization. Number of participants analyzed reflects the ITT population with available data

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	464	406	403	197
Least Squares Mean (95% Confidence Interval) [Liters]	0.202	0.186	0.059	0.022

17. Secondary Outcome

Title	FEV1 Measured at 15 Minutes Post-dose on Day 1
Description	Onset of Action as Assessed by FEV1 Day 1 at 15 Minutes Post-Dose. Reported is the FEV1 measured at 15 minutes post-dose on Day 1 as the first time point when the difference from Placebo was statistically significant
Time Frame	Assessed at 15-minute post dose on Day 1

Outcome Measure Data

Analysis Population Description

ITT Population - defined as all subjects who were randomized to treatment and received at least 1 dose of the study treatment. Subjects were analyzed according to the treatment they were assigned to at randomization. Number of participants analyzed reflects the ITT population with available data

Arm/Group Title	GFF MDI 14.4/9.6 ug	FF MDI 9.6 ug	GP MDI 14.4 ug	Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug	Formoterol Fumarate, Metered Dose Inhalation 9.6 ug	Glycopyrronium 14.4 ug Metered Dose Inhalation	Placebo Metered Dose Inhalation
Measure Participants	530	458	453	229
Least Squares Mean (95% Confidence Interval) [Liters]	0.241	0.220	0.105	0.033

Adverse Events

Time Frame	Adverse events were collected from the time the subject signed consent throughout the four treatment periods of 24 weeks and up to 10 days following the last dose of study drug.
Adverse Event Reporting Description	The Safety Population was defined as all subjects who were randomized to treatment regardless and received at least one dose of study treatment. Serious adverse events collected from the time the subject signed consent up to 14 days following the last dose of study drug.
Arm/Group Title	GFF MDI 14.4/9.6 ug		FF MDI 9.6 ug		GP MDI 14.4 ug		Placebo MDI
Arm/Group Description	Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug		Formoterol Fumarate, Metered Dose Inhalation 9.6 ug		Glycopyrronium 14.4 ug Metered Dose Inhalation		Placebo Metered Dose Inhalation
All Cause Mortality
	GFF MDI 14.4/9.6 ug		FF MDI 9.6 ug		GP MDI 14.4 ug		Placebo MDI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/551 (0.2%)		1/480 (0.2%)		1/474 (0.2%)		1/235 (0.4%)
Serious Adverse Events
	GFF MDI 14.4/9.6 ug		FF MDI 9.6 ug		GP MDI 14.4 ug		Placebo MDI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/551 (9.6%)		40/480 (8.3%)		34/474 (7.2%)		19/235 (8.1%)
Blood and lymphatic system disorders
Anaemia	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Cardiac disorders
Acute myocardial infarction	0/551 (0%)	0	1/480 (0.2%)	1	2/474 (0.4%)	2	0/235 (0%)	0
Coronary artery disease	0/551 (0%)	0	2/480 (0.4%)	2	1/474 (0.2%)	1	0/235 (0%)	0
Angina unstable	1/551 (0.2%)	1	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Myocardial infarction	1/551 (0.2%)	1	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Angina pectoris	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Atrial fibrillation	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Atrioventricular block	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Cardiac failure chronic	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Cardiac failure congestive	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Sinus node dysfunction	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Eye disorders
Angel closure glaucoma	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Cataract	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Retinal detachment	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Gastrointestinal disorders
Inguinal hernia	1/551 (0.2%)	1	0/480 (0%)	0	2/474 (0.4%)	2	0/235 (0%)	0
Gastrointestinal haemorrhage	1/551 (0.2%)	2	0/480 (0%)	0	0/474 (0%)	0	1/235 (0.4%)	1
Colitis ischemic	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Diarrhoea	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Dysphagia	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Food poisoning	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Gastric ulcer haemorrhage	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Haemorroids thrombosed	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Intestinal obstruction	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
General disorders
Non-cardiac chest pain	2/551 (0.4%)	2	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Chest pain	0/551 (0%)	0	0/480 (0%)	0	0/474 (0%)	0	1/235 (0.4%)	1
Hepatobiliary disorders
Cholecystitis acute	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Immune system disorders
Allergy to arthropod sting	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Infections and infestations
Pneumonia	7/551 (1.3%)	7	2/480 (0.4%)	2	3/474 (0.6%)	3	3/235 (1.3%)	3
Cellulitis	3/551 (0.5%)	3	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Lung Infection	0/551 (0%)	0	2/480 (0.4%)	2	1/474 (0.2%)	1	0/235 (0%)	0
Borrelia Infection	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Bronchiolitis	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Diverticulitis	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Gastroenteritis	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Gastrointestinal Infection	0/551 (0%)	0	0/480 (0%)	0	0/474 (0%)	0	1/235 (0.4%)	1
Hepatitis C	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Herpes Zoster	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Lower respiratory tract infection	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Post procedural infection	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Injury, poisoning and procedural complications
Humerous fracture	1/551 (0.2%)	1	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Rib fracture	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	1/235 (0.4%)	1
Clavicle fracture	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Head injury	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Lower limb fracture	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Lumbar vertebral fracture	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Muscle rupture	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Procedural hypotension	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Spinal compression fracture	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Subdural haematoma	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Metabolism and nutrition disorders
Diabetes melitus	1/551 (0.2%)	1	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Hyperlipidaemia	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	1/235 (0.4%)	1
Obesity	0/551 (0%)	0	0/480 (0%)	0	0/474 (0%)	0	1/235 (0.4%)	1
Musculoskeletal and connective tissue disorders
Intervertebral disc degeneration	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Pathological fracture	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Spinal osteoarthritis	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Spondyloarthropathy	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung cancer metastatic	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	1/235 (0.4%)	1
Breast neoplasm	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Cardiac myxoma	0/551 (0%)	0	0/480 (0%)	0	0/474 (0%)	0	1/235 (0.4%)	1
Colon adenoma	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Colon cancer	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Gastric cancer	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Haemangiopericytoma	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Laryngeal cancer	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Metastases to liver	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Metastases to lung	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Papillary thyroid cancer	0/551 (0%)	0	0/480 (0%)	0	0/474 (0%)	0	1/235 (0.4%)	1
Small cell lung cancer	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Squamous cell carcinoma of skin	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Nervous system disorders
Carotid artery disease	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Cerebral haemorrhage	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Cerebral infarction	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Dizziness	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Epilepsy	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Haemorrhagic stroke	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Hypoglycemic coma	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Ischaemic stroke	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Loss of consciousness	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Pseudoradicular syndrome	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Transient ischaemic attack	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Psychiatric disorders
Depression	0/551 (0%)	0	0/480 (0%)	0	0/474 (0%)	0	1/235 (0.4%)	1
Somatic symptom disorder	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Renal and urinary disorders
Calculus bladder	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Glomerulonephritis	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Hydronephrosis	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Nephrotic syndrome	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Renal failure	0/551 (0%)	0	0/480 (0%)	0	0/474 (0%)	0	1/235 (0.4%)	1
Ureterolithiasis	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	0/235 (0%)	0
Urinary retention	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Reproductive system and breast disorders
Vaginal haemorrhage	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease	16/551 (2.9%)	16	13/480 (2.7%)	13	12/474 (2.5%)	12	7/235 (3%)	7
Pneumothorax	0/551 (0%)	0	0/480 (0%)	0	1/474 (0.2%)	1	1/235 (0.4%)	1
Asthma-chronic obstructive pulmonary disease overlap syndrome	0/551 (0%)	0	1/480 (0.2%)	1	0/474 (0%)	0	0/235 (0%)	0
Cough	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Dyspnoea Exertional	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Vascular disorders
Aortic aneurysm	0/551 (0%)	0	0/480 (0%)	0	0/474 (0%)	0	1/235 (0.4%)	1
Hypertensive crisis	1/551 (0.2%)	1	0/480 (0%)	0	0/474 (0%)	0	0/235 (0%)	0
Other (Not Including Serious) Adverse Events
	GFF MDI 14.4/9.6 ug		FF MDI 9.6 ug		GP MDI 14.4 ug		Placebo MDI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	166/551 (30.1%)		123/480 (25.6%)		128/474 (27%)		61/235 (26%)
Infections and infestations
Viral upper respiratory tract infection	50/551 (9.1%)	56	46/480 (9.6%)	52	44/474 (9.3%)	55	16/235 (6.8%)	17
Upper respiratory tract infection	37/551 (6.7%)	44	29/480 (6%)	34	33/474 (7%)	40	20/235 (8.5%)	24
Pneumonia	9/551 (1.6%)	9	5/480 (1%)	5	5/474 (1.1%)	5	6/235 (2.6%)	6
Bronchitis	4/551 (0.7%)	5	6/480 (1.3%)	7	8/474 (1.7%)	8	5/235 (2.1%)	5
Pharyngitis	11/551 (2%)	11	4/480 (0.8%)	4	3/474 (0.6%)	3	0/235 (0%)	0
Musculoskeletal and connective tissue disorders
Back Pain	15/551 (2.7%)	16	5/480 (1%)	5	7/474 (1.5%)	7	1/235 (0.4%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	16/551 (2.9%)	16	13/480 (2.7%)	13	12/474 (2.5%)	12	7/235 (3%)	7
Cough	13/551 (2.4%)	14	8/480 (1.7%)	8	10/474 (2.1%)	11	2/235 (0.9%)	3
Dyspnoea	11/551 (2%)	11	7/480 (1.5%)	7	6/474 (1.3%)	8	7/235 (3%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Drafts of any and all publications or presentations of this study must be submitted at least 30 days prior to submission for publication or presentation to Pearl Therapeutics for review, approval, and to ensure consistency. Pearl Therapeutics has the right to request appropriate modification to correct facts and to represent it's opinions, or the opinions of the publication committee, if these differ with the proposed publication.