Efficacy and Safety of PT003, PT005, and PT001 in Subjects With Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD); (PINNACLE 1)

• Sponsor: Pearl Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01854645
• Collaborator: (none)
• Enrollment: 2,103
• Locations: 140
• Arms: 5
• Duration (Months): 21.1
• Patients Per Site: 15
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The overall objective of this study is to assess the efficacy and safety of treatment with PT003 (GFF MDI), PT005 (FF MDI), PT001 (GP MDI), and open-label tiotropium bromide inhalation powder compared with each other and Placebo MDI over 24 weeks in subjects with moderate to very severe COPD.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: GFF MDI; Drug: GP MDI; Drug: FF MDI; Drug: Open-label tiotropium bromide inhalation powder (Spiriva® Handihaler®); Drug: Placebo MDI	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 2103 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double Blind, Chronic Dosing, 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 and Spiriva® Handihaler® (Tiotropium Bromide 18 µg Open-Label) as an Active Control
• Study Start Date: May 1, 2013
• Actual Primary Completion Date: Feb 1, 2015
• Actual Study Completion Date: Feb 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GFF MDI Glycopyrronium Formoterol Fumarate (GFF) Metered Dose Inhaler (MDI) (PT003)	Drug: GFF MDI; GFF MDI administered as two puffs Bis in Di.e. Twice Daily (BID)
Experimental: GP MDI Glycopyrronium (GP) MDI (PT001)	Drug: GP MDI; GP MDI administered as two puffs BID
Experimental: FF MDI Formoterol Fumarate (FF) MDI (PT005)	Drug: FF MDI; FF MDI administered as two puffs BID
Active Comparator: Open-label tiotropium bromide inhalation powder Open-label tiotropium bromide inhalation powder (Spiriva® Handihaler®)	Drug: Open-label tiotropium bromide inhalation powder (Spiriva® Handihaler®); Taken as 1 capsule daily containing 18 µg of open-label tiotropium via the Handihaler dry powder inhaler (DPI)
Placebo Comparator: Placebo Placebo MDI	Drug: Placebo MDI; Inhaled placebo administered as two puffs BID

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 [Baseline and at Week 24]

   Change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) at Week 24

Secondary Outcome Measures

1. Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks [Baseline and Weeks 2 to 24]

   Change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) over 24 weeks. FEV1 was assessed at multiple time points post-baseline,and a modelbased average of all visits starting from Week 2 through week 24 inclusive was calculated. The change values reported in the table represent the change between the baseline and the average FEV1 post-baseline.

2. St. George's Respiratory Questionnaire (SGRQ) Score [Baseline and 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.

3. Rescue Ventolin Hydrofluoroalkane (HFA) Use [Baseline and at Week 24]

   Change from baseline in average daily rescue Ventolin HFA use

4. Onset of Action as Assessed by FEV1 [Assessed for 5- and 15-minute post dose on Day 1]

   Defined as the first time-point using the 5- and 15-minute post dose measurements where the difference in FEV1 from Placebo was statistically significant

5. Peak Change From Baseline in FEV1 Within 2 Hours Post-dose [Baseline and at Week 24]

   Peak change from baseline in forced expiratory volume in 1 second (FEV1) within 2 hours post-dose

Eligibility Criteria

Criteria

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

Key Inclusion Criteria:

• Male or female subjects at least 40 years of age and no older than 80 at Visit 1.

• 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.

• Average f the -60 and the -30 min pre-dose FEV1 assessments must be < 80% predicted normal value calculated using National Health and Nutrition Examination Survey (NHANES) III reference equations.

• Subjects willing and, in the opinion of the investigator, able to adjust current COPD therapy as required by the protocol

Key Exclusion Criteria:

• Significant diseases other than COPD, i.e. disease or condition which, in the opinion of the investigator, may put the patient 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

• Current diagnosis of asthma or alpha-1 antitrypsin deficiency

• Other active pulmonary disease such as active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, idiopathic interstitial pulmonary fibrosis, primary pulmonary hypertension, or uncontrolled sleep apnea

• Hospitalized due to poorly controlled COPD within 3 months prior to screening or during the Screening Period

• Poorly controlled COPD, defined as acute worsening of COPD that requires treatment with oral corticosteroids or antibiotics within 6 weeks prior to screening or during the Screening Period

• Lower respiratory tract infections that required antibiotics within 6 weeks prior to screening or during the Screening Period

• Unstable ischemic heart disease, left ventricular failure, or documented myocardial infarction within 12 months of enrollment.

• Recent history of acute coronary syndrome, percutaneous coronary intervention, coronary artery bypass graft within the past three months

• Congestive heart failure (CHF) New York Heart Association (NYHA) Class III/IV)

• Clinically significant abnormal 12-lead ECG

• Abnormal liver function tests defined as aspartate transaminase (AST), alanine transaminase (ALT), or total bilirubin ≥ 1.5 times upper limit of normal at Visit 1 and on repeat testing

• Cancer not in complete remission for at least five years

• History of hypersensitivity to β2-agonists, glycopyrronium or other muscarinic anticholinergics, lactose/milk protein or any component of the MDI

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pearl Investigative Site	Andalusia	Alabama	United States
2	Pearl Investigative Site	Anniston	Alabama	United States
3	Pearl Investigative Site	Athens	Alabama	United States
4	Pearl Investigative Site	Birmingham	Alabama	United States
5	Pearl Investigative Site	Mesa	Arizona	United States
6	Pearl Investigative Site	Phoenix	Arizona	United States
7	Pearl Investigative Site	Scottsdale	Arizona	United States
8	Pearl Investigative Site	Tucson	Arizona	United States
9	Pearl Investigative Site	Anaheim	California	United States
10	Pearl Investigative Site	Carlsbad	California	United States
11	Pearl Investigative Site	Lakewood	California	United States
12	Pearl Investigative Site	Los Angeles	California	United States
13	Pearl Investigative Site	Pasadena	California	United States
14	Pearl Investigative Site	Pasedena	California	United States
15	Pearl Investigative Site	Poway	California	United States
16	Pearl Investigative Site	Sacramento	California	United States
17	Pearl Investigative Site	San Diego	California	United States
18	Pearl Investigative Site	Tustin	California	United States
19	Pearl Investigative Site	Vista	California	United States
20	Pearl Investigative Site	Colorado Springs	Colorado	United States
21	Pearl Investigative Site	Denver	Colorado	United States
22	Pearl Investigative Site	Fort Collins	Colorado	United States
23	Pearl Investigative Site	Wheat Ridge	Colorado	United States
24	Pearl Investigative Site	Danbury	Connecticut	United States
25	Pearl Investigative Site	Waterbury	Connecticut	United States
26	Pearl Investigative Site	Brandon	Florida	United States
27	Pearl Investigative Site	Clearwater	Florida	United States
28	Pearl Investigative Site	Lehigh Acres	Florida	United States
29	Pearl Investigative Site	Miami	Florida	United States
30	Pearl Investigative Site	Ormond Beach	Florida	United States
31	Pearl Investigative Site	Panama City	Florida	United States
32	Pearl Investigative Site	Pensacola	Florida	United States
33	Pearl Investigative Site	St. Petersburg	Florida	United States
34	Pearl Investigative Site	Tampa	Florida	United States
35	Pearl Investigative Site	Winter Park	Florida	United States
36	Pearl Investigative Site	Atlanta	Georgia	United States
37	Pearl Investigative Site	Austell	Georgia	United States
38	Pearl Investigative Site	Columbus	Georgia	United States
39	Pearl Investigative Site	Duluth	Georgia	United States
40	Pearl Investigative Site	Gainesville	Georgia	United States
41	Pearl Investigative Site	Coeur d'Alene	Idaho	United States
42	Pearl Investigative Site	Champaign	Illinois	United States
43	Pearl Investigative Site	Evanston	Illinois	United States
44	Pearl Investigative Site	Peoria	Illinois	United States
45	Pearl Investigative Site	River Forest	Illinois	United States
46	Pearl Investigative Site	Anderson	Indiana	United States
47	Pearl Investigative Site	Avon	Indiana	United States
48	Pearl Investigative Site	Elwood	Indiana	United States
49	Pearl Investigative Site	Evansville	Indiana	United States
50	Pearl Investigative Site	Iowa City	Iowa	United States
51	Pearl Investigative Site	Topeka	Kansas	United States
52	Pearl Investigative Site	Louisville	Kentucky	United States
53	Pearl Investigative Site	Lafayette	Louisiana	United States
54	Pearl Investigative Site	Sunset	Louisiana	United States
55	Pearl Investigative Site	Baltimore	Maryland	United States
56	Pearl Investigative Site	Hollywood	Maryland	United States
57	Pearl Investigative Site	Livonia	Michigan	United States
58	Pearl Investigative Site	Southfield	Michigan	United States
59	Pearl Investigative Site	Edina	Minnesota	United States
60	Pearl Investigative Site	Fridley	Minnesota	United States
61	Pearl Investigative Site	Minneapolis	Minnesota	United States
62	Pearl Investigative Site	Woodbury	Minnesota	United States
63	Pearl Investigative Site	Springfield	Missouri	United States
64	Pearl Investigative Site	St Louis	Missouri	United States
65	Pearl Investigative Site	St. Charles	Missouri	United States
66	Pearl Investigative Site	Missoula	Montana	United States
67	Pearl Investigative Site	Bellevue	Nebraska	United States
68	Pearl Investigative Site	Omaha	Nebraska	United States
69	Pearl Investigative Site	Las Vegas	Nevada	United States
70	Pearl Investigative Site	Ocean	New Jersey	United States
71	Pearl Investigative Site	Albuquerque	New Mexico	United States
72	Pearl Investigative Site	Corning	New York	United States
73	Pearl Investigative Site	Burlington	North Carolina	United States
74	Pearl Investigative Site	Charlotte	North Carolina	United States
75	Pearl Investigative Site	Greensboro	North Carolina	United States
76	Pearl Investigative Site	Huntersville	North Carolina	United States
77	Pearl Investigative Site	Raleigh	North Carolina	United States
78	Pearl Investigative Site	Wilmington	North Carolina	United States
79	Pearl Investigative Site	Winston-Salem	North Carolina	United States
80	Pearl Investigative Site	Cincinnati	Ohio	United States
81	Pearl Investigative Site	Columbus	Ohio	United States
82	Pearl Investigative Site	Dayton	Ohio	United States
83	Pearl Investigative Site	Dublin	Ohio	United States
84	Pearl Investigative Site	Oregon	Ohio	United States
85	Pearl Investigative Site	Bend	Oregon	United States
86	Pearl Investigative Site	Medford	Oregon	United States
87	Pearl Investigative Site	Portland	Oregon	United States
88	Pearl Investigative Site	Monroeville	Pennsylvania	United States
89	Pearl Investigative Site	Philadelphia	Pennsylvania	United States
90	Pearl Investigative Site	Charleston	South Carolina	United States
91	Pearl Investigative Site	Easley	South Carolina	United States
92	Pearl Investigative Site	Gaffney	South Carolina	United States
93	Pearl Investigative Site	Greenville	South Carolina	United States
94	Pearl Investigative Site	Mt. Pleasant	South Carolina	United States
95	Pearl Investigative Site	Murrells Inlet	South Carolina	United States
96	Pearl Investigative Site	Myrtle Beach	South Carolina	United States
97	Pearl Investigative Site	Rock Hill	South Carolina	United States
98	Pearl Investigative Site	Spartanburg	South Carolina	United States
99	Pearl Investigative Site	Union	South Carolina	United States
100	Pearl Investigative Site	Rapid City	South Dakota	United States
101	Pearl Investigative Site	Bristol	Tennessee	United States
102	Pearl Investigative Site	Johnson City	Tennessee	United States
103	Pearl Investigative Site	Kingsport	Tennessee	United States
104	Pearl Investigative Site	Tullahoma	Tennessee	United States
105	Pearl Investigative Site	Austin	Texas	United States
106	Pearl Investigative Site	El Paso	Texas	United States
107	Pearl Investigative Site	Fort Worth	Texas	United States
108	Pearl Investigative Site	Houston	Texas	United States
109	Pearl Investigative Site	Huntsville	Texas	United States
110	Pearl Investigative Site	Longview	Texas	United States
111	Pearl Investigative Site	Lufkin	Texas	United States
112	Pearl Investigative Site	New Braunfels	Texas	United States
113	Pearl Investigative Site	San Antonio	Texas	United States
114	Pearl Investigative Site	Midvale	Utah	United States
115	Pearl Investigative Site	Salt Lake City	Utah	United States
116	Pearl Investigative Site	South Burlington	Vermont	United States
117	Pearl Investigative Site	Abingdon	Virginia	United States
118	Pearl Investigative Site	Richmond	Virginia	United States
119	Pearl Investigative Site	Spokane	Washington	United States
120	Pearl Investigative Site	Tacoma	Washington	United States
121	Pearl Investigative Site	Morgantown	West Virginia	United States
122	Pearl Investigative Site	West Allis	Wisconsin	United States
123	Pearl Investigative Site	New Lambton	New South Wales	Australia
124	Pearl Investigative Site	Westmead	New South Wales	Australia
125	Pearl Investigative Site	Brisbane	Queensland	Australia
126	Pearl Investigative Site	Cairns	Queensland	Australia
127	Pearl Investigative Site	Wooloongabba	Queensland	Australia
128	Pearl Investigative Site	Adelaide	South Australia	Australia
129	Pearl Investigative Site	Daw Park	South Australia	Australia
130	Pearl Investigative Site	Toorak Gardens	South Australia	Australia
131	Pearl Investigative Site	Box Hill	Victoria	Australia
132	Pearl Investigative Site	Heidelberg	Victoria	Australia
133	Pearl Investigative Site	Nedlands	Western Australia	Australia
134	Pearl Investigative Site	Perth	Western Australia	Australia
135	Pearl Investigative Site	Otahuhu	Aukland	New Zealand
136	Pearl Investigative Site	Caversham	Dunedin	New Zealand
137	Pearl Investigative Site	Greenlane	East Aukland	New Zealand
138	Pearl Investigative Site	Hamilton	Waikato	New Zealand
139	Pearl Investigative Site	Newtown	Wellington	New Zealand
140	Pearl Investigative Site	Tauranga		New Zealand

Sponsors and Collaborators

• Pearl Therapeutics, Inc.

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• PT003006-02 Protocol and Amendment-FINAL-Redacted

Publications

None provided.

• Responsible Party: Pearl Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT01854645
• Other Study ID Numbers: PT003006-00
• First Posted: May 15, 2013
• Last Update Posted: Mar 28, 2017
• Last Verified: Feb 1, 2017

• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Bromides; Tiotropium Bromide

Study Results

Participant Flow

Recruitment Details	Conducted at 160 sites throughout the US, Australia, and New Zealand from June 2013 - February 2015. Study participation was a maximum of 32 weeks.
Pre-assignment Detail	Study was a multicenter, randomized, double-blind, parallel group, chronic dosing, active- and placebo-controlled study; each patient was randomized to receive 1 of 5 possible treatments over the course of a 24-week treatment period

Arm/Group Title	GFF MDI (PT003)	GP MDI (PT001)	FF MDI (PT005)	Spiriva® Handihaler® (Open-label)	Placebo
Arm/Group Description	Glycopyrronium Formoterol Fumarate (GFF) Metered Dose Inhaler (MDI) 14.4/9.6 mcg	Glycopyrronium (GP) MDI 14.4 mcg	Formoterol Fumarate (FF) MDI 9.6 mcg	Open-label tiotropium bromide inhalation powder 18 mcg	Placebo MDI
Period Title: Overall Study
STARTED	527	451	452	453	220
COMPLETED	429	345	370	391	160
NOT COMPLETED	98	106	82	62	60

Baseline Characteristics

Arm/Group Title	GFF MDI (PT003)	GP MDI (PT001)	FF MDI (PT005)	Spiriva® Handihaler® (Open-label)	Placebo	Total
Arm/Group Description	Glycopyrronium Formoterol Fumarate (GFF) Metered Dose Inhaler (MDI) 14.4/9.6 mcg	Glycopyrronium (GP) MDI 14.4 mcg	Formoterol Fumarate (FF) MDI 9.6 mcg	Open-label tiotropium bromide inhalation powder 18 mcg	Placebo MDI	Total of all reporting groups
Overall Participants	526	451	449	451	219	2096
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.6 (8.4)	62.9 (8.4)	63.0 (8.3)	63.0 (8.6)	62.5 (8.3)	62.8 (8.4)
Sex: Female, Male (Count of Participants)
Female	236 44.9%	196 43.5%	203 45.2%	182 40.4%	97 44.3%	914 43.6%
Male	290 55.1%	255 56.5%	246 54.8%	269 59.6%	122 55.7%	1182 56.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24
Description	Change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) at Week 24
Time Frame	Baseline and at Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-Treat population with evaluable data (no imputation) for this outcome measure

Arm/Group Title	GFF MDI (PT003)	GP MDI (PT001)	FF MDI (PT005)	Spiriva® Handihaler® (Open-label)	Placebo
Arm/Group Description	Glycopyrronium Formoterol Fumarate (GFF) Metered Dose Inhaler (MDI) 14.4/9.6 mcg	Glycopyrronium (GP) MDI 14.4 mcg	Formoterol Fumarate (FF) MDI 9.6 mcg	Open-label tiotropium bromide inhalation powder 18 mcg	Placebo MDI
Measure Participants	429	344	367	390	161
Least Squares Mean (95% Confidence Interval) [Liters]	0.126	0.066	0.062	0.105	-0.024

2. Secondary Outcome

Title	Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks
Description	Change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) over 24 weeks. FEV1 was assessed at multiple time points post-baseline,and a modelbased average of all visits starting from Week 2 through week 24 inclusive was calculated. The change values reported in the table represent the change between the baseline and the average FEV1 post-baseline.
Time Frame	Baseline and Weeks 2 to 24

Outcome Measure Data

Analysis Population Description

Intent-to-Treat population with evaluable data (no imputation) for this outcome measure

Arm/Group Title	GFF MDI (PT003)	GP MDI (PT001)	FF MDI (PT005)	Spiriva® Handihaler® (Open-label)	Placebo
Arm/Group Description	Glycopyrronium Formoterol Fumarate (GFF) Metered Dose Inhaler (MDI) 14.4/9.6 mcg	Glycopyrronium (GP) MDI 14.4 mcg	Formoterol Fumarate (FF) MDI 9.6 mcg	Open-label tiotropium bromide inhalation powder 18 mcg	Placebo MDI
Measure Participants	519	440	439	446	208
Least Squares Mean (95% Confidence Interval) [Liters]	0.150	0.091	0.086	0.122	-0.007

3. Secondary Outcome

Title	St. George's Respiratory Questionnaire (SGRQ) Score
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	Baseline and at Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-Treat population with evaluable data (no imputation) for this outcome measure

Arm/Group Title	GFF MDI (PT003)	GP MDI (PT001)	FF MDI (PT005)	Spiriva® Handihaler® (Open-label)	Placebo
Arm/Group Description	Glycopyrronium Formoterol Fumarate (GFF) Metered Dose Inhaler (MDI) 14.4/9.6 mcg	Glycopyrronium (GP) MDI 14.4 mcg	Formoterol Fumarate (FF) MDI 9.6 mcg	Open-label tiotropium bromide inhalation powder 18 mcg	Placebo MDI
Measure Participants	503	425	434	435	213
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	-3.1	-1.2	-2.4	-2.7	-0.8

4. Secondary Outcome

Title	Rescue Ventolin Hydrofluoroalkane (HFA) Use
Description	Change from baseline in average daily rescue Ventolin HFA use
Time Frame	Baseline and at Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-Treat population with evaluable data (no imputation) for this outcome measure

Arm/Group Title	GFF MDI (PT003)	GP MDI (PT001)	FF MDI (PT005)	Spiriva® Handihaler® (Open-label)	Placebo
Arm/Group Description	Glycopyrronium Formoterol Fumarate (GFF) Metered Dose Inhaler (MDI) 14.4/9.6 mcg	Glycopyrronium (GP) MDI 14.4 mcg	Formoterol Fumarate (FF) MDI 9.6 mcg	Open-label tiotropium bromide inhalation powder 18 mcg	Placebo MDI
Measure Participants	525	449	446	449	218
Least Squares Mean (95% Confidence Interval) [Puffs / Day]	-0.8	-0.5	-0.8	-0.4	0.3

5. Secondary Outcome

Title	Onset of Action as Assessed by FEV1
Description	Defined as the first time-point using the 5- and 15-minute post dose measurements where the difference in FEV1 from Placebo was statistically significant
Time Frame	Assessed for 5- and 15-minute post dose on Day 1

Outcome Measure Data

Analysis Population Description

Intent-to-Treat population with evaluable data (no imputation) for this outcome measure

Arm/Group Title	GFF MDI (PT003)	GP MDI (PT001)	FF MDI (PT005)	Spiriva® Handihaler® (Open-label)	Placebo
Arm/Group Description	Glycopyrronium Formoterol Fumarate (GFF) Metered Dose Inhaler (MDI) 14.4/9.6 mcg	Glycopyrronium (GP) MDI 14.4 mcg	Formoterol Fumarate (FF) MDI 9.6 mcg	Open-label tiotropium bromide inhalation powder 18 mcg	Placebo MDI
Measure Participants	418	363	366	364	172
5 min post dose	0.185	0.042	0.182	0.048	-0.002
15 min post dose	0.226	0.101	0.212	0.117	0.022

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GFF MDI (PT003), Placebo
	Comments	At 5 min post dose
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GFF MDI (PT003), Placebo
	Comments	At 15 min post dose
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	GP MDI (PT001), Placebo
	Comments	At 5 min post dose
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	GP MDI (PT001), Placebo
	Comments	At 15 min post dose
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	FF MDI (PT005), Placebo
	Comments	At 5 min post dose
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	FF MDI (PT005), Placebo
	Comments	At 15 min post dose
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

6. Secondary Outcome

Title	Peak Change From Baseline in FEV1 Within 2 Hours Post-dose
Description	Peak change from baseline in forced expiratory volume in 1 second (FEV1) within 2 hours post-dose
Time Frame	Baseline and at Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-Treat population with evaluable data (no imputation) for this outcome measure

Arm/Group Title	GFF MDI (PT003)	GP MDI (PT001)	FF MDI (PT005)	Spiriva® Handihaler® (Open-label)	Placebo
Arm/Group Description	Glycopyrronium Formoterol Fumarate (GFF) Metered Dose Inhaler (MDI) 14.4/9.6 mcg	Glycopyrronium (GP) MDI 14.4 mcg	Formoterol Fumarate (FF) MDI 9.6 mcg	Open-label tiotropium bromide inhalation powder 18 mcg	Placebo MDI
Measure Participants	428	343	367	388	160
Least Squares Mean (95% Confidence Interval) [Liters]	0.356	0.223	0.263	0.259	0.065

Adverse Events

Time Frame	SAEs and AEs were collected throughout study participation and for two weeks after study completion.
Adverse Event Reporting Description	Safety population included all participants who received at least one dose of investigational drug participants were included in safety population according to the investigational drug received
Arm/Group Title	GFF MDI (PT003)		GP MDI (PT001)		FF MDI (PT005)		Spiriva® Handihaler® (Open-label)		Placebo
Arm/Group Description	Glycopyrronium Formoterol Fumarate (GFF) Metered Dose Inhaler (MDI) 14.4/9.6 mcg		Glycopyrronium (GP) MDI 14.4 mcg		Formoterol Fumarate (FF) MDI 9.6 mcg		Open-label tiotropium bromide inhalation powder 18 mcg		Placebo MDI
All Cause Mortality
	GFF MDI (PT003)		GP MDI (PT001)		FF MDI (PT005)		Spiriva® Handihaler® (Open-label)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	GFF MDI (PT003)		GP MDI (PT001)		FF MDI (PT005)		Spiriva® Handihaler® (Open-label)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	44/526 (8.4%)		36/451 (8%)		29/452 (6.4%)		36/451 (8%)		16/220 (7.3%)
Blood and lymphatic system disorders
Anaemia	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Cardiac disorders
Coronary artery disease	1/526 (0.2%)	1	1/451 (0.2%)	1	0/452 (0%)	0	1/451 (0.2%)	1	1/220 (0.5%)	1
Acute myocardial infarction	1/526 (0.2%)	1	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	1/220 (0.5%)	1
Atrial fibrillation	1/526 (0.2%)	1	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Myocardial infarction	1/526 (0.2%)	1	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Cardiac failure congestive	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	3	0/220 (0%)	0
Atrial flutter	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Atrial tachycardia	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Atrioventricular block complete	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	1/220 (0.5%)	1
Bradycardia	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Cardiac arrest	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Coronary artery occlusion	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Ischaemic cardiomyopathy	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Myocardial ischaemia	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	1/220 (0.5%)	1
Endocrine disorders
Hyperparathyroidism	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/526 (0.2%)	1	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Abdominal pain lower	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Constipation	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Enteritis	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Intestinal obstruction	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Pancreatitis chronic	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Small intestinal obstruction	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Upper gastrointestinal haemorrhage	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
General disorders
Chest pain	1/526 (0.2%)	1	2/451 (0.4%)	2	1/452 (0.2%)	1	0/451 (0%)	0	2/220 (0.9%)	2
Inflamation	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Pyrexia	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Sudden cardiac death	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Hepatobiliary disorders
Cholecystitis acute	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Infections and infestations
Pneumonia	8/526 (1.5%)	8	7/451 (1.6%)	7	0/452 (0%)	0	1/451 (0.2%)	1	1/220 (0.5%)	1
Cellulitis	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	2/451 (0.4%)	2	1/220 (0.5%)	1
Lobar pneumonia	2/526 (0.4%)	2	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Sepsis	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Bronchitis	0/526 (0%)	0	1/451 (0.2%)	2	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Atypical pneumonia	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Diverticulitis	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Influenza	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Opthalmic herpes zoster	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Postoperative wound infection	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Pyelonephritis	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	1/220 (0.5%)	1
Rhinovirus infection	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Injury, poisoning and procedural complications
Alcohol poisoning	0/526 (0%)	0	2/451 (0.4%)	2	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Fall	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	1/451 (0.2%)	1	0/220 (0%)	0
Fibula fracture	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Afferent loop syndrome	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	1/220 (0.5%)	1
Femoral neck fracture	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Gun shot wound	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Humerus fracture	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Overdose	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Pneumothorax traumatic	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Radius fracture	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Splenic rupture	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Thermal burn	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Metabolism and nutrition disorders
Diabetes mellitus	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Diabetic ketoacidosis	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Hyperglycaemia	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Musculoskeletal and connective tissue disorders
Intervertebral disc degeneration	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Spinal pain	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of lung	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	3/451 (0.7%)	3	0/220 (0%)	0
Lung adenocarcinoma	1/526 (0.2%)	1	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Breast cancer	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Chronic lymphocytic leukaemia	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	1/220 (0.5%)	1
Laryngeal cancer	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Laryngeal cancer stage 0	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Lung neoplasm malignant	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Malignant melanoma	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Metastatic neoplasm	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Oesophageal adenocarcinoma	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Small cell lung cancer metastatic	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Squamous cell carcinoma of skin	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Squamous cell carcinoma of the oral cavity	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Translational cell carcinoma	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Nervous system disorders
Transient ischaemic attack	0/526 (0%)	0	1/451 (0.2%)	1	1/452 (0.2%)	1	1/451 (0.2%)	1	0/220 (0%)	0
Cerebrovascular accident	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Generalised tonic-clonic seizure	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Syncope	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Psychiatric disorders
Anxiety	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Completed suicide	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Depression	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Homicidal ideation	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Intentional self-injury	0/1 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	1/451 (0.2%)	1	0/220 (0%)	0
Suicide attempt	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Renal and urinary disorders
Bladder cyst	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Reproductive system and breast disorders
Epididymal cyst	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	15/526 (2.9%)	15	17/451 (3.8%)	20	8/452 (1.8%)	8	8/451 (1.8%)	8	7/220 (3.2%)	7
Acute respiratory failure	0/526 (0%)	0	1/451 (0.2%)	1	2/452 (0.4%)	2	0/451 (0%)	0	0/220 (0%)	0
Pulmonary embolism	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	1/220 (0.5%)	1
Acute respiratory distress syndrome	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Bronchospasm	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Epistatxis	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	1/220 (0.5%)	1
Pleurisy	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Pulmonary oedema	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Respiratory failure	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Skin and subcutaneous tissue disorders
Angioedema	0/526 (0%)	0	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	1/220 (0.5%)	1
Vascular disorders
Aortic aneurysm	0/526 (0%)	0	0/451 (0%)	0	2/452 (0.4%)	2	0/451 (0%)	0	0/220 (0%)	0
Deep vein thrombosis	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	1/451 (0.2%)	1	0/220 (0%)	0
Peripheral vascular disorder	1/526 (0.2%)	1	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Aortic dissection	0/526 (0%)	0	1/451 (0.2%)	1	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Hypertensive crisis	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Hypotension	0/526 (0%)	0	0/451 (0%)	0	1/452 (0.2%)	1	0/451 (0%)	0	0/220 (0%)	0
Peripheral artery stenosis	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Thrombophlebitis superficial	1/526 (0.2%)	1	0/451 (0%)	0	0/452 (0%)	0	0/451 (0%)	0	0/220 (0%)	0
Other (Not Including Serious) Adverse Events
	GFF MDI (PT003)		GP MDI (PT001)		FF MDI (PT005)		Spiriva® Handihaler® (Open-label)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	73/526 (13.9%)		59/451 (13.1%)		57/452 (12.6%)		58/451 (12.9%)		47/220 (21.4%)
Infections and infestations
Nasopharyngitis	43/526 (8.2%)	45	23/451 (5.1%)	24	28/452 (6.2%)	32	26/451 (5.8%)	26	18/220 (8.2%)	21
Upper respiratory tract infection	17/526 (3.2%)	18	20/451 (4.4%)	21	14/452 (3.1%)	14	17/451 (3.8%)	18	16/220 (7.3%)	16
Respiratory, thoracic and mediastinal disorders
Dyspnoea	13/526 (2.5%)	13	16/451 (3.5%)	19	15/452 (3.3%)	16	15/451 (3.3%)	15	13/220 (5.9%)	14

Limitations/Caveats

[Not Specified]

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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 its opinions, or the opinions of the publication committee, if these differ with the proposed publication.