Efficacy and Safety Trial of 12 Weeks of Treatment With Nebulized SUN-101 in Patients With COPD (GOLDEN-4)

• Sponsor: Sunovion Respiratory Development Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02347774
• Collaborator: (none)
• Enrollment: 641
• Locations: 45
• Arms: 3
• Duration (Months): 10
• Patients Per Site: 14.2
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

This is a trial of 12 weeks of treatment with nebulized SUN-101 using an Investigational eFlow® Closed System (CS) nebulizer in subjects with chronic obstructive pulmonary disease (COPD) according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD 2014) guidelines.

Condition or Disease	Intervention/Treatment	Phase
COPD; Chronic Obstructive Pulmonary Disease	Drug: SUN-101 50 mcg BID eFlow (CS) nebulizer; Drug: SUN-101 25 mcg BID eFlow (CS) nebulizer; Drug: Placebo eFlow (CS) nebulizer	Phase 3

Detailed Description

This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter, efficacy and safety trial of 12 weeks of treatment with nebulized SUN-101 using an Investigational eFlow® Closed System (CS) nebulizer in approximately 645 subjects with chronic obstructive pulmonary disease (COPD) according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD 2014) guidelines.

SUN-101 or placebo will be administered twice daily as an oral inhalation using the investigational eFlow CS nebulizer.

Study Design

• Study Type: Interventional
• Actual Enrollment: 641 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Efficacy and Safety Trial of 12 Weeks of Treatment With Nebulized SUN-101 in Patients With COPD: GOLDEN-4 (Glycopyrrolate for Obstructive Lung Disease Via Electronic Nebulizer
• Study Start Date: Feb 1, 2015
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SUN-101 50 mcg BID eFlow (CS) nebulizer SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer	Drug: SUN-101 50 mcg BID eFlow (CS) nebulizer; SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer
Experimental: SUN-101 25 mcg BID e-Flow (CS) nebulizer SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer	Drug: SUN-101 25 mcg BID eFlow (CS) nebulizer; SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer
Placebo Comparator: Placebo BID Eflow (CS) nebulizer Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer	Drug: Placebo eFlow (CS) nebulizer; Placebo BID eFlow (R) Closed System (CS) nebulizer

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 [baseline and Week 12]

   All collected Spirometry was performed according to internationally accepted standards. Trough FEV1 at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. All collected values were used in this analyses, regardless if the subject remained on randomized treatment or not, and regardless if the values might potentially be affected by other therapies or not Values not collected remained as missing values and were assumed to be missing at random (MAR).

2. Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) Week 12 [Week 12]

   On-treatment Spirometry was performed according to internationally accepted standards. Trough FEV1 at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. Only on-treatment values (which included only data collected while subjects were taking study drug) are used for this analysis. Values affected by other medication use were set to missing. Non-collected or missing data were not imputed for this analysis. Values not collected remained as missing values and were assumed to be missing at random (MAR).

Secondary Outcome Measures

1. Change From Baseline in Trough Forced Vital Capacity (FVC) at Week 12 [baseline and Week 12]

   All collected Spirometry was performed according to internationally accepted standards. Trough FVC at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. All collected values were used in the analyses, regardless if the subject remained on randomized treatment or not, and regardless if the values might potentially be affected by other therapies or not Values not collected remained as missing values and were assumed to be missing at random (MAR).

2. Change From Baseline in Trough Forced Vital Capacity (FVC)Week 12 [baseline and Week 12]

   On-treatment Spirometry was performed according to internationally accepted standards. Trough FVC at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. Only on-treatment values (which included only data collected while subjects were taking study drug) are used for this analysis. Values affected by other medication use were set to missing. Non-collected or missing data were not imputed for this analysis. Values not collected remained as missing values and were assumed to be missing at random (MAR).

3. Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) at Week 12/End of Study [baseline and Week 12]

   All collected Participants reported change in health status by using the SGRQ. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: symptoms, activity, and impacts. A score was calculated for each of these 3 subscales and a "Total" score was calculated. In each case the lowest possible value is 0 and the highest 100. Higher values correspond to greater impairment of health status. All collected values were used in the analyses, regardless if the subject remained on randomized treatment or not. Values not collected remained as missing values and were assumed to be missing at random (MAR).

4. Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) Week 12/End of Study [baseline and Week 12]

   On-treatment Participants reported change in health status by using the SGRQ. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: symptoms, activity, and impacts. A score was calculated for each of these 3 subscales and a "Total" score was calculated. In each case the lowest possible value is 0 and the highest 100. Higher values correspond to greater impairment of health status. Only on-treatment values (which included only data collected while subjects were taking study drug) are used for this analysis. Values affected by other medication use were set to missing. Non-collected or missing data were not imputed for this analysis. Values not collected remained as missing values and were assumed to be missing at random (MAR).

5. Change in Number of Rescue Medication Puffs Per Day Over the 12-week Double-blind Treatment Period [Week 0-12]

   All collected Participants completed an electronic diary (eDiary) daily (night time) to record the number of puffs of rescue medication inhaled in the previous 24 hours. A negative change from baseline indicates improvement. All collected values were used in the analyses, regardless if the subject remained on randomized treatment or not. Values not collected remained as missing values and were assumed to be missing at random (MAR).

6. Number of Subjects With Treatment Emergent Adverse Events (TEAE) [Week 0-12]

   On-treatment A TEAE is defined as any non-serious AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE.

7. Percentage of Subjects With Treatment Emergent Adverse Events (TEAE) [Week 0-12]

   A TEAE is defined as any non-serious AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE.

8. Number of Subjects With Treatment Emergent Serious Adverse Events (SAE) [Week 0-12]

   A treatment emergent SAE is defined as any SAE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent SAE is an on-treatment SAE.

9. Percentage of Subjects With Treatment Emergent Serious Adverse Events (SAE) [Week 0-12]

   A treatment emergent SAE is defined as any SAE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent SAE is an on-treatment SAE.

10. Number of Subjects Who Discontinue Treatment Due to TEAE [Week 0-12]

    A TEAE is defined as any AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE.

11. Percentage of Subjects Who Discontinue Treatment Due to TEAE [Week 0-12]

    A TEAE is defined as any AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE.

12. Number of Subjects With Major Adverse Cardiac Events (MACE) [Week 0-12]

    All deaths and any other findings suggestive of a potential MACE (including clinically relevant information and SAEs, and all PTs form the SMQs "myocardial infarction", "other ischemic heart disease", "central nervous system hemorrhages and cerebrovascular conditions") were sent to an adjudication committee for review and categorized as CV death, nonfatal MI, and nonfatal stroke. The MACE score was defined as the total number of subjects with CV deaths, nonfatal MIs, and nonfatal strokes. These events were collected for the double-blind period (from the first date of study medication until the date of last contact)

13. Percentage of Subjects With Major Adverse Cardiac Events (MACE) [Week 0-12]

    All deaths and any other findings suggestive of a potential MACE (including clinically relevant information and SAEs, and all PTs form the SMQs "myocardial infarction", "other ischemic heart disease", "central nervous system hemorrhages and cerebrovascular conditions") were sent to an adjudication committee for review and categorized as CV death, nonfatal MI, and nonfatal stroke. The MACE score was defined as the total number of subjects with CV deaths, nonfatal MIs, and nonfatal strokes. These events were collected for the double-blind period (from the first date of study medication until the date of last contact)

14. Incidence Rate Per 1000 Person-years of Subjects With Major Adverse Cardiac Events (MACE) [Week 0-12]

    All deaths and any other findings suggestive of a potential MACE (including clinically relevant information and SAEs, and all PTs form the SMQs "myocardial infarction", "other ischemic heart disease", "central nervous system hemorrhages and cerebrovascular conditions") were sent to an adjudication committee for review and categorized as CV death, nonfatal MI, and nonfatal stroke. The MACE score was defined as the total number of subjects with CV deaths, nonfatal MIs, and nonfatal strokes. These events were collected for the double-blind period (from the first date of study medication until the date of last contact) Incidence rate: TT= Total Time in years. Total Time (TT) is defined as the time from the first date of study drug until the latter of the date of last contact or 30 days after the date of last dose. Incidence Rate (per 1000 person-years) = n/TT x 1000.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Male or female patients age ≥ 40 years, inclusive

2. A clinical diagnosis of COPD according to the GOLD 2014 guidelines

3. Current smokers or ex-smokers with at least 10 pack-year smoking history (eg, at least 1 pack/day for 10 years, or equivalent)

4. Post-bronchodilator (following inhalation of ipratropium bromide) FEV1 < 80% of predicted normal and > 0.7 L during Screening (Visit 1)

5. Post-bronchodilator (following inhalation of ipratropium bromide) FEV1/FVC ratio < 0.70 during Screening (Visit 1)

6. Ability to perform reproducible spirometry according to the American Thoracic Society (ATS) and European Respiratory Society (ERS) guidelines (2005)

7. Subject, if female ≤ 65 years of age and of child bearing potential, must have a negative serum pregnancy test at Visit 1. Females of childbearing potential must be instructed to and agree to avoid pregnancy during the study and must use an acceptable method of birth control: a) an oral contraceptive, an intrauterine device (IUD), implantable contraceptive, transdermal or injectable contraceptive for at least 1 month prior to entering the study with continued use throughout the study and for thirty days following participation; b) barrier method of contraception, eg, condom and /or diaphragm with spermicide while participating in the study; and/or c) abstinence

8. Willing and able to provide written informed consent

9. Willing and able to attend all study visits and adhere to all study assessments and procedures

Exclusion Criteria:

1. Severe comorbidities including unstable cardiac or pulmonary disease or any other medical conditions that would, in the opinion of the Investigator, preclude the subject from safely completing the required tests or the study, or is likely to result in disease progression that would require withdrawal of the subject

2. Concomitant clinically significant respiratory disease other than COPD (eg, asthma, tuberculosis, bronchiectasis or other non-specific pulmonary disease).

3. Recent history of COPD exacerbation requiring hospitalization or need for increased treatments for COPD within 6 weeks prior to Screening (Visit 1).

4. Use of daily oxygen therapy > 12 hours per day

5. Respiratory tract infection within 6 weeks prior to Screening (Visit 1)

6. Use of oral, intravenous, or intramuscular steroids within 3 months prior to Screening (Visit 1)

7. History of malignancy of any organ system, treated or untreated within the past 5 years, with the exception of localized basal cell carcinoma of the skin

8. Prolonged QTcF (> 450 msec for males and > 470 msec for females) during Screening (Visit 1) as determined from the report provided by the central laboratory, or history of long QT syndrome

9. History of or clinically significant on-going bladder outflow obstruction or history of catheterization for relief of bladder outflow obstruction within the previous 6 months

10. History of narrow angle glaucoma

11. History of hypersensitivity or intolerance to aerosol medications

12. Recent documented history (within the previous 3 months) of substance abuse

13. Significant psychiatric disease that would likely result in the subject not being able to complete the study, in the opinion of the Investigator

14. Participation in another investigational drug study where drug was received within 30 days prior to Screening (Visit 1) or current participation in another investigational drug trial, including a SUN-101 study

15. Previously received SUN-101 (active treatment; formerly known as EP-101)

16. Contraindicated for treatment with, or having a history of reactions/hypersensitivity to anticholinergic agents, beta2 agonists, or sympathomimetic amines

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	SEC Lung, LLC	Andalusia	Alabama	United States	36420
2	Jasper Summit Research, LLC	Jasper	Alabama	United States	35501
3	Pulmonary Associates, PA	Glendale	Arizona	United States	85306
4	Phoenix Medical Research Institute, LLC	Peoria	Arizona	United States	85381
5	Clinical Research Consortium	Tempe	Arizona	United States	85283
6	Center for Clinical Trials of Sacramento, Inc.	Sacramento	California	United States	95823
7	Institute of HealthCare Assessment, Inc	San Diego	California	United States	92120
8	Innovative Clinical Research	Broomfield	Colorado	United States	80023
9	IMMUNOe International Research Centers	Centennial	Colorado	United States	80112
10	Longmont Pulmonary and Critical Care	Longmont	Colorado	United States	80501
11	Ribo Research, LLC dba Peninsula Research Inc.	Ormond Beach	Florida	United States	32174
12	Progressive Medical Research	Port Orange	Florida	United States	32127
13	Pulmonary Care Research Group, PA	Winter Park	Florida	United States	32789
14	Atlanta Center for Medical Research	Atlanta	Georgia	United States	30331
15	Duluth Biomedical Research, LLC	Duluth	Georgia	United States	30096
16	Southeast Regional Research Group	Rincon	Georgia	United States	31326
17	Asthma and Allergy Center of Chicago, SC	River Forest	Illinois	United States	60305
18	LaPorte County Institute for Clinical Research	Michigan City	Indiana	United States	46360
19	George Stanley Walker, MD	New Orleans	Louisiana	United States	70115
20	Minnesota Lung Center	Minneapolis	Minnesota	United States	55407
21	CAR.E. Clinical Research	Saint Louis	Missouri	United States	63141
22	The Clinical Research Center, LLC	Saint Louis	Missouri	United States	63141
23	Delaware Valley Clinical Research	Marlton	New Jersey	United States	08053
24	Clinical Research of Gastonia	Gastonia	North Carolina	United States	28054
25	PharmQuest	Greensboro	North Carolina	United States	27408
26	Clinical Research of Lake Norman	Huntersville	North Carolina	United States	28078
27	PMG Research of Raleigh, LLC	Raleigh	North Carolina	United States	27609
28	Southeastern Research Center, LLC	Winston-Salem	North Carolina	United States	27103
29	Liliestol Research LLC	Fargo	North Dakota	United States	58103
30	New Horizons Clinical Research	Cincinnati	Ohio	United States	45242
31	Remington-Davis, Inc	Columbus	Ohio	United States	43215
32	Sridhar Guduri, MD	Dublin	Ohio	United States	43016
33	IPS Research Company	Oklahoma City	Oklahoma	United States	73103
34	Allergy Associates Research Center	Portland	Oregon	United States	97202
35	Lowcountry Lung and Critical Care, PA	Charleston	South Carolina	United States	29406
36	Easley Clinical Research	Easley	South Carolina	United States	29640
37	Gaffney Pharmaceutical Research	Gaffney	South Carolina	United States	29340
38	Spectrum Medical Research, LLC	Gaffney	South Carolina	United States	29341
39	Clinical Research of Charleston	Mount Pleasant	South Carolina	United States	29464
40	CU Pharmaceutical Research	Rock Hill	South Carolina	United States	29732
41	Hope Clinical Research	Seneca	South Carolina	United States	29678
42	New Phase Research & Development	Knoxville	Tennessee	United States	37919
43	Health Research of Hampton Roads, Inc.	Newport News	Virginia	United States	23606
44	Pulmonary Associates of Richmond, Inc	Richmond	Virginia	United States	23229
45	Multicare Pulmonary Specialists	Tacoma	Washington	United States	98405

Sponsors and Collaborators

• Sunovion Respiratory Development Inc.

Investigators

• Study Director: Respiratory Medical Director, MD, Sunovion Respiratory Development

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sunovion Respiratory Development Inc.
• ClinicalTrials.gov Identifier: NCT02347774
• Other Study ID Numbers: SUN101-302
• First Posted: Jan 27, 2015
• Last Update Posted: Mar 13, 2018
• Last Verified: Feb 1, 2018

• Keywords provided by Sunovion Respiratory Development Inc.: Chronic Obstructive Pulmonary Disease; COPD
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive

Study Results

Participant Flow

Pre-assignment Detail	All enrolled were randomized. All subjects were to be followed for the full 12-week treatment period of the study, whether or not they continued on the study drug, .until the end of the treatment period. One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Period Title: Study Participation
STARTED	214	214	213
COMPLETED	199	193	188
NOT COMPLETED	15	21	25
Period Title: Study Participation
STARTED	214	214	213
COMPLETED	190	183	177
NOT COMPLETED	24	31	36

Baseline Characteristics

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer	Total
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer	Total of all reporting groups
Overall Participants	214	214	212	640
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	119 55.6%	109 50.9%	111 52.4%	339 53%
>=65 years	95 44.4%	105 49.1%	101 47.6%	301 47%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.6 (9.20)	63.6 (8.66)	63.7 (9.26)	63.3 (9.04)
Sex: Female, Male (Count of Participants)
Female	87 40.7%	90 42.1%	88 41.5%	265 41.4%
Male	127 59.3%	124 57.9%	124 58.5%	375 58.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 1.4%	2 0.9%	3 1.4%	8 1.3%
Not Hispanic or Latino	211 98.6%	212 99.1%	209 98.6%	632 98.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.5%	0 0%	1 0.2%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	1 0.5%	1 0.2%
Black or African American	26 12.1%	27 12.6%	19 9%	72 11.3%
White	188 87.9%	185 86.4%	192 90.6%	565 88.3%
More than one race	0 0%	1 0.5%	0 0%	1 0.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	214 100%	214 100%	212 100%	640 100%
Cardiovascular risk (low/high) and categories for high cardiovascular risk (participants) [Number]
low cardiovascular risk	80 37.4%	78 36.4%	76 35.8%	234 36.6%
high cardiovascular risk	134 62.6%	136 63.6%	136 64.2%	406 63.4%
ischemic heart disease	20 9.3%	24 11.2%	20 9.4%	64 10%
cerebrovascular disease	10 4.7%	8 3.7%	9 4.2%	27 4.2%
peripheral arterial disease	7 3.3%	9 4.2%	17 8%	33 5.2%
clinically significant arrhythmia	8 3.7%	7 3.3%	6 2.8%	19 3%
heart failure	4 1.9%	4 1.9%	6 2.8%	14 2.2%
hypertension	124 57.9%	123 57.5%	125 59%	372 58.1%
Background long-acting beta(2) agonist (LABA) use (participants) [Number]
background LABA use = yes	67 31.3%	69 32.2%	69 32.5%	205 32%
background LABA use = no	147 68.7%	145 67.8%	143 67.5%	435 68%
Forced expiratory volume in one second (FEV1) (liters) [Least Squares Mean (Standard Deviation) ]
Least Squares Mean (Standard Deviation) [liters]	1.3506 (0.55380)	1.3232 (0.50179)	1.13355 (0.48612)	1.3365 (0.51414)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12
Description	All collected Spirometry was performed according to internationally accepted standards. Trough FEV1 at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. All collected values were used in this analyses, regardless if the subject remained on randomized treatment or not, and regardless if the values might potentially be affected by other therapies or not Values not collected remained as missing values and were assumed to be missing at random (MAR).
Time Frame	baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) Population: all subjects who were randomized to treatment and received at least one dose of study medication. Subjects were analyzed based on the treatment they were randomized to.One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
Least Squares Mean (Standard Error) [liters]	0.0847 (0.01423)	0.0921 (0.01446)	0.0111 (0.01452)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SUN-101 50 mcg BID eFlow (CS) Nebulizer, Placebo BID Eflow (CS) Nebulizer
	Comments	The change from baseline in trough FEV1 was analyzed using a mixed model repeated measures including terms for treatment, cardiovascular risk, background LABA use, visit week, visit week by treatment interaction, and baseline FEV1 as a covariate. An unstructured covariance matrix was used.
	Type of Statistical Test	Superiority
	Comments	A sample size of 215 subjects per treatment would give ~ 90% power to detect a treatment difference of 80 mL in the change from baseline in trough FEV1 at Week 12 between each of the 2 SUN-101 dose groups and placebo at alpha= 0.05, assuming a standard deviation of 255 mL and using a 2-sided test.
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Least Mean Squared (SE)
	Comments
Method of Estimation	Estimation Parameter	Least Mean Squared (SE)
	Estimated Value	0.0736
	Confidence Interval	(2-Sided) 95%; 0.0346 to 0.1127
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.01989
	Estimation Comments	In order to control the family-wise Type I error rate, the Hochberg procedure (a tree-structured gatekeeping procedure) was used for comparisons of the primary efficacy endpoints and the key secondary efficacy endpoints.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	SUN-101 25 mcg BID e-Flow (CS) Nebulizer, Placebo BID Eflow (CS) Nebulizer
	Comments	The change from baseline in trough FEV1 was analyzed using a mixed model repeated measures including terms for treatment, cardiovascular risk, background LABA use, visit week, visit week by treatment interaction, and baseline FEV1 as a covariate. An unstructured covariance matrix was used.
	Type of Statistical Test	Superiority
	Comments	A sample size of 215 subjects per treatment would give ~ 90% power to detect a treatment difference of 80 mL in the change from baseline in trough FEV1 at Week 12 between each of the 2 SUN-101 dose groups and placebo at alpha= 0.05, assuming a standard deviation of 255 mL and using a 2-sided test.
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Least Mean Squared (SE)
	Comments
Method of Estimation	Estimation Parameter	Least Mean Squared (SE)
	Estimated Value	0.0810
	Confidence Interval	(2-Sided) 95%; 0.0416 to 0.1204
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.02006
	Estimation Comments	In order to control the family-wise Type I error rate, the Hochberg procedure (a tree-structured gatekeeping procedure) was used for comparisons of the primary efficacy endpoints and the key secondary efficacy endpoints.

2. Primary Outcome

Title	Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) Week 12
Description	On-treatment Spirometry was performed according to internationally accepted standards. Trough FEV1 at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. Only on-treatment values (which included only data collected while subjects were taking study drug) are used for this analysis. Values affected by other medication use were set to missing. Non-collected or missing data were not imputed for this analysis. Values not collected remained as missing values and were assumed to be missing at random (MAR).
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) Population: all subjects who were randomized to treatment and received at least one dose of study medication. Subjects were analyzed based on the treatment they were randomized to.

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
Least Squares Mean (Standard Error) [liters]	0.0890 (0.01479)	0.0909 (0.01492)	0.0069 (0.01502)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SUN-101 50 mcg BID eFlow (CS) Nebulizer, Placebo BID Eflow (CS) Nebulizer
	Comments	The change from baseline in trough FEV1 was analyzed using a mixed model repeated measures model including terms for treatment, cardiovascular risk, background LABA use, visit week, visit week by treatment interaction, and baseline FEV1 as a covariate. An unstructured covariance matrix was used.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	In order to control the family-wise Type I error rate, the Hochberg procedure (a tree-structured gatekeeping procedure) was used for comparisons of the primary efficacy endpoints and the key secondary efficacy endpoints.
	Method	Least Mean Squared (SE)
	Comments	I
Method of Estimation	Estimation Parameter	Least Mean Squared (SE)
	Estimated Value	0.0820
	Confidence Interval	(2-Sided) 95%; 0.0417 to 0.1224
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.02055
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	SUN-101 25 mcg BID e-Flow (CS) Nebulizer, Placebo BID Eflow (CS) Nebulizer
	Comments	The change from baseline in trough FEV1 was analyzed using a mixed model repeated measures model including terms for treatment, cardiovascular risk, background LABA use, visit week, visit week by treatment interaction, and baseline FEV1 as a covariate. An unstructured covariance matrix was used.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	In order to control the family-wise Type I error rate, the Hochberg procedure (a tree-structured gatekeeping procedure) was used for comparisons of the primary efficacy endpoints and the key secondary efficacy endpoints.
	Method	Least Mean Squared (SE)
	Comments
Method of Estimation	Estimation Parameter	Least Mean Squared (SE)
	Estimated Value	0.0840
	Confidence Interval	(2-Sided) 95%; 0.0433 to 0.1246
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.02069
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Trough Forced Vital Capacity (FVC) at Week 12
Description	All collected Spirometry was performed according to internationally accepted standards. Trough FVC at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. All collected values were used in the analyses, regardless if the subject remained on randomized treatment or not, and regardless if the values might potentially be affected by other therapies or not Values not collected remained as missing values and were assumed to be missing at random (MAR).
Time Frame	baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) Population: all subjects who were randomized to treatment and received at least one dose of study medication. Subjects were analyzed based on the treatment they were randomized to. One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
Least Squares Mean (Standard Error) [liters]	0.1090 (0.02205)	0.1346 (0.2239)	0.0156 (0.02247)

4. Secondary Outcome

Title	Change From Baseline in Trough Forced Vital Capacity (FVC)Week 12
Description	On-treatment Spirometry was performed according to internationally accepted standards. Trough FVC at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. Only on-treatment values (which included only data collected while subjects were taking study drug) are used for this analysis. Values affected by other medication use were set to missing. Non-collected or missing data were not imputed for this analysis. Values not collected remained as missing values and were assumed to be missing at random (MAR).
Time Frame	baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) Population: all subjects who were randomized to treatment and received at least one dose of study medication. Subjects were analyzed based on the treatment they were randomized to. One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
Least Squares Mean (Standard Error) [liters]	0.1210 (0.02332)	0.1385 (0.02354)	0.0084 (0.02367)

5. Secondary Outcome

Title	Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) at Week 12/End of Study
Description	All collected Participants reported change in health status by using the SGRQ. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: symptoms, activity, and impacts. A score was calculated for each of these 3 subscales and a "Total" score was calculated. In each case the lowest possible value is 0 and the highest 100. Higher values correspond to greater impairment of health status. All collected values were used in the analyses, regardless if the subject remained on randomized treatment or not. Values not collected remained as missing values and were assumed to be missing at random (MAR).
Time Frame	baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) Population: all subjects who were randomized to treatment and received at least one dose of study medication. Subjects were analyzed based on the treatment they were randomized to.One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
Least Squares Mean (Standard Error) [units on a scale]	-3.825 (0.8060)	-3.225 (0.8168)	-0.138 (0.8067)

6. Secondary Outcome

Title	Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) Week 12/End of Study
Description	On-treatment Participants reported change in health status by using the SGRQ. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: symptoms, activity, and impacts. A score was calculated for each of these 3 subscales and a "Total" score was calculated. In each case the lowest possible value is 0 and the highest 100. Higher values correspond to greater impairment of health status. Only on-treatment values (which included only data collected while subjects were taking study drug) are used for this analysis. Values affected by other medication use were set to missing. Non-collected or missing data were not imputed for this analysis. Values not collected remained as missing values and were assumed to be missing at random (MAR).
Time Frame	baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) Population: all subjects who were randomized to treatment and received at least one dose of study medication. Subjects were analyzed based on the treatment they were randomized to.One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
Least Squares Mean (Standard Error) [units on a scale]	-3.609 (0.8237)	-3.637 (0.8269)	-0.052 (0.8212)

7. Secondary Outcome

Title	Change in Number of Rescue Medication Puffs Per Day Over the 12-week Double-blind Treatment Period
Description	All collected Participants completed an electronic diary (eDiary) daily (night time) to record the number of puffs of rescue medication inhaled in the previous 24 hours. A negative change from baseline indicates improvement. All collected values were used in the analyses, regardless if the subject remained on randomized treatment or not. Values not collected remained as missing values and were assumed to be missing at random (MAR).
Time Frame	Week 0-12

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) Population: all subjects who were randomized to treatment and received at least one dose of study One subject randomized in error to the placebo arm was never dosed . medication. Subjects were analyzed based on the treatment they were randomized to.One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
Least Squares Mean (Standard Error) [puffs (medication used)]	-0.845 (0.1311)	-0.959 (0.1310)	-0.678 (0.1339)

8. Secondary Outcome

Title	Number of Subjects With Treatment Emergent Adverse Events (TEAE)
Description	On-treatment A TEAE is defined as any non-serious AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE.
Time Frame	Week 0-12

Outcome Measure Data

Analysis Population Description

Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication.One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
Count of Participants [Participants]	114 53.3%	101 47.2%	111 52.4%

9. Secondary Outcome

Title	Percentage of Subjects With Treatment Emergent Adverse Events (TEAE)
Description	A TEAE is defined as any non-serious AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE.
Time Frame	Week 0-12

Outcome Measure Data

Analysis Population Description

Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication. One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
Number [percentage of participants]	53.3 24.9%	47.2 22.1%	52.4 24.7%

10. Secondary Outcome

Title	Number of Subjects With Treatment Emergent Serious Adverse Events (SAE)
Description	A treatment emergent SAE is defined as any SAE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent SAE is an on-treatment SAE.
Time Frame	Week 0-12

Outcome Measure Data

Analysis Population Description

Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication. One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
Count of Participants [Participants]	8 3.7%	5 2.3%	13 6.1%

11. Secondary Outcome

Title	Percentage of Subjects With Treatment Emergent Serious Adverse Events (SAE)
Description	A treatment emergent SAE is defined as any SAE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent SAE is an on-treatment SAE.
Time Frame	Week 0-12

Outcome Measure Data

Analysis Population Description

Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication. One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
Number [percentage of participants]	3.7 1.7%	2.3 1.1%	6.1 2.9%

12. Secondary Outcome

Title	Number of Subjects Who Discontinue Treatment Due to TEAE
Description	A TEAE is defined as any AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE.
Time Frame	Week 0-12

Outcome Measure Data

Analysis Population Description

Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication. One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
Count of Participants [Participants]	9 4.2%	15 7%	19 9%

13. Secondary Outcome

Title	Percentage of Subjects Who Discontinue Treatment Due to TEAE
Description	A TEAE is defined as any AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE.
Time Frame	Week 0-12

Outcome Measure Data

Analysis Population Description

Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication. One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
Number [percentage of participants]	4.2 2%	7.0 3.3%	9.0 4.2%

14. Secondary Outcome

Title	Number of Subjects With Major Adverse Cardiac Events (MACE)
Description	All deaths and any other findings suggestive of a potential MACE (including clinically relevant information and SAEs, and all PTs form the SMQs "myocardial infarction", "other ischemic heart disease", "central nervous system hemorrhages and cerebrovascular conditions") were sent to an adjudication committee for review and categorized as CV death, nonfatal MI, and nonfatal stroke. The MACE score was defined as the total number of subjects with CV deaths, nonfatal MIs, and nonfatal strokes. These events were collected for the double-blind period (from the first date of study medication until the date of last contact)
Time Frame	Week 0-12

Outcome Measure Data

Analysis Population Description

Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication. One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
MACE score	0 0%	0 0%	0 0%
cardiovascular death	0 0%	0 0%	0 0%
non-fatal myocardial infarction	0 0%	0 0%	0 0%
non-fatal stroke	0 0%	0 0%	0 0%

15. Secondary Outcome

Title	Percentage of Subjects With Major Adverse Cardiac Events (MACE)
Description	All deaths and any other findings suggestive of a potential MACE (including clinically relevant information and SAEs, and all PTs form the SMQs "myocardial infarction", "other ischemic heart disease", "central nervous system hemorrhages and cerebrovascular conditions") were sent to an adjudication committee for review and categorized as CV death, nonfatal MI, and nonfatal stroke. The MACE score was defined as the total number of subjects with CV deaths, nonfatal MIs, and nonfatal strokes. These events were collected for the double-blind period (from the first date of study medication until the date of last contact)
Time Frame	Week 0-12

Outcome Measure Data

Analysis Population Description

Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication.One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
MACE score	0 0%	0 0%	0.9 0.4%
cardiovascular death	0 0%	0 0%	0 0%
non-fatal myocardialinfarction	0 0%	0 0%	0.9 0.4%
non-fatal stroke	0 0%	0 0%	0 0%

16. Secondary Outcome

Title	Incidence Rate Per 1000 Person-years of Subjects With Major Adverse Cardiac Events (MACE)
Description	All deaths and any other findings suggestive of a potential MACE (including clinically relevant information and SAEs, and all PTs form the SMQs "myocardial infarction", "other ischemic heart disease", "central nervous system hemorrhages and cerebrovascular conditions") were sent to an adjudication committee for review and categorized as CV death, nonfatal MI, and nonfatal stroke. The MACE score was defined as the total number of subjects with CV deaths, nonfatal MIs, and nonfatal strokes. These events were collected for the double-blind period (from the first date of study medication until the date of last contact) Incidence rate: TT= Total Time in years. Total Time (TT) is defined as the time from the first date of study drug until the latter of the date of last contact or 30 days after the date of last dose. Incidence Rate (per 1000 person-years) = n/TT x 1000.
Time Frame	Week 0-12

Outcome Measure Data

Analysis Population Description

Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication.One subject randomized in error to the placebo arm was never dosed .

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID e-Flow (CS) Nebulizer	Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer	SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer	Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
Measure Participants	214	214	212
Number [incidence rate]	64.6	63.0	62.2

Adverse Events

Time Frame	Week 0-12
Adverse Event Reporting Description	A treatment emergent SAE is defined as any SAE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent SAE is an on-treatment SAE.
Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer		SUN-101 25 mcg BID e-Flow (CS) Nebulizer		Placebo BID Eflow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer		SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer		Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer
All Cause Mortality
	SUN-101 50 mcg BID eFlow (CS) Nebulizer		SUN-101 25 mcg BID e-Flow (CS) Nebulizer		Placebo BID Eflow (CS) Nebulizer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	SUN-101 50 mcg BID eFlow (CS) Nebulizer		SUN-101 25 mcg BID e-Flow (CS) Nebulizer		Placebo BID Eflow (CS) Nebulizer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/214 (3.7%)		5/214 (2.3%)		13/212 (6.1%)
Blood and lymphatic system disorders
haemorrhagic anaemia	0/214 (0%)	0	0/214 (0%)	0	1/212 (0.5%)	1
Cardiac disorders
acute myocardial infarction	0/214 (0%)	0	0/214 (0%)	0	1/212 (0.5%)	1
artiral fibrillation	0/214 (0%)	0	0/214 (0%)	0	2/212 (0.9%)	2
artiral flutter	0/214 (0%)	0	0/214 (0%)	0	1/212 (0.5%)	1
cardiomyoathy	0/214 (0%)	0	0/214 (0%)	0	1/212 (0.5%)	1
ventricular tachycardia	0/214 (0%)	0	0/214 (0%)	0	1/212 (0.5%)	1
Ear and labyrinth disorders
vertigo	0/214 (0%)	0	1/214 (0.5%)	1	0/212 (0%)	0
Gastrointestinal disorders
gastric ulcer	0/214 (0%)	0	0/214 (0%)	0	1/212 (0.5%)	1
gastrointestinal haemorrhage	0/214 (0%)	0	0/214 (0%)	0	1/212 (0.5%)	1
nausea	0/214 (0%)	0	1/214 (0.5%)	1	0/212 (0%)	0
pancreatitis necrotising	0/214 (0%)	0	0/214 (0%)	0	1/212 (0.5%)	1
General disorders
asthenia	0/214 (0%)	0	1/214 (0.5%)	1	0/212 (0%)	0
non-cardiac chest pain	1/214 (0.5%)	1	0/214 (0%)	0	0/212 (0%)	0
Hepatobiliary disorders
cholelithiasis	0/214 (0%)	0	0/214 (0%)	0	1/212 (0.5%)	1
Infections and infestations
pneumonia	0/214 (0%)	0	0/214 (0%)	0	3/212 (1.4%)	4
Injury, poisoning and procedural complications
chest injury	1/214 (0.5%)	1	0/214 (0%)	0	0/212 (0%)	0
coronary artery restenosis	0/214 (0%)	0	0/214 (0%)	0	1/212 (0.5%)	1
rib fracture	1/214 (0.5%)	1	0/214 (0%)	0	0/212 (0%)	0
Metabolism and nutrition disorders
obesity	0/214 (0%)	0	1/214 (0.5%)	1	0/212 (0%)	0
Musculoskeletal and connective tissue disorders
osteoarthritis	1/214 (0.5%)	1	0/214 (0%)	0	0/212 (0%)	0
Nervous system disorders
carotid artery stenosis	0/214 (0%)	0	1/214 (0.5%)	2	1/212 (0.5%)	1
Renal and urinary disorders
nephrolithiasis	2/214 (0.9%)	2	0/214 (0%)	0	0/212 (0%)	0
Respiratory, thoracic and mediastinal disorders
bronchitis chronic	1/214 (0.5%)	1	0/214 (0%)	0	0/212 (0%)	0
chronic obstructive pulmonary disease	2/214 (0.9%)	2	0/214 (0%)	0	2/212 (0.9%)	2
Skin and subcutaneous tissue disorders
hyperhidrosis	0/214 (0%)	0	1/214 (0.5%)	1	0/212 (0%)	0
Other (Not Including Serious) Adverse Events
	SUN-101 50 mcg BID eFlow (CS) Nebulizer		SUN-101 25 mcg BID e-Flow (CS) Nebulizer		Placebo BID Eflow (CS) Nebulizer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/214 (19.2%)		47/214 (22%)		39/212 (18.4%)
Respiratory, thoracic and mediastinal disorders
chronic obstructive pulmonary disease	12/214 (5.6%)	13	17/214 (7.9%)	17	17/212 (8%)	19
cough	18/214 (8.4%)	19	14/214 (6.5%)	14	14/212 (6.6%)	14
dyspnoea	11/214 (5.1%)	12	16/214 (7.5%)	16	8/212 (3.8%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

In the event the Study is part of a multi-center study , the first publication of the results of the Study shall be made in conjunction with the results of other participating study sites as a multi-center publication; provided however, if a multi-center publication is not forthcoming within twenty-four (24) months following completion of the Study at all sites, Institution and Investigator shall be free to publish.